Antimicrobial Biomaterials and Biofilm Infection: a stepping stone symposium Tianjin, China 16-18 September, 2018

Organized by State Key Laboratory of Medicinal Chemical Biology, Nankai University, China Institute of polymer chemistry, Nankai University, China AO Foundation, Switzerland Chinese Association for Biomaterials (CAB)

Sponsored by State Key Laboratory of Medicinal Chemical Biology, Nankai University, China National Natural Science Foundation of China AO Foundation, Switzerland Sino Swiss Science and Technology Cooperation (SSSTC) as part of the Bilateral Science and Technology Cooperation Programme with Asia by the Swiss State Secretariat for Education, Research and Innovation (SERI)

Organization Symposium Chair: Linqi Shi (China) Co-Chair: Fintan Moriarty (Switzerland) Henk Busscher (Netherland) Bingyun Li (USA) Secretary Zhenkun Zhang (China)

Registration You can register by sending an email to the symposium secretary at: [email protected] Registration and attendance is free of charge, but you are responsible for payment and making of your own travel and accommodation requirements.

Confirmed invited Speakers Henk Busscher (Netherland),

Bingyun Li (West Virginia University, USA) ), Weiping Ren (Wayne state University, USA), Jessica Amber Jennings (University of Memphis, USA) (In no particular order)

Fintan Moriarty (AO Foundation, Switzerland), Katharina Maniuria (EMPA, St. Gallen, Switzerland), Jens Moeller (ETH Zurich, Switzerland), Cora-Ann Schoenenberger (University of Basel, Group C. Palivan, Switzerland), Qin Ren (EMPA St. Gallen., Switzerland) (In no particular order)

Fujin Xu/Shun Duan (Beijing University of Chemical Technology, China), Xin Wang (Beijing University of Chemical Technology, China), Jianzhong Du (Tongji University, China), Lei Zhang (Tianjin University, China), Jian Ji (Zhejiang University), Menghua Xiong (South China University of Technology), Weihui Wu (Nankai University, China), Xinge Zhang (Nankai University, China), Linqi Shi/Zhenkun Zhang (Nankai University, China) (In no particular order)

Industry delegates: Jie Xiong (JOHNSON & JOHNSON), Liangliang Wang(JOHNSON & JOHNSON), Josh Yu (Silvan Medical), Ke Yang (Silvan Medical) (In no particular order)

Scientific Topics Biofilm infection Nanocarriers of antibiotics targeting biofilm infection Biomaterial related infection Antimicrobial surfaces and polymers

Symposium Schedule Date Morning Afternoon Evening Sept. 16, Sun Registration (9:00-20:00, Hall of the Huigao Garden hotel) Sept. 17, Mon Opening Symposium Sessions Reception (8:30~ 9:00) (14:00-16:20) Symposium Sessions Posters Sessions (9:00-12:00) (16:20-17:30) Sept. 18, Tue Symposium Sessions Symposium Sessions Closing Ceremony (9:00-12:00) (14:00-15:15) Panel discussion (15:30-17:30) Sept. 19, Wed Departure Accommodation and Conference location Accommodation The Huigao Garden hotel nearby the old Campus of Nankai University is highly recommended. A limited number of rooms at the Huigao Garden hotel have been reserved for attendees in discounted prices. The price for a standard double room is 380 RMB per night including double breakfast. A bus will be arranged from the Hotel to the conference location.

Conference location Mengminwei Building, the old campus of Nankai University (No. 94, Weijing Road, Tianjin)

Industry Partner The organization committee would like to acknowledge the following Industry partners for supporting this symposium.

INVITED TALK Linqi Shi, Professor

Employment Details Director College of Chemistry Institute of polymer Chemistry, Nankai University Key Laboratory of Functional Address: Weijin Rd 94, Polymer Materials of Ministry of 300071 Tianjin Education (MOE), E-mail Address: Nankai University [email protected]

Background Prof. Linqi Shi received his B.S. in the Department of Chemistry, Hebei University, China (1984) and his Ph.D. in Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, China (1993). He is currently a Professor and the Director of the Institute of Polymer Chemistry at Nankai University and Key Laboratory of Functional Polymer Materials of Ministry of Education (MOE). He is also the vice director of the State Key Laboratory of Medicinal Chemical Biology (SKLMCB). His research focuses on living radical polymerizations, self-assembly of block copolymers, and polymeric nanocarriers for drug delivery. He has over 90 peer-reviewed publications in polymer science and has been awarded the excellent Professor Award by Ministry of Education, China (2002). He is one of the Distinguished Young Scholars financed by the National Natural Science Foundation of China (2006). A primary research theme in his lab is to develop a local antibiotic delivery system to cure biofilm-related infections through deliver sufficiently high local concentrations of antibiotics inside the biofilm in order to kill biofilms, also when consisting of strains currently known to be resistant at concentrations tolerated by the human body. The antibiotic carriers are based on antibiotic loaded polymeric micelles with a surface-adaptive property, targeting in different cases of biofilm-related infections in novel way.

Selected Publications 1. Yong Liu, Henk J. Busscher, Bingran Zhao, Yuanfeng Li, Zhenkun Zhang, Henny C. van der Mei*, Yijin Ren, and Linqi Shi* ， Surface-Adaptive, Antimicrobially Loaded, Micellar Nanocarriers with Enhanced Penetration and Killing Efficiency in Staphylococcal Biofilms， ACS Nano, 2016, 10 (4), 4779–4789 2. Yong Liu, Henny C. van der Mei*, Bingran Zhao, Yan Zhai, Tangjian Cheng, Yuanfeng Li Zhenkun Zhang, Henk J. Busscher, Yijin Ren, Linqi Shi*, Eradication of Multidrug‐Resistant Staphylococcal Infections by Light‐Activatable Micellar Nanocarriers in a Murine Model. Advanced Functional Materials, 2017，27(44), 1701974. 3. Zhenkun Zhang, Rujiang Ma, Linqi Shi*. Cooperative macromolecular self-assembly toward polymeric assemblies with multiple and bioactive functions. Accounts of Chemical Research, 2014, 47(4): 1426-1437. 4. Fan Huang, Jianzhu Wang, Aoting Qu, Liangliang Shen, Liu J., LiuJ, Zhang Z., An, Y and Shi, L*. Maintenance of Amyloid b-Peptide Homeostasis by Artificial Chaperones Based on Mixed ‐Shell Polymeric Micelles. Angew. Chem. Int. Ed., 53(34): 8985-8990, 2014. 5. Liu Y.; Du J. J.; Yan M.; Lau M. Y.; Hu J.; Han H.; Yang O. O.; Liang S.; Wei W.; Wang H.; Li J. M.; Zhu X. Y.; Shi L. Q.*; Chen W.*; Ji C.*; Lu Y. F.*, Biomimetic enzyme nanocomplexes and their use as antidotes and preventive measures for alcohol intoxication, Nature Nanotech., 8(3), 187, 2013. Henk J Busscher PhD

Employment Details PhD, Division Head Address: University Medical Center University Medical Center Groningen Groningen Department of Biomedical Department of Biomedical Engineering Engineering Antonius Deusinglaan 1 Antonius Deusinglaan 1 9713 AV Groningen, the Netherlands 9713 AV Groningen, the Netherlands E-mail address: [email protected] Phone: +1-31-50-3636161

Background Henk J. Busscher obtained his MSc degree in Engineering, Physics and Materials Science at the University of Groningen, The Netherlands, where he also obtained his PhD on streptococcal adhesion to surfaces within the Faculty of Dentistry, after which he moved to the Faculty of Medical Sciences. He became full professor in 1998 with as a specialty biomaterials science to prevent and cure biomaterial-associated infections, owns a consulting company “Scientific and Applied Surface Advice” and is editor of “Colloids and Surfaces B: Biointerfaces”. In 1995 he founded the Kolff Institute for Biomedical Engineering and Material Science at the University Medical Center Groningen, The Netherlands. His research interests focus on physico-chemical, microbiological and clinical aspects of biofilm- associated infections, infection prevention and control, especially of infections occurring on biomaterials implants and devices. He has published over six hundred peer reviewed papers (H-factor 71).

Content of the presentation Key-players in clearing biomaterial-associated infection Most human infection are due to bacteria growing in a surface-attached, biofilm-mode of growth that provides them with protective, emergent properties, like embedding themselves in extracellular-polymeric-substances. In most human infections, the surfaces involved are surfaces of other bacteria or cells, bone cells or teeth and causative pathogens are inadvertently introduced in the body. Biomaterial-associated infections form a special class of infections. Firstly, because the human immune system is frustrated due to its inability to clear a huge chunk of foreign material out of the body, making it less effective against infecting bacteria. Secondly, infection is frequently caused by per-operative introduction of pathogens to a biomaterial surface, although post-operative introduction through the hematogenous route is also possible. Very few measures are clinically available to treat biofilms on biomaterial implants or devices and often removal and replacement is the sole cure, but also current preventive measures are not always effective due to bacterial resistance against a growing number of strains and species. Key-players determining the success of biomaterials implants and devices are therewith the materials surface, colonizing bacteria, tissue cells trying to integrate the implant and macrophages. Macrophages can either adapt an inflammatory “fighting” M1-phenotype or a tissue stimulating “fix-and- repair” M2-phenotype. In presence of gold-nanoparticle coated surfaces and various dental implant materials, macrophages adapted their fighting M1-phenotype to combat the material, but when the biomaterial was contaminated with bacteria, macrophages immediately adapted their fix-and-repair M2 phenotype, assuming there was tissue damage to be repaired. Arguably, might macrophages delay their decision to adapt the M2 phenotype and stay longer in their fighting M1-mode, they might aid more in the prevention of biomaterials-associated infection. 10 Weiping Ren, MD, PhD

Employment Details Associate Professor Address: 6135 Woodward Ave, Dept. Biomedical Engineering IBIO Centre, Detroit, MI, USA Wayne State University E-mail: [email protected] John Dingell VA Medical Center Phone: +001-313-577-1383 Detroit, MI, USA

Background Dr. Ren is currently Associate Professor of Biomedical Engineering, Wayne State University, Health Specialist Scientist at Detroit VA Medical Center and Director of Providence Hospital Orthopaedic Research. Dr. Ren has developed and led a well-formed Orthopaedic Research Program in Wayne State University. One of the focus of this Research Program is the engineering approach to prevent and treat orthopaedic infection by developing implant surface coating as local controllable antibiotics eluting devices and bactericidal bone graft substitutes.

Content of the presentation Engineering Approach to Prevent and Treat Periprosthetic Infection Failure of osseointegration and implant infection are the two main causes of implant failure and loosening. There is an urgent need for orthopaedic implants that promote rapid osseointegration and prevent infection, particularly when placed in bone compromised by disease or physiology of the patients. This talk will focus on the current engineering approach and technologies to prevent and treat periprosthetic infection using both in vitro and in vivo models. In addition, description of a novel injectable polymeric antibiotic- impregnated bone graft substitute developed in Dr. Ren’s lab will be presented and its potential clinical application will be discussed.

11 Qiao Jin

Employment Details PhD Address: Zheda Road 38 E-mail Address: Zhejiang University 310027 [email protected] Hangzhou, China Phone: +86 571 8795 3931

Background （Optional） Qiao Jin is an associate professor in the research group of Biomimetic Self-assembly interfaces & Nano-biomedical Materials, Zhejiang University. The research interests of our research group are utilizing interface self-assembly and modification technique to prepare functional materials with micro-nano bionic structure and applying micro-nano biomimic principles along with advanced manufacturing technology to investigate and develop brand new biomedical materials and devices, hence provide a new way to solve the problem of human major diseases. For more information go to http://polymer.zju.edu.cn/biointerfaces /index.php?l=en. A primary research of Dr. Qiao Jin is the synthesis and self-assembly of smart block copolymers, the design of stimuli-responsive drug nanocarriers for disease treatment.

Content of the presentation Biofilm microenvironment-activatable nanoparticles for phototherapy of biofilm infection Biofilms which lead to the persistent bacterial infections pose serious threats to global public health, mainly due to their resistance to antibiotics penetration and escaping innate immune attacks by phagocytes. Therefore, it is vital to develop novel antibacterial agents to effectively kill biofilms. Due to the heterogeneous physiological activity, biofilms exhibit specific microenvironments, such as low pH, hypoxia, etc. There is therefore a great opportunity to take advantage of biofilm microenvironments to develop new antibiofilm strategies. In this regard, we developed a series of biofilm microenvironment-activatable nanoparticles for the treatment of biofilm infection. In this presentation, we will give an in- depth description of the rational design of nanoparticles which could respond to biofilm microenvironments for phototherapy of biofilm infection. The potential antibiofilm strategies include: 1) The design of surface-adaptive gold nanoparticles with effective adherence for enhanced photothermal ablation of MRSA biofilm; 2) The fabrication of vancomycin modified polydopamine nanoparticle for photothermal ablation of MRSA biofilm; 3) The design of activatable co-delivery nanocarriers for photodynamic ablation of MRSA biofilm.

12 Bingyun Li

Employment Details PhD, Professor Director, Nanomedicine Laboratory Tel: +1-304-293-1075 (O); Email: Department of Orthopedics [email protected] School of Medicine URL: http://medicine.hsc.wvu.edu/ West Virginia University, Morgantown, ortho/research/li WV 26506, USA Background: Dr. Bingyun Li has more than25 years of expertise in engineering, microbiology, and immunology. His research includes bone infection, nanomedicine, and animal models. Dr. Li has originally proposed and proved that stimulating appropriate host immune responses could significantly reduce open fracture-associated infections. Within the last several years, Dr. Li’s research in bone infection has been recognized multiple times nationally and internationally: (1) the 2011 Berton Rahn Research Prize from AO Foundation (Switzerland), (2) the 2013 Pfizer Best Scientific Paper Award from the Asia Pacific Orthopedic Association Annual Meeting, and (3) the 2013 Collaborative Exchange Award from the Orthopedic Research Society. Since 2005, Dr. Li’s group has published more than 70 (senior author of 50) peer-reviewed papers (among a total of more than 90 peer-reviewed papers), and supervised approximately 100 trainees including PhD students, master’s students, undergraduate students, medical students, high school students, postdoctoral research associates, and orthopedic research residents.

Content of the presentation Local Immunoengineering Strategies to Reduce Implant-Associated Infections Implant-associated infections are often difficult to treat and have significant rates of treatment failure leading to chronic and recurrent infections. Currently, antibiotics (along with surgery) are the mainstays of treatment for implant-associated infections. However, the overuse of antibiotics has led to the emergence of antibiotic-resistant strains of bacteria, such as methicillin resistant Staphylococcus aureus (MRSA). Moreover, Staphylococcus aureus (S. aureus), the leading cause of various infections worldwide, has shown the ability to survive intracellularly, further complicating treatment options. In this talk, the challenges in dealing with implant-associated infections are discussed, the potential roles of intracellular bacteria are examined, and promising immunoengineering therapeutic approaches are presented.

13 Yong Liu

Employment Details PhD Biofilm-associated infection control, ： Address Antonius Deusinglaan University of Groninen and Univerisity 1, 9713 AV Groningen, the Medical Center of Groningen, Netherlands. Department of Biomedical Tel: +31 6 39396957; Engineering Email: [email protected]

Background （Optional） Yong Liu obtained his PhD degree from Nankai University (NKU) supervised by Prof. Linqi Shi in 2016, majoring in polymer chemistry and physics. After that, he joined Department of Biomedical Engineering (BME) at University Medical Center Groningen (UMCG) and Rijksuniversiteit Groningen (RUG) as a candidate of MD under the co-supervision of Prof. dr. Henk J. Busscher, Prof. dr. Henny C. van der Mei and Prof. dr. Yijin Ren. Currently, his research interests focus on using nanotechnologies to bypass the barriers of biofilms, enhance the killing efficacy, and attenuate the side effects of antimicrobial treatments.

Content of the presentation Micellar delivery of antimicrobials to kill infectious biofilm bacteria Bacterial-infections are mostly due to bacteria in an adhering, biofilm-mode of growth and not due to suspended bacteria in their planktonic-mode of growth. Biofilms are much more recalcitrant to conventional antimicrobials than planktonic bacteria due to (1) their low penetration and accumulation in biofilm, (2) disabling of antimicrobials due to acidic and anaerobic conditions prevailing in biofilm, and (3) enzymatic modification or inactivation of antimicrobials by biofilm inhabitants. In recent years, new nanotechnology-based antimicrobials have been designed to kill planktonic, antibiotic-resistant bacteria, but additional requirements than the mere killing of suspended bacteria must be met to combat biofilm-infections. Herein, the rational design and application of micellar nanoparticles to deliver antimicrobials and enhance their killing efficacy will be described.

14 J. Amber Jennings, PhD

Employment Details Assistant Professor Address: 303B Engineering Tech Department of Biomedical Engineering -nology Bldg Memphis, TN 38122 University of Memphis Phone: +1 9016782283 E-mail Address: Jjnnings @memphis.edu

Background Amber Jennings is an assistant professor at the University of Memphis whose research aims to develop novel therapeutic interventions for musculoskeletal infection. Her research group focuses on biomaterial systems for antimicrobial delivery, biofilm prevention, and tissue regeneration. She is a member of the Society for Biomaterials, Orthopaedic Research Society, and ASTM. She co-edited a two-volume set of books, “Chitosan Based Biomaterials”, and contributed chapters on chitosan-based antimicrobial delivery systems, lyophilized chitosan sponges, and biodegradability of chitosan. A primary research theme in her lab is engineering systems for the delivery of biofilm dispersal signals to treat implant- associated infection. Projects ongoing in her lab include biodegradable implants, injectable drug delivery systems, biofilm-resistant coatings, and smart drug delivery systems. She has expertise in preclinical evaluation of biomaterials for infection prevention and treatment.

Content of the presentation Delivery of biofilm dispersal signals A leading cause of implant failure is biofilm-based infection, which poses significant challenges in healthcare. Local delivery of antimicrobials supplements systemic antimicrobial delivery for infection prevention. Therapeutic options after biofilm forms are limited and often involve implant removal, aggressive debridement, and lengthy treatment protocols. Recent research has led to the discovery of biofilm inhibitors and dispersal agents, including naturally derived fatty acids and metabolites. The presentation will describe preliminary evaluations of biofilm dispersal agents, their combination with antimicrobials, and local delivery systems. Challenges and opportunities for future research in infection prevention and treatment will include smart biomaterials for stimuli-responsive release of antimicrobials.

15 Jianzhong Du

Employment Details PhD, Group Leader Department of Polymeric Address: 4800 Caoan Road, Materials, Tongji University Shanghai, 201804, China Shanghai Tenth People's E-mail Address: Hospital [email protected] Phone: +86-21-69580239

Background Jianzhong Du was appointed as an 'Eastern Scholar' professor at Tongji University in Shanghai in 2009, Shanghai 1000 Talents Plan professor in 2011, and adjunct Professor in Shanghai Tenth People’s Hospital in 2015. At present he is head of department of polymeric materials, Tongji University, Fellow of the Royal Society of Chemistry (FRSC), and Committee Member of Polymer Division, Chinese Chemical Society. He was awarded National Award for the Progress in Science and Technology in 2016, Excellent PhD Thesis Supervisor of Chinese Composite Materials Society (2017), Innovative Research Article Award for Basic Research in Polymer Science, Chinese Chemical Society (2017), etc. His current research focuses on the synthesis, characterization, and biomedical applications of polymers and useful polymeric nanomaterials such as polymer vesicles. He also has wide interests in the interdisciplinary bridging between polymer science, biomedicine, and materials science, such as controlled drug delivery, gene delivery, antibacterial materials, theranostic vesicles, and treatment of diabetes, etc. He has published more than 80 peer- reviewed articles in the above fields. A primary research theme in his lab is the antibacterial polymer vesicles and hydrogels. As the abuse of the antibiotics leading to serious problems of antimicrobial resistance, polymeric antibacterial nanomaterials have become a kind of new antibacterial agents due to the efficient antibacterial activity and less risk of driving antimicrobial resistance. Prof. Du have done a series of original work in this field. For more information please visit the group website: https://jzdu.tongji.edu.cn

Content of the presentation Antibacterial Polymer Vesicles and Hydrogels Antibiotics can inhibit or destroy bacteria or other microorganisms at low concentrations but can drive antimicrobial resistance. There is a present and urgent need to develop new antimicrobial therapies. Polymer vesicles are promising biomedical nanomaterials. We found that antibacterial polymers can self-assemble into micelles, nanosheets and a range of vesicles with significantly enhanced antibacterial activities due to the locally amplified positive charges. Moreover, these antibacterial polymer vesicles are less susceptible to antibiotic resistance. Recently, we incorporated antibacterial polymer vesicles into hydrogels to afford long-acting hybrid antibacterial materials. The talk will commence with the synthesis and self-assembly of the antibacterial polymers, with a further study on the antibacterial mechanism.

16 Qun Ren

Employment Details PhD, Group Leader E-mail: [email protected] Bacteria at Surfaces Phone: +41 58 765 7688 Laboratory for Biointerfaces Empa Swiss Federal Laboratories for Materials Science and Technology Lerchenfeldstrasse 5 9014 St. Gallen Background （Optional） Qun Ren is a senior scientist leading a research group with research focus on designing new approaches to battle against bacterial infectious disease and to detect antimicrobial resistance. Empa is an interdisciplinary research and services institution for material sciences and technology development within the Swiss ETH Domain. One target of the Laboratory of Biointerfaces at Empa is to combine material and biological science for novel solutions to antifouling and antibacterial materials for therapeutic and diagnostic use. One of the primary research themes in Dr. Ren’s group is to understand the basic mechanisms of bacterial adhesion on material surfaces, with the ultimate goal to reduce and prevent bacterial pathogen infections in the clinical settings.

Content of the presentation Can material stiffness influence bacterial adhesion? From both bulk material and surface properties Among nosocomial infection, infections associated to materials are the most frequent and severe due to biofilm formation. As a heterogeneous community embedded into a matrix of polymers, bacteria in biofilms are highly resistant to environmental stress, antibiotic and host immune response. To avoid biofilm formation, prevention of bacterial adhesion, the first step of biofilm development, should mitigate the infection problem. We are particular interested in biophysical approaches to prevent bacterial contamination by modulating material mechanical properties and surface topographies. To do so, it is essential to understand the underlying mechanisms of bacteria and surface interactions. Bacterial adhesion to surfaces is a complex process that is driven both by the physicochemical properties of the material and bacterial surfaces and the mechanosensing abilities of bacteria. In this talk I will provide new mechanistic insight into the impact of material biophysical properties on the initial bacterial adhesion. I will illustrate our findings with biomedically relevant examples such as pathogen adhesion on stainless steel surfaces having different roughness and polydimethylsiloxane (PDMS) having different viscoelasticity.

17 Menghua Xiong

Employment Details PhD School of Biomedical Science and Address: 382 Waihuan E. Road Engineering, South China University of Guangzhou, China, 510006 Technology E-mail Address: [email protected] Phone: +86 188 2418 7698

Background Menghua Xiong is currently working in the School of Biomedical Science and Engineering at South China University of Technology. He received the B.S. degree and Ph.D. in Polymer Science and Engineering from University of Science and Technology of China in 2007 and 2013, respectively, supervised by Prof. Jun Wang. He was a postdoctoral associate working with Prof. Jianjun Cheng at University of Illinois at Urbana-Champaign during 2013 to 2017. Menghua mainly focused on the design of bacterial responsive nanoparticles as carriers of antibiotics, and radially amphiphilic antimicrobial polypeptides for the treatment of bacterial infection.

Content of the presentation Selective Kill Bacteria with Bacteria-Activated Antimicrobial Peptides The application of AMPs is limited is largely hindered by their non-specific toxicity, which is usually associated with hydrophobicity, helical structure, and charge density. We developed a class of cationic, helical homo-polypeptide antimicrobials with a hydrophobic internal helical core and a charged exterior shell, possessing unprecedented radial amphiphilicity. These AMPs show high antibacterial activity and decreased non-specific toxicity, which related with its RA structure. Furthermore, we introduced a random coil-to-helix transition mechanism into the design of AMPs. The AMPs exhibited random coiled structure in the normal tissues, and inhibited toxicity against mammalian cells; while at the infectious site, the AMPs were activated by bacterial phosphatase to restore the helical structure, thus contributing to strong membrane disruptive capability and potent antimicrobial activity. In another study, we designed pH responsive helix-coil conformation transitionable antimicrobial polypeptides (HCT-AMPs). The HCT-AMPs exhibited a random coiled structure under physiological condition with inhibited toxicity against mammalian cells; while under acidic condition, the AMPs exhibit helical structure with potent antimicrobial activity. The strategies remarkably minimize the toxicity against mammalian cells while maintain high antimicrobial activity.

18 Serena Rigo

Employment Details PhD Student Address: Mattenstrasse 24a, University of Basel, 4058 Basel Physical chemistry E-mail Address: Mattenstrasse 24a, BPR 1096 [email protected] 4058 Basel, Switzerland Phone: +41 61 207 57 92

Background Serena Rigo is a PhD Student in the research group of Prof. Cornelia G. Palivan. The group focuses on the combination of biomolecules with synthetic assemblies in order to generate smart functional materials, such as active surfaces, catalytic nanocompartments, hybrid biosensors or artificial organelles and cells. During her Master thesis, Serena studied the insertion of biopores into synthetic nanocompartments which results in a controlled permeability of such synthetic hybrid membranes. Her PhD thesis focuses on creating hybrid membrane-based smart antimicrobial surfaces by using advanced techniques to immobilize synthetic functional assemblies.

Content of the presentation Strategies to create smart surfaces by immobilization of Nanostructures Amphiphilic block-copolymers are the main building blocks of self-assembled polymeric micro- and nanostructures, such as polymersomes, micelles, tubes, and particles. Their physicochemical characteristics and subsequent modifications influence the properties of the resulting self-assembled nanostructures. The talk will consist of a description of amphiphilic block-copolymers and their self-assembly into various structures with a focus on vesicular structures. Vesicular assemblies named polymersomes, are extremely appealing because they allow the encapsulation of a variety of active compounds (including proteins, in particular enzymes, and mimics) and the insertion of channel proteins or biopores that permeabilize their membrane and support a selective exchange of molecules across the membrane. Such bio-synthetic compartments serve as nanoreactors, which can produce in situ active agents and release them “on demand”. The presentation will show how such nanoreactors serve to create antimicrobial surfaces to efficiently fight bacterial growth. The concept is based on a novel strategy that involves co-immobilization of antimicrobial producing nanoreactors and micelles carrying antimicrobial peptides. This strategy is highly appealing because it is an active strategy that is able to locally fight device-associated infections (DAI) and thereby reduce the antibiotics associated side effects.

19 Lei Zhang

Employment Details PhD, Professor Department of Biochemical Engineering Address: Peiyang Park Campus: School of Chemical Engineering and No.135 Technology Yaguan Road, Haihe Education Park, Tianjin University Tianjin, 300350 E-mail Address: [email protected]

Content of the presentation Antibacterial and Pro-Healing Wound Dressing That can Treat Wound Infections Preventing bacterial contamination, treating wound infection and promoting wound healing have been major challenges in wound care management. In this work, a novel wound dressing based on zwitterionic poly-carboxybetaine (PCB) hydrogel and antibacterial silver nanoparticles (AgNPs) is developed via a one-step method for efficient treatment of infected wounds. The PCB-AgNPs hydrogel exhibits effective antibacterial ability against both Gram positive bacteria (Saphylococcus aureus) and Gram negative bacteria (Escherichia coli). Furthermore, in a murine model, the PCB-AgNPs hydrogel is found to efficiently treat the S.aureus infection and accelerate the cutaneous wound healing. After a two-week healing process, histological tests indicate that it can promote the reconstruction of intact epidermis, which is much faster than those treated with commercial wound dressing (Duoderm® film). This new bifunctional wound dressing provides new opportunities for highly efficient skin wounds care and management.

20 Thomas Fintan Moriarty

Employment Details PhD, Group Leader Address: Clavadelerstrasse 9, Musculoskeletal Infection, 7270 Davos Platz AO Research Institute Davos E-mail Address: Clavadelerstrasse 8 [email protected] 7270 Davos, Switzerland rg Phone: +41 81 414 23 97

Background （Optional） Fintan Moriarty is a research scientist leading a research group focussed on the implant related bone infection at the AO Foundation. The AO Foundation is a medically guided non- profit organization led by an international group of surgeons specialized in the treatment of trauma and disorders of the musculoskeletal system. Founded in 1958 by 13 visionary surgeons, AO today fosters one of the most extensive networks of currently more than 12,000 surgeons, operating room personnel, and scientists in over 100 countries. For more information go to www.aofoundation.org A primary research theme in his lab is the customisation of preclinical in vivo models of Fracture-Related Infection (FRI) to more closely match the clinical situation. As regulatory bodies demand preclinical models more closely resemble the eventual clinical use of any new device, this has become a critical point in the translation of antimicrobial technologies to the clinic. Mechanisms for failure of antibiotic therapy, including biofilm formation and antibiotic resistance are other themes within his lab.

Content of the presentation Local antibiotic delivery systems designed for traumatic open wounds Device associated infection remains a serious clinical problem in orthopaedic surgery. The emergence of resistant organisms such as methicillin resistant Staphylococcus aureus (MRSA) has further exacerbated this problem by limiting the range of treatment options. There is therefore a major need for novel interventional strategies, including antimicrobial biomaterials, to support in the prevention and treatment of these infections. The problem of Fracture-Related Infection (FRI), in open traumatic wounds, offers challenges not present in other similar device associated infections, and this particular challenge is the target of much of our research. The talk will commence with an in-depth description of the clinical reality of FRI including the impact it may have on patients. The clinical needs will then be described as a roadmap for future antimicrobial device development.

21 Weihui Wu

Employment Details PhD, Principal investigator Address: 216 Biology Building Nankai University College of Life Sciences 94 Weijin Road, Nankai District E-mail Address: Tianjin, China 300071 [email protected] Phone: 86 13043227463

Background （Optional） Weihui Wu obtained his BS and MS degrees in Microbiology from Nankai University, Tianjin, China, in 1998 and 2001, and Ph.D. degree from University Florida, Gainesville, Florida, the United States in 2006, in Immunology and Microbiology. He then did his postdoctoral trainings in M.D. Anderson Cancer Center in Houston (2006-2009) and Brigham and Women’s Hospital, Harvard Medical School in Boston (2009-2011). In 2011, he joined the faculty of Nankai University as a Professor of Microbiology. In 2012, he was selected in the Tianjin 1,000 Yong Talents Plan. Research in Wu laboratory is focused on pathogenic bacteria. Currently, the bacteria under investigation in his laboratory is Pseudomonas aeruginosa, which is an opportunistic pathogen causing a variety of infections. His laboratory is mainly working on the regulation of bacterial virulence factors and the mechanisms of antibiotic resistance, as well as host pathogen interaction and vaccine development. He has published first author or corresponding author original research articles in Nat Immunol., Am. J. Respir. Crit. Care Med., MBio, Infect Immun, Antimicrob Agents Chemother, J Bacteriol, etc.

Content of the presentation Combination of azithromycin and gentamicin as an efficient therapy against acute and chronic Pseudomonas aeruginosa infections The development of antibiotic resistance imposes severe threat to human health. It is urgent to identify novel drug targets and to develop effective medicines and treatment strategies. The trans-translation system for ribosome rescue plays an important role in bacterial resistance to environmental stresses, but it is absent in animals, making it an ideal antimicrobial target. Here, we found that the trans-translation system plays an essential role in Pseudomonas aeruginosa tolerance to azithromycin and multiple aminoglycoside antibiotics. Azithromycin has been used to treat P. aeruginosa infections due to its anti- biofilm and immunomodulatory effects. We found that gentamicin could repress the activation of the trans-translation by azithromycin treatment. Compared to the single antibiotic, combination of gentamicin and azithromycin increased the killing efficacy against planktonic and biofilm associated P. aeruginosa cells of a reference strain PA14 and its isogenic carbapenem-resistance oprD mutant as well as multiple clinical isolates. Furthermore, the gentamicin-azithromycin combination resulted in improved bacterial clearance in a murine acute pneumonia and a biofilm implant infection model, indicating its great potential in combating P. aeruginosa infections.

22 Xing Wang

Employment Details PhD, Group Leader Address: P.O. Box53, BUCT, Biomedical Materials Group Beisanhuan East Road 15, College of Life Science and Technology Beijing 100029, P.R. China Beijing University of Chemical Technology E-mail Address: No.15, Beisanhuan East Road, [email protected] Beijing 100029, P.R. China Phone: +86 139 1152 7186

Background Dr. Xing Wang received his PhD degree in polymer chemistry and physics at Jilin University in 2006. After postdoctoral research on the topic of constructing biopolymers on various substrates as bio-surface and bio-interface at Muenster University of Germany, he joined Beijing University of Chemical Technology with the talent honor in December of 2011 and appointed as associate professor in the college of life science and technology. In 2013, he was named as doctoral supervisor. He won the Young-Talents of BUCT in 2017 and then he was promoted to full professor since 2018. Currently, his research program mainly focuses on biomedical polymers, including antimicrobial materials, hemostasis and drug delivery system. He has published more than 40 peer reviewed SCI articles and 8 patents of China. He presides over a number of funds from NSFC, Beijing NSF, FDP, FRFCU and Cooperative Enterprise Programs, over 5 million RMB, totally. The social services include expert and vice secretary general on Academic Committee of Association of Antibacterial Industry, expert on Committee of Biotechnology and Cellular Applications of Chinese Non-government Medical Institutions Association, fund reviewer of NSFC, Beijing NSF and CONICYT-Chile.

Content of the presentation Study on Chiral Polymer for Antimicrobial Applications Stereochemistry is an essentially natural phenomenon. It attracts us to develop new antimicrobial materials and explore deeper antimicrobial mechanisms. The chiral polymers were designed and antimicrobial activity on Escherichia coli, Staphylococcus aureus, and Mucor racemosus etc were tested. All the results demonstrated that the chiral stereochemistry have superior property of antimicrobial adhesion. In-depth insight shows that asymmetric carbon stereochemistry can be used as an advanced strategy for antimicrobial adhesion. Moreover, no cytotoxicity was found on those materials. It thus not only presents a deeper insight on the nature of microbial adhesion, but also further indicates a great potential for the design of antifouling biomaterials based on the advanced stereochemistry strategy.

23 Xinge Zhang

Employment Details PhD, Group Leader Address: 94#, Weijin Road, Biomedical polymer, Nankai District, Tianjin, China Institute of Polymer Chemistry, Nankai University E-mail Address: [email protected] Phone: + 86 137 5233 5245

Background （Optional） Xinge Zhang is the Associate Professor of Chemistry at Nankai University. She received her B.S. in Chemistry in 2000 from Beijing Normal University, and her Ph. D. in 2006 in Polymer Chemistry from Nankai University. She joined the faculty at Nankai University in 2006, and was a research associate fellow at University of Washington (Seattle) from 2013-2014. Her research program focuses on using synthetic organic chemistry to engineer the interface between the synthetic and biological worlds, and spans the areas of polymers and nanotechnology, with over 71 peer-reviewed papers published to date. She is actively involved in the area of polymer synthesis and bionanotechnology, and her research includes programs in delivery, imaging, diagnostics and nanotoxicology.

Near-infrared light-activated thermosensitive liposomes as efficient agents for photothermal and antibiotic synergistic therapy of bacterial biofilm Yu Zhao, Xiaomei Dai, Xiaosong Wei, Yunjian Yu, Xuelei Chen, Xinge Zhang * 1. Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China. E-mail: [email protected] Virulent biofilms cause the majority of persistent bacterial infections diseases in humans, such as chronic otitis media, chronic sinusitis, native valve endocarditis, and chronic airway infections in cystic fibrosis patients [1]. Antibiotics dose used for biofilms elimination can reach to 1000-fold greater than the dose for the planktonic bacteria [2]. Development of effective therapy strategies to control biofilm infection is still challenging. Aiming at biofilm architecture, we designed and prepared near-infrared-activated thermosensitive liposomes with photothermal and antibiotic synergistic therapy capacity to eliminate Pseudomonas aeruginosa (P. aeruginosa) biofilm. The liposomes with positive charge and small size aided to enter the biofilm microchannels and locally released antibiotics in infection site. The liposomes could remain stable at 37 °C and release about 80% antibiotics over 45 °C. The biofilm dispersion rate was up to 80%, which was a 7- to 8-fold rise compared to excess antibiotic alone, indicating that the localized antibiotic release and photothermal cotherapy improved the antimicrobial efficiency. In vivo drug-loaded liposomes in treating P. aeruginosa-induced abscess exhibited an outstanding therapeutic effect. Furthermore, photothermal treatment could stimulate the expression of bcl2-associated athanogene 3 to prevent normal tissue from thermal damage. The near-infrared-activated nanoparticle carriers had the tremendous therapeutic potential to dramatically enhance the efficacy of antibiotics through thermos-triggered drug release and photothermal therapy. References (1) Herget, K., Frerichs, H., Pfitzner, F., Tahir M. N., Thremel, W. (2018). Fuctional enzyme mimics for oxidative halogenations reactions that combat biofilm formation. Adv Mater. 2018, 1707073. (2) Potera, C. Antibiotic resistance: biofilm dispersing agent rejuvenates older antibiotics. Environ Health Perspect, 2010, 118(7), A288-A291. 24 Jens Moeller

Employment Details PhD Junior Group Leader Address: Vladmir-Prelog-Weg 4, Applied Mechanobiology, HCI E415, 8093 Zurich, ETH Zurich E-mail Address: Vladimir-Prelog-Weg 4 [email protected] 8093 Zurich, Switzerland Phone: +41 44 633 69 21

Background Jens Moeller is a Junior group leader in the Laboratory of Applied Mechanobiology, Institute of Translational Medicine and a lecturer at the Department of Health Sciences and Technology, ETH Zurich. The preservation of health and quality of life presents a great challenge for our society and for our health care system in particular given the demographic developments, a progressively aging population and the increasing proportion of obese persons. The Department of Health Sciences and Technology integrates research from molecules to cells and organisms at the interface of engineering, neurological, movement and food sciences as well as biology, medicine and social sciences. The strategic research priorities are defined as: i) Healthy Aging, ii) Healthy Food and Nutrition, iii) Neural Control, Plasticity and Rehabilitation, and iv) Biomaterials and Regenerative Technologies. For more information go to https://www.hest.ethz.ch/en. The Applied Mechanobiology Laboratory exploits nanotechnology tools to decipher how bacteria, mammalian cells, and micro-tissues take advantage of mechanical forces to recognize and respond to material properties in their native environments. Our overarching goal is to discover mechanisms how nature exploits mechanical forces as an additional dimension of functional regulation and how these insights can be exploited for biomedical applications and in regenerative medicine. This includes asking how bacteria sense mechanical forces which regulate their adhesion to surfaces and tissue fibers, and how immune cells use mechanical forces to fight bacterial infections.

Content of the presentation To clear invading pathogens from the host, macrophages as major component of the innate immune system, are recruited to the site of inflammation. Upon target binding, the actin cytoskeleton of the macrophages is remodelled, leading to the formation of the phagocytic cup and subsequent bacterial internalization. While the underlying biochemical pathways of bacterial phagocytosis are well studied, little is known about the role of mechanical forces, the impact of bacterial shape, and the adhesion strength of the pathogens to the underlying substrate. Within my talk, I will discuss how alterations in E. coli shape upon exposure to antibiotics affect the phagocytosis rate and how high-aspect ratio bacterial filaments accelerate biofilm formation under fluid flow. I will further describe a multistep process that macrophages exploit to pick-up firm surface adhering bacteria. Our study highlights that the kinetics and mechanical properties of the macrophage filopodia, lamellipodia as well as the E. coli fimbriae have to be tightly tuned to facilitate bacterial uptake from surfaces. Finally, our study suggests that soluble inhibitors that are exploited to suppress bacterial adhesion might instead have an unanticipated adverse effect by protecting firmly adhering E. coli from being sensed and cleared by host immune cells.

25 Shun Duan

Employment Details PhD Address: No. 15, Beijing Laboratory of Biomedical Beisanhuan East Road Materials, Beijing University of E-mail Address: Chemical Technology [email protected] 100029 Beijing, China Phone: +86 10 6442 1243

Background （Optional） Shun Duan is an associate professor focused on antibacterial materials and surface functionalization of biomedical devices at Beijing Laboratory of Biomedical Materials (BLBM), Beijing University of Chemical Technology. Beijing Laboratory of Biomedical Materials was founded in 2013, which was leading by Beijing University of Chemical Technology. The objective of the BLBM is to develop novel biomedical materials and devices with high performances for the great demands of national health. In recent years, BLBM was working on the major issues of biomedical materials, including biomedical materials of the repair of hard tissues, biomedical materials for the repair of soft tissues and controlled drug delivery, design and construct of the surfaces and interfaces of biomedical materials, and polymeric medical supplies. The research outputs of BLBM were transformed by the enterprises of medical appliances. By these achievements, BLBM has established a platform which integrated development of novel materials in university, application in clinic and manufacture in industry.

Content of the presentation Controlled surface functionalization of biomedical materials and antibacterial materials When the biomedical materials are applied in vivo, the surfaces are initially contact with proteins, cells and bacteria. Therefore, the performances of biomedical materials significantly depend on the properties of the surfaces. In our research, we constructed functionalized surfaces and antibacterial materials based on living polymerization, which enhanced the anti-fouling and antibacterial properties of biomedical materials. The contents of the presentation include polymer brushes on the surfaces of biomedical materials, novel antibacterial materials and applied research of antibacterial materials.

26 Katharina Maniura, PhD

Employment Details Head E-mail: Laboratory for Biointerfaces [email protected] Empa Swiss Federal Laboratories for Phone: +41 58 765 7447 Materials Science and Technology Lerchenfeldstrasse 59014 St. Gallen Switzerland Background （Optional） Katharina Maniura is heading the Biointerface team at Empa, the Swiss Federal Laboratories for Materials Science and Technology. She studied Chemistry at the Philipps-University in Marburg, Germany, and received the PhD at the University of Newcastle upon Tyne, UK, researching on cause and mechanisms of mitochondrial diseases employing in vitro cell models. This was followed by postdoctoral studies in Physiology departments of the Universities of Heidelberg and Cologne on mitochondrial biogenesis and mitochondrial disease. With the move to Empa in 2002 scientific and research interests focused on biomaterials, biointerfaces, surface modification, cell scaffold materials and most importantly, the characterization of the biological response to materials. For this predictive in vitro models for mammalian cell response and models for bacterial response are being developed. Biochemical and (physico)chemical methods are being used to investigate the nature of the interface. Since March 2018 Katharina Maniura is affiliated with ETH Zürich as Adjunct Professor in the Department of Health Sciences and Technology.

Content of the presentation The Biointerface lab is active in research and development of novel materials-based healthcare solutions. We thrive to understand, characterise, and steer interactions of biomolecules, bacteria and human cells at materials surfaces. We study biointerfaces which encompass natural interfaces between biomolecules, their assemblies and water, between cells and extra cellular matrix, between populations of bacteria and human cells and their surroundings and those between the biological environment and materials for medical applications. Designed biointerfaces are vital elements for the functionality of bio-related processes and devices. We carry out research on biointerfaces and through this develop materials for biosensors, diagnostics, biomimetic materials, (stem) cell technology, drug-delivery systems, materials for regenerative medicine, and biomaterials for medical implants and functional tissue engineering. We steer the properties and nature of the biointerface by combining materials and biological science for healthcare solutions. With this we provide key contributions to novel antifouling, antibacterial and functional biomaterials for therapeutic and diagnostic use, such as implants, wound healing materials or sensors.

27 Cora-Ann Schoenenberger PhD

Employment Details Senior Scientist Address: Department of Chemistry BioPark 1096 University of Basel, Switzerland Mattenstrasse 24A 4058 Basel, Switzerland E-mail Address: cora-ann.schoenenberger@ unibas.ch Phone: +41 61 207 5789

Background Cora-Ann Schoenenberger is a cell biologist who has been working as a group leader at the Biozentrum before she joined Prof. Cornelia Palivan’s group in the Department of Chemistry at the University of Basel. Her research centers around the role of the cytoskeleton in cell-cell and cell-substrate interactions. Specifically, she has studied the mechanical response of cells and tissues to tumorigenic transformation. In the Palivan group she explores the interactions of living cells with different types of polymer assemblies. Her main research areas include the fate of polymer-based nanostructures in biological systems, ranging from individual cells to entire organisms and how cells behave on biomimetic polymer surfaces. In addition, she explores the interactions between cellular organelles and polymer-based compartments.

Content of the presentation Creating new types of biointerfaces by combining polymer-based membranes and biomolecules The Palivan group focuses on the design and development of hybrid nanosystems with advanced functionality based on the combination of biomolecules (proteins, in particular enzymes, DNA, mimics) and synthetic supramolecular assemblies. A particularly appealing direction of research is devoted to obtaining smart and functional membrane model systems based on amphiphilic block copolymers, which are developed together with the group of Prof. W. Meier (University of Basel). Amphiphilic copolymers self-assemble in specific aqueous conditions into a variety of supramolecular structures that have an increased mechanical stability compared to (phospho)lipids. Two basic types of polymer assemblies will be discussed, vesicular structures, so-called polymersomes, where the polymer membrane forms the border of a confined space and planar polymer membranes creating surfaces with increased stability. Moreover, chemical engineering of copolymers allows for an extensive flexibility in the design of membranes with different physicochemical properties. Endowing polymer assemblies with biological functions can be achieved by different means. For example, polymersomes can be equipped with biopores and turned into biosensors, into nanoreactors, or even into artificial organelles that mimick the natural ones inside cells. Similarly, planar solid-supported polymer membranes can be associated with biomolecules to create robust surfaces with activities tailored to translational applications, such as biosensing. I will present several examples where polymer membranes host biomolecules including recent work from the Palivan lab towards antimicrobial surfaces for smart device development.

28 Ke Yang

Employment Details Division Head Address: 72 Wenhua Road Specialized Materials and Shenyang 110016, China Devices Division E-mail Address: [email protected] Institute of Metal Research Phone: +86 24 23971628 Chinese Academy of Sciences 72 Wenhua Road Background Shenyang 110016, China Ke Yang is a professor leading a large research team focusing on novel medical metal materials and application, including antibacterial metals (stainless steels, titanium alloys and cobalt based alloys), biodegradable metals (magnesium based alloys and iron based alloy), biofunctionalized metals, surface modifications, and their applications in orthopaedics, dentistry and coronary stent. Ke Yang is the Chair of Metallic Biomaterials Branch, China Association of Biomaterials.

Content of the presentation Research and Application of Antibacterial Medical Metals Implant associated infection remains a serious clinical problem and many attempts have been tried to reduce infections to occur. Copper (Cu) is a well known antibacterial metal element that is also an often used alloying element in metals to obtain a certain property. Through proper addition of Cu in the currently used medical metal materials, a series antibacterial medical metals, including stainless steels, titanium alloys, cobalt based alloys and magnesium alloy, have been developed, which possess strong, broad spectrum and durable antibacterial activities and have great potentials in clinical applications. Currently several antibacterial metal devices have been developed for medical applications.

29 POSTER

30 Synthesis of Pt Hollow Nanodendrites with Enhanced Peroxidase-like Activity against Bacterial Infections: Implication for Wound Healing

Renfei Wu, Yu Chong, Ge Fang, Xiumei Jiang, Yue Pan, Chunying Chen, Jun-Jie Yin, Cuicui Ge*

School for Radiological and Interdisciplinary Sciences (RAD-X), Collaborative Innovation Center of Radiation Medicine of Jiangsu Higher Education Institutions, Soochow University, Suzhou 215123, China E-mail: [email protected]

Improving the antibacterial activity of H2O2 and reducing its usage are requirements for wound disinfection. Nanomaterials with intrinsic peroxidase-like properties have been developed to enhance the antibacterial performance of H2O2 and avoid the toxicity seen with high H2O2 levels. Here, we synthesized Pd-Pt core-frame nanodendrites consisting of a dense array of Pt branches on a Pd core, and subsequently converted them to Pt hollow nanodendrites by selective removal of the Pd cores by wet etching. The fabricated Pt hollow nanodendrites exerted striking peroxidase-like activity due to the maximized utilization efficiency of the Pt atoms and the presence of high-index facets on their surfaces. By catalyzing the decomposition of H2O2 into more toxic hydroxyl radicals (•OH), Pt hollow nanodendrites exhibited excellent bactericidal activity against both Gram-negative and Gram- positive bacteria with the assistance of low concentrations of H2O2. Furthermore, Pt hollow nanodendrites accelerated wound healing in the presence of low doses of H2O2. In addition, no obvious adverse effects were observed at the given dose of nanodendrites. Our findings can be used to guide the design of noble metal-based nanomaterials as potential enzyme- mimetic systems and advance the development of nanoenzymes to potentiate the antibacterial activity of H2O2.

References (1) Sun H, Gao N, Dong K, Ren J, Qu X. Graphene quantum dots-band-aids used for wound disinfection. ACS nano, 2014, 8(6), 6202-6210. (2) Tao Y, Ju E, Ren J, Qu X. Bifunctionalized mesoporous silica-supported gold nanoparticles: intrinsic oxidase and peroxidase catalytic activities for antibacterial applications. Adv. Mater., 2015, 27(6), 1097- 1104. (3) Xia X, Zhang J, Lu N, Kim M, Ghale K, Xu Y, Mckenzie E, Liu J, Ye H. Pd-Ir core-shell nanocubes: a type of highly efficient and versatile peroxidase mimic. ACS nano, 2015, 9(10), 9994-10004.

31 Preparation and Antibacterial Mechanism Insight of Polypeptide-Based Micelles with Excellent Antibacterial Activities

Yuejing Xi, Tao Song, Songyao Tang, Nuosha Wang, Jianzhong Du*

Shanghai Tenth People’s Hospital, Tongji University School of Medicine, 301 Middle Yanchang Road, Shanghai 200072, China Department of Polymeric Materials, School of Materials Science and Engineering, Tongji University, 4800 Caoan Road, Shanghai 201804, China E-mail: [email protected]

Traditional antibiotics usually sterilize in chemical ways, which may lead to serious drug resistance. By contrast, peptide-based antibacterial materials are less susceptible to drug resistance. Herein we report the preparation of an antibacterial peptide-based copolymer micelle and the investigation of its membrane-penetration antibacterial mechanism by transmission electron microscopy (TEM). The copolymer is poly(L-lactide)-block- poly(phenylalanine-stat-lysine) [PLLA31-b-poly(Phe24-stat-Lys36)], which is synthesized by ring-opening polymerization. The PLLA chains form the core, whereas the polypeptide chains form the coronas of the micelle in aqueous solution. This micelle boasts excellent antibacterial efficacy against both Grampositive and Gram-negative bacteria. Furthermore, TEM studies clearly reveal that the micelles pierce and then destroy the cell membrane of the bacteria. We also compared the advantages and disadvantages of two general methods for measuring the Minimal Inhibitory Concentration (MIC) values of antibacterial micelles. Overall, this study provides us with direct evidence for the antibacterial mechanism of polypeptide-based micelles and a strategy for synthesizing biodegradable antibacterial nanomaterials without antibiotic resistance.

References (1) Xi, Y. J.; Song, T.; Tang, S. Y.; Wang, N. S.; Du, J. Z.*, Preparation and Antibacterial Mechanism Insight of Polypeptide-Based Micelles with Excellent Antibacterial Activities, Biomacromolecules 2016, 17, 3922–3930. (2) Gao, J. Y.; Wang, M. Z.; Wang, F. Y. K; Du, J. Z.*, Synthesis and Mechanism Insight of a Peptide- Grafted Hyperbranched Polymer Nanosheet with Weak Positive Charges but Excellent Intrinsically Antibacterial Efficacy, Biomacromolecules 2016, 17, 2080-2086. (3) Sun , H.; Hong , Y. X.; Xi , Y. J.; Zou , Y. J.; Gao , J. Y.; Du, J. Z.*, Synthesis, Self-Assembly and Biomedical Applications of Antimicrobial Peptide-Polymer Conjugates, Biomacromolecules 2018, 19, 1701−1720.

32 New Designs of Dendrimer-based Functional Materials for Antibacterial Applications

Guimei Jiang, Xu Fang, Rui Shen, Jian Liu*

Institute of Functional Nano and Soft Materials, Soochow Univeristy, 199 RenAi Road, Suzhou Industrial Park, Jiangsu Province, China 215123, E.mail: [email protected]

Antibiotic-resistant bacteria have aroused serious concerns for human healthcare issues because of overuse of antibacterial agents in clinics. It poses urgent calls for the development of new strategies and effective agents against antimicrobial resistance. We reported an approach to synthesize peptide-templated Au nanoclusters (AuNCs) for theranostic radiosensitization.[1] Moreover, we have developed a microfluidic approach with droplets in combination with Au nanoclusters for the sensitive detection of H2O2 secreted by a single cell which can also applied in detection of bacteria. [2] Noble metal nanoclusters are powerful nano- weapons against multidrug-resistant bacteria. In order to avoid drug resistance as much as possible, we have developed a synergisitic strategy to fight against antibiotic resistance by integrating several different antibacterial agents into one system through dendrimer-based chemistry.

References 1. Xu Fang, Yaling Wang, Xiaochuan Ma, Yingying Li, Zhaolei Zhang, Zhisheng Xiao, Lijia Liu, Xueyun Gao , Jian Liu. Mitochondria-targeting Au nanoclusters enhance radiosensitivity of cancer cells. J. Mater. Chem. B, 2017, 5, 4190-4197. 2. Rui Shen, Peipei Liu, Yiqiu Zhang, Zhao Yu, Xuyue Chen, Lu Zhou, Baoqing Nie, Anna Ż aczek, Jian Chen, Jian Liu. Sensitive Detection of Single-Cell Secreted H2O2 by Integrating a Microfluidic Droplet Sensor and Au Nanoclusters. Anal. Chem. 2018, 90, 4478−4484.

33 Rapid Fabrication of Core-Shell Hydrogel Microfibers for Weavable and Sustainable Antibacterial Applications

Sidi Liu, Zhao Yu, Chuntao Chen, Jian Liu*

Institute of Functional Nano and Soft Materials (FUNSOM), Soochow University, 199 Ren Ai Road, Suzhou Industrial Park, Suzhou, Jiangsu Province 215123, China E-mail：[email protected]

The contaminated implants by bacteria have been a big problem to human health, thus it is important to develop new biomaterials with better antibacterial applications. We have reported a flow focusing capillary microfluidic device which was assembled using “off- the-shelf” fluidic components for high-throughput generation of microdroplets. [1] Furthermore, we have presented a microfluidic approach which based on a capillary microfluidic device to fabricate smart responsive microfiber-system. The antibacterial materials are made up of core-shell GO-AgNPs/BC (graphene oxide-silver nanoparticles/bacterial cellulose) hydrogel microfibers with controlled-releasing and long- lasting antibacterial performance. A large-scale size composite microfiber can be obtained in a short time by using a homemade microfluidic wet-spinning device. The as-prepared microfibers exhibit well-controlled morphological features at the nanoscale and excellent mechanical properties. We have demonstrated that the composite microfibers can effectively sterilize both Gram positive and negative bacterial strains, while remaining friendly to normal mammalian cells. This flexible approach of synthesizing core-shell composite microfibers promises important biomedical applications including materials science, tissue engineering, and regenerative medicine. [2]

References 1. Zhao Yu, Lu Zhou, Ting Zhang, Rui Shen, Chenxi Li, Xu Fang, Gareth Griffiths, and Jian Liu. (2017) Sensitive Detection of MMP9 Enzymatic Activities in Single Cell Encapsulated Microdroplets as an Assay of Cancer Cell Invasiveness. ACS Sens. 2017, 2, 626−634 2. Chuntao Chen, Ting Zhang, Beibei Dai, Heng Zhang, Xiao Chen, Jiazhi Yang, Jian Liu, and Dongping Sun. (2016) Rapid Fabrication of Composite Hydrogel Microfibers for Weavable and Sustainable Antibacterial Applications. ACS Sustainable Chem. Eng. 2016, 4, 6534−6542

34 Deep eradication of staphylococcal aureus biofilm by superparamagnetic iron oxide-bound gentamicin nanocomposite

Kecheng Quana,b, Zexin Zhanga, Hong Chena*, Yijin Renc, Henny C. van der Meib, Henk J Busscherb* aState and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, 199 Ren’ai Road, Suzhou 215123, People’s Republic of China bUniversity of Groningen and University Medical Center Groningen, Department of Biomedical Engineering, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands cUniversity of Groningen and University Medical Center Groningen, Department of Orthodontics, Hanzeplein 1, 9700 RB Groningen, The Netherlands E-mail: [email protected]

Biofilm infection has become a tenacious clinical problem because of antibiotic tolerance. [1] One of the main reasons of the tolerance is that antibiotics are difficult to penetrate the full depth of biofilm in the presence of extracellular polymeric substances (EPS).[2] EPS can prevent the penetration of antibiotic molecules by physical block, charge attraction, efflux pump, enzymatic degradation etc.. In this study, we used superparamagnetic iron oxide nanoparticles (SPIONs) as carriers to deliver antibiotic gentamicin into the deep staphylococcus aureus (S. aureus) biofilm by magnetic targeting (MT).[3] Both the antibacterial efficacy and the biocompatibility of gentamicin were improved after combining with SPIONs. The magnetic nanoparticle-bound gentamicin (MG) composite penetrated 50- 100 µm thick S.aureus biofilm easily under an external magnetic field. Moreover, we found that it is the distribution of gentamicin in the biofilm, which was controlled by the magnet exposing time, that significantly affected the anti-biofilm efficacy. Therefore, by systematically exploring the relationship between magnet exposing time and material distribution, an optimal reaction time group was developed to realize effective biofilm eradication. This work demonstrates that MT is a promising method to enhance the anti- biofilm efficacy of antibiotics.

References (1) H. Flemming and J. Wingender, The biofilm matrix, Nat. Rev. Microbiol., 2010, 8 (9), 623–633. (2) Y. Liu, H. Mei, B. Zhao, Y. Zhai, T. Cheng, Y. Li, Z. Zhang, H. Busscher, Y. Ren and L. Shi., Eradication of Multidrug-Resistant Staphylococcal Infections by Light-Activatable Micellar Nanocarriers in a Murine Model, Adv. Funct. Mater., 2017, 27 (44), 1701974. (3) G. Subbiahdoss, S. Sharifi, S. Laurent, H. Mei, M. Mahmoudi and H. Busscher, Magnetic targeting of surface-modified superparamagnetic iron oxide nanoparticles yields antibacterial efficacy against biofilms of gentamicin-resistant staphylococci. Acta Biomater., 2012, 8 (6), 2047-2055.

35 Adhesion force-sensitive gene expression in Streptococcus mutans on substrata with different hydrophobicity

Can Wang12, Jiapeng Hou2, Henny C. van der Mei2, Henk J. Busscher2, Yijin Ren1 *

1. University of Groningen and University Medical Center Groningen, Department of Orthodontics, Hanzeplein 1, 9713 GZ Groningen, The Netherlands. 2. University of Groningen and University Medical Center Groningen, Department of Biomedical Engineering, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: [email protected]

Initial adhesion of bacteria to substratum surfaces is the first step in biofilm formation. Bacteria sense different adhesion forces from different substratum surfaces [1] and adapt differently to adhesion on different substratum surfaces. Responsive behaviors of bacteria to their adhering state are causing phenotypically heterogeneous, emergent micro-environments in biofilms [2] and are important but yet poorly understood issues. We found that stationary adhesion force of Streptococcus mutans UA 159 ranged from 4.1 nN to 19.2 nN on the four surfaces with different hydrophobicities (water contact angle 11, 50, 82 and 103 degrees) and for its luxS mutant strain from 3.3 nN to 20.2 nN. The gbpB, brpA, comDE gene expression in 5 h S. mutans UA 159 biofilm and gbpB, brpA expression in 5 h luxS mutant biofilm showed a positive relation to adhesion forces of these bacterial strains on the different substratum surfaces. The structure of the biofilm was determined by measuring the whiteness of the biofilm by optical coherence tomography. The differences in biofilm whiteness on glass and silicone rubber were up 50 µm above the substratum surface, implying that initial colonizers may only be able to guide the behavior of bacteria existing in and around the bottom layer of the biofilm. These findings contribute to a better understanding of the influence of adhesion forces on biofilm gene expression and may imply the important roles of initial colonizers which sense adhesion forces directly from the surfaces and may act as trigger providers for the development of phenotypically heterogeneous, emergent micro-environments in a biofilm.

References (1) Harapanahalli, AK., Chen, Y., Li, J., Busscher, H.J., van der Mei, H.C. (2015). Influence of adhesion force on icaA and cidA gene expression and production of matrix components in Staphylococcus aureus biofilms. Appl Environ Microbiol, 2015, 81(10), 3369-78. (2) Ren, Y., Wang, C., Chen, Z., Allan, E., van der Mei, H. C., & Busscher, H. J. (2018). Emergent heterogeneous microenvironments in biofilms: substratum surface heterogeneity and bacterial adhesion force- sensing. FEMS microbiology reviews, 2018, 42(3), 259-272.

36 Antimicrobial adhesion cotton textile decorated by borneol maintains ecological balance of skin flora

Jiangqi Xu, Zixu Xie, Xing Wang*

Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, P. R. China E-mail: [email protected]; [email protected]

Cellulose textiles (CT) modified with antimicrobial activity have attracted much attention due to their versatile applications although there are still some problems associated with the conventional protocols, including the toxicity to organisms, unwanted resistance, and gradually increasing environmental pressure. Some commercial antibacterial textiles have been confirmed that they have a short-term impact on the microflora after the application. New type of antimicrobial cellulose designed with natural and safe strategy is desired. Herein, we report a borneol-grafted CT (BGCT) utilizing an advanced antimicrobial strategy of surface stereochemistry [1,2] that mainly resist microbes’ adhesion and growth. BGCT has strong and broad-spectrum antimicrobial adhesion activities against gram-positive bacteria (Staphylococcus aureus and Staphylococcus epidermidis), gram-negative bacteria (Escherichia coli and Pseudomonas aeruginosa) and fungi (Aspergillus niger and Mucor racemosus). Because of its unique antimicrobial mechanism, BGCT is harmless to normal skin flora. In addition, BGCT exhibits prominent durability of antimicrobial capability by bearing 50 times of accelerated laundering due to its high structural stability in pH 5-10. And, it causes no skin irritation. Therefore, this BGCT shows great potential for applications in the new generation of textiles, food packaging and medical protection.

References (1) Shi, B., Luan, D., Wang, S., Zhao, L., Tao, L., Yuan, Q., Wang, X. (2015). Borneol-grafted cellulose for antifungal adhesion and fungal growth inhibition. RSC Adv., 2015, 5 (64), 51947-51952. (2) Sun, X., Qian, Z., Luo, L., Yuan, Q., Guo, X., Tao, L., Wei, Y., Wang, X. (2016). Antibacterial adhesion of poly(methyl methacrylate) modified by borneol acrylate. ACS Appl. Mater. Interfaces, 2016, 8 (42), 28522- 28528.

37 Surface-Adaptive Poly-Zwitterionic Nanocarriers with Enhanced Antimicrobial Efficacy towards Multidrug Resistant Bacterial Biofilms Shuang Tian1, Yong Liu2, Zhenkun Zhang1, Henk J. Busscher1, 2, Linqi Shi1 *

1. State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Functional Polymer Materials, Ministry of Education, Institute of Polymer Chemistry, Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China 2. University of Groningen and University Medical Center Groningen, Department of Biomedical Engineering, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands. E-mail: [email protected]

Biofilm-related bacterial infections account for over 60% of all human infections. In the biofilm mode, bacteria cause chronic infections. Biofilm infections are often recalcitrant to the antibiotics.1 Biofilm matrix protects bacteria against the host immune system and antibiotic therapy by diffusion barriers, cooperation between cells, dormant cells and gene transfer. Mature biofilms are spatially highly heterogeneous as gradients of oxygen, nutrients, pH, etc.2 Here we hypothesize that MSPMs composed of PEG and pH responsive zwitterionic polymer will 1) circulate in the blood without premature release of the loaded antibiotic agents; 2) accumulate at the infectious sites with biofilms in a targeting way or responsive to the difference between the physiological conditions and the infected sites; 3) enter and diffuse inside the biofilm either passively through the water channel of the biofilm, or positively through some mechanisms such as biofilm dispersion, and then release the loaded antibiotics under local stimuli. Under the low pH conditions in the close vicinity of bacterial cell surfaces (pH ≈ 5) to the physiological pH conditions (pH 7.4), zwitterionic functionalized PAE undergoes neutral to cationic electricity transition. Micellar nanocarriers made of poly (ethylene glycol) (PEG) and zwitterionic PAE mixed shells and poly (ε-caprolactone) cores possess a zeta potential ranging from -13.80 ± 0.78 mV at pH 7.4 to +12.84 ± 0.56 mV at pH 5, which allows them to target themselves through electrostatic attraction to negatively charged bacteria over a pH range. These results demonstrated this nanocarrier could be the potential drug delivery system against bacteria and biofilms.

References 1. Flemming, H. C.; Wingender, J., The biofilm matrix. Nat Rev Microbiol 2010, 8 (9), 623-33. 2. Liu, Y.; Busscher, H. J.; Zhao, B.; Li, Y.; Zhang, Z.; van der Mei, H. C.; Ren, Y.; Shi, L., Surface-Adaptive, Antimicrobially Loaded, Micellar Nanocarriers with Enhanced Penetration and Killing Efficiency in Staphylococcal Biofilms. ACS Nano 2016, 10 (4), 4779-89.

38 All-in-one NIR-activated nanoplatforms for enhanced bacterial biofilm eradication

Xiaomei Dai, Yunjian Yu, Xiaosong Wei, Xinge Zhang *

Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China. E-mail: [email protected] The ongoing emergence of antibiotic-resistant bacteria has become one of the greatest global problems in public healthcare [1]. The antibiotic-resistant bacteria not only result from the gene mutation or structure transformation of bacteria, but also arise from the formation of bacterial biofilms [2]. It is estimated that up to 80% of clinical infections, such as tooth decay, catheters and fracture fixation infection, are accompanied by bacteria able to form a biofilm, an aggregate of bacteria embedded in self-produced extracellular polymeric substances (EPS) [3]. In the present work, we developed a novel antibacterial nanoplatform showing the most efficient antibiotic-resistant bacteria inhibition and biofilm eradication. This particular formulation contained tobramycin-conjugated graphene oxide for efficiently capturing bacteria through electrostatic interaction and eliminating bacteria as a “nano-knife”, and copper sulphide nanoparticles for enhanced the photothermal and photodynamic properties. This novel formulation could selectively eliminate bacteria over NIH 3T3 cells, and biofilm eradication capacity was up to 70%. Importantly, the nanoplatforms could inhibit bacterial growth and promote the repair of antibiotic-resistant bacteria-infected wound on rats without nonspecific damage to normal tissue. This work provides an effective, simple, and rapid way for the design and fabrication of near-infrared light-induced nanoplatforms that offer possibilities to treat the biofilm-related infections.

References (1) Lázár, V., Martins, A., Spohn, R., Daruka, L., Grézal, G., Fekete, G., Számel, M., Jangir, P. K., Kintses, B., Csörgő, B., Nyerges, Á., Györkei, Á., Kincses, A., Dér, A., Walter, F. R., Deli, M. A., Urbán, E., Hegedűs, Z., Olajos, G., Méhi, O., Bálint, B., Nagy, I., Martinek, T. A., Papp, B., Pál, C. (2018). Antibiotic-resistant bacteria show widespread collateral sensitivity to antimicrobial peptides. Nat Microbiol. 2018, 3, 718-731. (2) Hu, D., Li, H., Wang, B., Ye, Z., Lei, W., Jia, F., Jin, Q., Ren, K.-F., Ji, J. Surface-adaptive gold nanoparticles with effective Adherence and enhanced photothermal ablation of methicillin-resistant Staphylococcus aureus biofilm. ACS Nano 2017, 11, 9330-9339. (3) Baek, J.-S., Tan, C. H., Ng, N. K. J., Yeo, Y. P., Rice, S. A., Loo, S. C. J. A Programmable lipid-polymer hybrid nanoparticle system for localized, sustained antibiotic delivery to gram-positive and gram-negative bacterial biofilms. Nanoscale Horiz. 2018, 3, 305-311.

39 Glycomimetic-conjugated photosensitizer for specific Pseudomonas aeruginosa recognition and targeted photodynamic therapy

Yu Zhao, Xiaomei Dai, Xiaosong Wei, Yunjian Yu, Xinge Zhang* Key Laboratory of Functional Polymer Materials of Ministry of Education, Institute of Polymer Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China. E-mail: [email protected] With the rapid development of the drug resistance of bacteria, controlling bacterial infections is extremely important in applications ranging from health care to improving the quality of normal life [1]. The current strategies of antibiotic medications for fighting bacteria have confronted increasing challenges because of the development of bacterial multidrug resistance [2]. Photodynamic therapy has been identified as a promising bactericidal method to conquer antibiotic-resistant pathogens [3]. To solve the problem of photosensitizer damage to normal tissues in vivo, we developed a Boron-dipyrrolemethene (BODIPY)-based glycosylated photosensitizer for ablating Pseudomonas aeruginosa (P. aeruginosa). This glycosylated 1 photosensitizer exhibited good water solubility and generated O2 rapidly in an aqueous solution under light exposure. The photosensitizer did not cause detectable toxicity to human cells in the dark. Importantly, the photosensitizer was able to selectively attach to P. aeruginosa over normal cells, thus resulting in effective pathogen ablation by reactive oxygen species. Moreover, the photosensitizer inhibited over 90% of the biofilm formation produced by P. aeruginosa. The results indicate that the design of the macromolecular photosensitizer- induced bacterial death and inhibited biofilm formation provide a novel strategy for overcoming bacterial infection.

References (1) Parthasarathy, A., Goswami, S., Corbitt, T. S., Ji, E., Dascier, D., Whitten, D. G., and Schanze, K. S. (2013) Photophysics and light-activated biocidal activity of visible-light-absorbing conjugated oligomers. ACS Appl. Mater. Interfaces 2013, 5, 4516-4520. (2) Chen, S., Chen, Q. X., Li, Q. Y., An, J. X., Sun, P., Ma, J. B., and Gao, H. (2018) Biodegradable synthetic antimicrobial with aggregation-induced emissive luminogens for temporal antibacterial activity and facile bacteria detection. Chem. Mater. 2018, 30, 1782-1790. (3) Choi, K.-H., Lee, H.-J., Park, B. J., Wang, K.-K., Shin, E. P., Park, J.-C., Kim, Y. K., Oh, M.-K., and Kim, Y.-R. (2012) Photosensitizer and vancomycin-conjugated novel multifunctional magnetic particles as photoinactivation agents for selective killing of pathogenic bacteria. Chem. Commun. 2012, 48, 4591-4593.

40 Adaptive chitosan hollow microspheres as efficient drug carrier

Ya-nan Fu1, Yongsan Li2, Guofeng Li1, Lei Yang3, Qipeng Yuan1, Lei Tao2, Xing Wang1 *

1. Beijing Laboratory of Biomedical Materials, Beijing University of Chemical Technology, Beijing 100029, People’s Republic of China. 2. The Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua University, Beijing 100084, People’s Republic of China. 3. Cancer Institute and Hospital, Peking Union Medical College and Chinese Academy of Medical Science, Beijing 100021, People’s Republic of China. E-mail: [email protected]; [email protected]

A serious challenge is posed to lipophilic anticancer drugs due to poor water solubility, high toxicity of naked drugs and low bioavailability [1]. To address these issues, a wide variety of drug carriers have been proposed [2]. Though each of them has unique characteristics, most of them are traditional materials with fixed form. Smart drug carrier with function-oriented adaptations is thus highly desired due to its unique properties in medical applications. Herein, adaptive chitosan hollow microspheres (CHM) are fabricated by employing interfacial Schiff- base bonding reaction. Hydrophilic macromolecules of glycol chitosan are fixed at the oil/water interface through numerous hydrophobic small molecules of borneol 4- formylbenzoate, forming the CHM with a positively charged surface and lipophilic cavity. These CHM have an average size of 400−1000 nm after passing through the 0.22 μm apertures of filter paper. This phenomenon combined with SEM measurements demonstrates its remarkable shape-adaptive behavior. Furthermore, the CHM present a pH-dependence of structural stability. When pH value reduces from 7.06 to 5.01, the CHM begin to lose their integrity. All those characteristics make the CHM an intelligent drug carrier, especially for water-insoluble anticancer drugs, paclitaxel (PTX) in particular. Both cell uptake and cell cytotoxicity assays suggest that the PTX-loaded CHM are highly efficient on HepG2 and A549 cells. Therefore, rather than most of the traditional materials, these adaptive CHM show great potential as a novel drug carrier [3].

References (1) Yue, Z. G., Wei, W., You, Z. X., Yang, Q. Z., Yue, H., Su, Z. G., Ma, G. H. (2011). Iron oxide nanotubes for magnetically guided delivery and pH-activated release of insoluble anticancer drugs. Adv Funct Mater, 2011, 21, 3446-3453. (2) Tiwari, G., Tiwari, R., Sriwastawa, B., Bhati, L., Pandey, S., Pandey, P., Bannerjee, S. K. (2012). Drug delivery systems: an updated review. Int J Pharm Invest, 2012, 2(1), 2-11. (3) Fu, Y. N., Li, Y. S., Li, G. F., Yang, L., Yuan, Q. P., Tao, L., Wang, X. (2017). Adaptive chitosan hollow microspheres as efficient drug carrier. Biomacromolecules, 2017, 18(7), 2195-2204.

41 Occurrence of multi-antibiotic resistant E. coli and resistance genes in urban recreational waters, Beijing, China

Xiaoxiao Yang1, Zhenchao Gao1, Xiujun Tian1, Zhongguo Zhang2, Jiuyi Li 1,*

1. Department of Municipal and Environmental Engineering, Beijing Jiaotong University, Beijing, China; 2. Environmental Protection Research Institute of Light Industry, Beijing Academy of Science and Technology, Beijing, China E-mail: [email protected]

Parks and urban recreational waters (URWs) play a crucial role in urban life, and water microbiological quality is of superior importance due to direct and indirect contact of human body in URWs. The quality of URWs is highly impacted by discharge of various waste streams in cities, such as storm run-off, effluent from wastewater treatment plants, etc. These routes introduce pathogenic bacteria, especially antibiotic resistant bacteria (ARB), into URWs. However, the situation of bacterial antibiotic resistance in URWs is largely unknown in freshwater resource deficient cities, in which URWs are commonly replenished with effluent from municipal wastewater treatment plant and storm water. In this study, antibiotic resistance was investigated in eight recreational waters from April to November, 2017, in Beijing, China. The concentrations of E. coli resistant to 12 antibiotics in the water column −1 varied up to 2.7 log10 MPN·100 mL . A total of 697 E. coli clones was isolated from URWs in different seasons. Results of antibiotic susceptibility assay exhibited high levels of antibiotic resistance, e.g. sulbactam (91%), followed by amoxicillin (63.1%) and ampicillin (35.8%).The low levels of antibiotic resistance, gentamicin (18.2%) and levofloxacin (17.9%), followed by amikacin (1.4%). Multidrug-resistant (MDR) is high of 215 E. coli were resistant to three (27.4%, 59/215), four (17.7%, 38/215) in summer, MDR is high of 225 E. coli were resistant to four (31.1%, 70/225), three (24%, 54/225) in autumn. The 697 E. coli were employed to understand the level sulfanilamide and β -lactam resistant genes, isolates resistant to beta-lactams most frequently harbored blaTEM genes, ampicillin(37%) and amoxicillin(66%) resistance can be explained by blaTEM. sul( Ⅰ ) genes resistance to sulfanilamide was frequently represented, followed by sul(Ⅱ), and sul(Ⅲ). The results showed that recreational waters could serve as reservoirs for MAR bacteria, and provide information of public health to reduce the risk.

42 Dual fluorescent-nuclear and self-assembling vancomycin for in vivo imaging of bacterial infections

Cuihong Yang, Chunhua Ren, Jie Zhou, Jinjian Liu, Yumin Zhang, Fan Huang, and Jianfeng Liu*

Institute of Radiation Medicine, Chinese Academy of Medical Science & Peking Union Medical College, Tianjin 300192, P.R. China Email:[email protected]

The increase of bacterial resistance demands rapid and accurate diagnosis of bacterial infections. Biosurface-induced supramolecular assemblies for diagnosis and therapy has received less attention in detecting bacterial infections[1]. We present a dual fluorescent- nuclear probe, which is based on self-assembly of vancomycin (Van) on gram-positive bacteria, for imaging bacterial infection[2]. A Van- and rhodamine-modified peptide derivative (Rho-FF-Van), as the imaging agent, binds to the terminal peptide of the methicillin-resistant staphylococcus aureus (MRSA) by combining solid-phase peptide synthesis (SPPS) and liquid-phase synthesis. The peptide self-assembles to form nanoaggregates on the surface of MRSA by visualizing the confocal laser scanning microscopy (CLSM) images and transmission electron microscope (TEM). In an in vivo myositis model, Rho-FF-Van results in a significant increase fluorescence signal at the MRSA infected site, which was about 8.7-fold higher than the E. coli-infected tissue. Being radiolabeled by iodine-125, Rho-FF-Van shows strong radioactive signal in the MRSA- infected lungs in a murine model, about 8.9- to 13.3-fold of isotope signals higher than the other three groups did. As a highly sensitive and selective probe for detecting Gram-positive bacteria, this novel dual fluorescent and nuclear probe promises a new way for in vivo imaging of bacterial infections. Besides, based on the “surface-induced self-assembly” strategy and with the second modality of radio-nuclide, rationally designed self-assembling small molecular would provide a platform approach for applications in protein-protein interaction, tumor therapy, and tissue engineering.

References [1] Ren C, Wang H, Zhang X, Ding D, Wang L, Yang Z*. Interfacial self-assembly leads to formation of fluorescent nanoparticles for simultaneous bacterial detection and inhibition. Chem Commun (Camb). 2014 Apr 4;50(26):3473-5. [2] Yang C, Ren C, Zhou J, Liu J, Zhang Y, Huang F, Ding D, Xu B* and Liu J*. Dual Fluorescent- and Isotopic-Labelled Self-Assembling Vancomycin for in vivo Imaging of Bacterial Infections. Angew Chem Int Ed Engl., 56(9):2356-2360, 2017.

43 AIE-active probe containing antimicrobial peptide for bacterial wash-free imaging and killing

Junjian Chen, Lin Wang, Menghua Xiong, Yingjun Wang*

National Engineering Research Center for Tissue Restoration and Reconstruction, School of Biomedical Science and Engineering, South China University of Technology, Guangzhou 510006, China E-mail: [email protected]

Bacterial infection has been one of the most serious complications in the modern healthcare industry [1]. Compared to antibiotics or antimicrobial metal ions, antimicrobial peptides (AMPs) are identified as a potential alterative approach against bacteria. AMPs have shown excellent antimicrobial property and are able to kill multi-drug resistant (MDR) bacteria with low probability for developing resistance or cytotoxicity to mammalian cells [2]. Due to the various advantages of AMPs, many AMP derivatives have been investigated to improve their antimicrobial activity. It is greatly interesting to in situ observe the interaction between AMPs and bacteria during the killing process. Recently, fluorescent methods have found broad applications in biological study, but these fluorophores suffer from aggregation-caused quenching drawback (ACQ), which require a low concentration of fluorescence-labeled AMPs for observation [3]. In this work, we designed and synthesized a fluorescence light-up probe for real-time imaging of bacteria killing. The probe was composed of an antimicrobial peptide (KRWWKWWRR) and a hydrophobic aggregation-induced emission (AIE) fluorogen in bacterial solution, the probe displayed significant fluorescence enhancement by binding with bacteria, and showed excellent antimicrobial activity. Moreover, the fluorescent intensity of the probe increased along with time. The light-up nature of the probe allowed real-time monitoring of binding process to bacteria with a high signal-to-noise ratio, which provides a new tool for investigation of antimicrobial peptide.

References (1) Hetrick, E. M.; Schoenfisch, M. H. Reducing implant-related infections: Active release strategies, Chem. Soc. Rev. 2006, 35, 780-789. (2) He, Y.; He, X. Molecular design and genetic optimization of antimicrobial peptides containing unnatural amino acids against antibiotic-resistant bacterial infection, Biopolymers, 2016, 106, 746-756. (3) Mendive-Tapia, L.; Zhao, C.; Akram, A. R.; Preciado, S.; Albericio, F.; Lee, M.; Serrels, A.; Kielland, N.; Read, N. D.; Lavilla, R.; Vendrell, M. Spacer-free BODIPY fluorogens in antimicrobial peptides for direct imaging of fungal infection in human tissue, Nat. Commun. 2016, 7, 10940.

44 Development of Phenazine Antibiotic Inspired Biofilm-Eradicating Agents

Fang Bai, Tongtong Fu, Yonxin Jin, Zhihui Cheng, Weihui Wu, Shouguang Jin

State Key Laboratory of Medicinal Chemical Biology, Key Laboratory of Molecular Microbiology and Technology of the Ministry of Education, Department of Microbiology, College of Life Sciences, Nankai University, Tianjin 300071, China

Biofilms house metabolically dormant, non-dividing persister cells that are encased within a protective extracellular polymeric matrix of biomolecules and display tolerance to every known class of antibiotic. For the last 20 years, biofilms have been widely recognized as detrimental to human health as they are unchallenged by our arsenal of antibiotic treatments. Despite the urgent need for clinical agents to effectively kill persistent biofilms, no biofilm- eradicating therapeutic currently exists, thus the development of the first biofilm-eradicating therapeutic agent would be one of the most critical biomedical breakthroughs of the twenty- first century. Our group has recently discovered a series of phenazine antibiotic inspired analogues (named as halogenated phenazines, HPs) that potently eradicated the bacterial biofilms of several major human pathogens (Staphylococcus aureus, Staphylococcus epidermidis, Enterococcus faecium and Mycobacterium tuberculosis). Unlike typical of established biofilm-eradicating agents (i.e., antimicrobial peptides) they destruct cellular membranes, HPs showed no cytotoxicity against mammalian cells. We have demonstrated that HPs eradicate biofilms through a unique, persister cell killing mechanism. Understanding the antimicrobial mechanism of HPs will provide critical insights into persister cell biology, and allow us to identify novel anti-biofilm drug targets.

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