DOCSLIB.ORG

(12) United States Patent (10) Patent No.: US 9,452,198 B2 Ribbeck Et Al

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent No.: US 9,452,198 B2 Ribbeck Et Al USOO9452198B2 (12) United States Patent (10) Patent No.: US 9,452,198 B2 Ribbeck et al. (45) Date of Patent: Sep. 27, 2016 (54) LECTIN CONUGATES FOR MIUCN 2015,003.0661 A1 1/2015 Ribbeck et al. HYDRATION 2015,005.1139 A1 2, 2015 Lieleg et al. 2015,00942.55 A1 4/2015 Ribbeck et al. 2015,0283208 A1 10, 2015 Ribbeck et al. (71) Applicant: Massachusetts Institute of Technology, Cambridge, MA (US) FOREIGN PATENT DOCUMENTS (72) Inventors: Katharina Ribbeck, Cambridge, MA JP O2-191225 A 7, 1990 (US); Thomas Crouzier, Somerville, WO WOOO, 23O23 A1 4/2000 MA (US) WO WO O3,O14078 A2 2, 2003 WO WO 2007 132355 A2 11/2007 WO WO 2013, 119668 A1 8, 2013 (73) Assignee: Massachusetts Institute of WO WO 2013,1197OO A1 8, 2013 - OTHER PUBLICATIONS (*) Notice: Subject to any disclaimer, the term of this patent is extended or adjusted under 35 Gao et al. Lectin-conjugated PEG-PLA nanoparticles:Preparation U.S.C. 154(b) by 0 days. and brain delivery after intranasal administration. Biomaterials. 2006. vol. 27, pp. 3482-3490.* (21) Appl. No.: 14/394,947 Gipson et al. Visualization of Conjunctival Goblet Cell Actin Cytoskeleton and Mucin Content in Tissue Whole Mounds. Exp Eye (22) PCT Filed: Mar. 15, 2013 Res,Shinogi 1997, et al.vol. Quantitative 65, pp. 407-415.* Analysis of Mucin and Lectin in Max illary Sinus Fluids in Patients With Acute and Chronic Sinusitis. The (86). PCT No.: PCT/US2O13/032442 Laryngospcope. 2001. vol. 111, pp. 240-251.* S 371 (c)(1), Ogasawara et al. Sialic acid is an essential moiety of mucin as a (2) Date: Oct. 16, 2014 hydroxyl radical scavenger. FEBS Letters, 2007. vol. 581, pp. 2473-2477.* (87) PCT Pub. No.: WO2013/162771 Liu et al. Nose-to-Brain Transport Pathways of Wheat Germ. Agglu tinin Conjugated PEG-PLA Nanoparticles. Pharm Res. 2012. Pub PCT Pub. Date: Oct. 31, 2013 lished online Dec. 4, 2011. vol. 29, pp. 546-558.* Roberts et al. Chemistry for peptide and protein PEGylation. (65) Prior Publication Data Advanced Drug Delivery Reviews, 2002. vol. 54, pp. 459-476.* Andrews, G.P. et al., “Mucoadhesive Polymeric Platforms for US 2015/OO942.55 A1 Apr. 2, 2015 Controlled Drug Delivery'. European Journal of Pharmaceutics and Biopharmaceutics, 71: 505-518 (2009). Cao, Y, et al., “Initiation of Glycogen Synthesis,” Journal of Related U.S. Application Data Biological Chemistry, 268(29):21717-21721 (1993). Caruso, F. et al., “Characterization of Polyelectrolyte-Protein (60) Provisional application No. 61/637,017, filed on Apr. Multilayer Films by Atomic Force Microscopy, Scanning Electron 23, 2012. Microscopy, and Fourier Transfor Infrared Reflection-Absorption Spectroscopy”. Langmuir, 14(16): 4559-4655 (1998). (51) Int. Cl. Celli, J. et al., “Viscoclastic Properties and Dynamics of Porcine AOIN 37/18 (2006.01) Gastric Mucin”, Biomacromolecules, 6., 1329-1333 (2005). A6 IK 38/00 (2006.01) Celli, J.P., et al., "Rheology of Gastric Mucin Exhibits a pH A6IP3I/00 (2006.01) Dependent Sol-Gel Transition'. Biomacromolecules, 8(5): 1580 1586 (2007). A6 IK 38/17 (2006.01) Cheetham, S., et al., “Binding Patterns of Human Norovirus-Like A6 IK 47/48 (2006.01) Particles to Buccal and Intestinal Tissues of Gnotobiotic Pigs in (52) U.S. Cl. Relation to AH Histo-Blood Group Antigen Expression”, Journal CPC ..... A61K 38/1732 (2013.01); A61K 47/48215 of Virology, 81(7): 3535-3544 (2007). (2013.01) (Continued) (58) Field of Classification Search CPC .................... A61K 47/48215: A61K 38/1732 Primary Examiner — Marcela M Cordero Garcia See application file for complete search history. (74) Attorney, Agent, or Firm — Hamilton, Brook, Smith & (56) References Cited Reynolds, P.C. U.S. PATENT DOCUMENTS (57) ABSTRACT The invention provides, interalia, conjugates of a hydratable 4,996,296 A 2f1991 Pecht et al. polymer (such as PEG, polyethylene glycol) and a lectin 5,284.934 A 2/1994 Allen, Jr. 7,687,608 B2 * 3/2010 Lancaster .............. A61K 38.25 (such as wheat germ agglutinin, WGA), compositions com 424,124 prising these conjugates, as well as methods and targeted 2003, OO77317 A1 4, 2003 Santos et al. uses of these conjugates and compositions for, e.g., lubri 2004/0086499 All 52004 Caldwell et al. cating, maintaining hydration of rehydrating, and/or inhib 2005/0112188 A1* 5, 2005 EliaZ .................... A61K424/450 9,0004 iting microorganism colonization of a biological Surface in 2006/0058736 A1 3f2006 Alchas et al. need thereof. 2008/O151180 A1 6, 2008 Vanderbilt et al. 2008/0286211 A1 11/2008 Barker 7 Claims, 9 Drawing Sheets US 9,452,198 B2 Page 2 (56) References Cited Marshall, P. et al., “Localised mapping of water movement and hydration inside a developing bioadhesive bond,” Journal of Con OTHER PUBLICATIONS trolled. Release; 95(3): 435-436 (Mar. 2004). Critchfield, A., et al., “Permeability Properties of Cervical Mucus in Neumann, G., et al., “Emergence and Pandemic Potential of Swine Women at High Risk for Preterm Birth”32nd Annual Meeting of the Origin H1N1 Influenza Virus', Nature, 459(7249): 931-939 (2009). Society for Maternal-Fetal Medicin: The Pregnancy Meeting, Feb. Saladino, R., et al., “Efficacy of a Recombinant Endotoxin Neu 6-11, 2012, Dallas, Texas; Doppler Assessment, Fetus, Prematurity tralizing Protein in Rabbits with Escherichia coli Sepsis'. Circ. Poster Session III. 450, 2 pages. Shock, 42(2):104-110 (1994). Crouzier, T., “Extreme pH and Salt Resistance of a Polysaccharide Shi, L., et al., “Mucin Coating on Polymeric Material Surfaces to based Multilayer Film by Mucin-lcctin Coupling.” Poster #40 from Suppress Bacterial Adhesion.” Colloids and Surfaces B. Materials Processing Center Research Review Poster Session (Oct. Biointerfaces, 17:229-239 (2000). 2011). Crouzier, T., et al., “Mucin Multilayers Assembled through Sugar Stern, G.A. and Zam, Z.S., “The Effect of Enzymatic Contact Lens Lectin Interactions.” Biomacromolecules, 13: 3401-3408 (2012). Cleaning on Adherence of Pseudomonas aeruginosa to Soft Contact Dam, T. and Brewer, C.F., “Multivalent Lectin-Carbohydrate Inter Lenses,” Ophthalmology, 94:115-119 (1987). actions: Energetics and Mechanisms of Binding.” Advances in Tian, P., et al., “Porcine Gastric Mucin Binds to Recombinant Carbohydrate Chemistry and Biochemistry, 63:139-164 (2010). Norovirus Particles and Competitively Inhibits Their Binding to de Repentigny, L., et al., "Characterization of Binding of Candida Histo-Blood Group Antigens and Caco-2 Cells'. Letters. In Applied albicans to Small Intestinal Mucin and Its Role in Adherence to Microbiology, 41:315-320 (2005). Mucosal Epithelial Cells.” Infection and Immunity, 68(6):3172 Tian, P. et al., “Two-Log Increase in Sensitivity for Detection of 3179 (2000). Norovirus in Complex Samples by Concentration with Porcine Derrien, M., et al., “Mucin-Bacterial Interactions in the Human Oral Gastric Mucin Conjugated to Magnetic Beads'. Applied and Envi Cavity and Digestive Tract.” Gut Microbes, 1(4): 254-268 (2010). ronmental Microbiology, 74(14):4271-4276 (2008). Fogelsen, S.J., “Treatment of Peptic Ulcer with Gastric Mucin.” Tian, P. et al., “Specificity and Kinetics of Norovirus Binding to Experimental Biology and Medicine, 28:138 (1930). Magnetic Bead-Conjugated Histo-Blood Group Antigens'. Journal Foster, S.N.E., et al., “Interaction of Polyacrylates with Porcine of Applied Microbiology, 109: 1753-1762 (2010). Pepsin and the Gastric Mucus Barrier: A Mechanism for Mucosal Vladescu, I., et al., “An Adsorption Chromatography Assay to Probe Protection’, Clinical Science, 87:719-726 (1994). Bulk Particle Transport Through Hydrogels”, Journal of Pharma Frenkel, E.S. and Ribbeck, K., "Salivary Mucins Protect Surfaces ceutical Sciences, 101(1):436-442 (2012). from Colonization by Cariogenic Bacteria, Applied and Environ Voinova, M.V. et al., “Visoelastic Acoustic Response of Layered mental Microbiology, 81(1):332-338 (2015). Polymer Films. At Fluid–Solid Interfaces: Continuum Mechanics Gandhi, K.M., et al., “Binding of Virus-Like Particles of Norwalk Approach”, Physica Scripta, 59:391-412 (1999). Virus to Romaine Lettuce Veins”. Applied and Environmental Weber, N. et al., “Formation of Viscoelastic Protein Layers on Microbiology, 76(24):7997-8003 (2010). Polymeric Surfaces Relevant to Platelet Adhesion”, J Biomed Mater Gou, Y, et al., “Controlled Alternate Layer-by-Layer Assembly of Res A, 72(4): 420-427 (2005). Lectins and Glycopolymers. Using QCM-D.ACS Macro. Lett. 1: Wirth, M., et al., “Lectin-mediated Drug Delivery: Influence of 180-183 (2012). Mucin on Cytoadhesion of Plant Lectins in vitro.” Journal of Habte, H. H., et al., “Antiviral Activity of Purified Human Breast Controlled Release, 79:183-191 (2002). Milk Mucin.” Neonatology, 92: 96-104 (2007). Yolken, R. H., et al., “Human Milk Mucin Inhibits Rotavirus Horisberger, M., “An Application of Ellipsometry: Assessment of Replication and Prevents Experimental Gastroenteritis,” J. Clin. Polysaccharide and Glycoprotein Interaction with Lectin at a Liq Invest., 90: 1984-1991 (1992). uid/Solid Interface.” Biochimica et Biophysica Acta, 632: 298-309 Yu, H., et al., “Interleukin-13 Induces Mucin 5AC Production (1980). Involving STAT6/SPDEF in Human Airway Epithelial Cells”. Cell Huang, L.C., et al., “In Vitro Activity of Human B-Defensin 2 Communication & Adhesion, 17: 83-92 (2011). Against Pseudomonas aeruginosa in the Presences of Tear Fluid.” Notification of Transmittal of the International Search Report and Antimicrobial Agents and Chemotherapy, 51(11):3853-3860 the Written Opinion for International Application No. PCT/US2013/ (2007). 032442; entitled, “Lectin Conjugates for Mucin Hydration”. Date Kohri, K, et al., “Pseudomonas aeruginosa Induces MUC5AC of Mailing: Jun. 27, 2013. Production via Epidermal Growth Factor Receptor.” Eur RespirJ. Notification Concerning Transmittal of International Preliminary 20:1263-1270 (2002). Report on Patentability for International Application No. PCT/ Kristl, A. and Legen, I., “Mucous/Mucin Dispersions as a Model for US2013/032442, entitled, “Lectin Conjugates for Mucin Hydra Drug Absorption”, Farmacevitski Vestnik, 50:270-271 (1999). tion', Date of Mailing: Nov.
Load more

Recommended publications
  • With Synthetic Mucus, Researchers Take Aim at Antibiotic Resistance 26 April 2017
    With synthetic mucus, researchers take aim at antibiotic resistance 26 April 2017 Researchers are pursuing an innovative and "Over millions of years, the mucus has evolved the unexpected new avenue in the quest to fight ability to keep a number of these problematic antibiotic resistance: synthetic mucus. By studying pathogenic microbes in check, preventing them and replicating mucus' natural ability to control from causing damage," said Ribbeck. "But the pathogenic bacteria, the scientists hope to find mucus does not kill the microbes. Instead, it tames new methods for combatting infections. them." Katharina Ribbeck, professor of tissue engineering In its new work, her team investigated how mucins, at the Massachusetts Institute of Technology, will the sugar-coated molecules that form the mucus present the work at the American Society for gel, influence the makeup of our internal microbial Biochemistry and Molecular Biology annual communities by constraining the formation of meeting during the Experimental Biology 2017 multicellular assemblies (also known as biofilms) by meeting, to be held April 22–26 in Chicago. the microbes. As a case study, the scientists looked at the mucins that are found in saliva, called "I am so excited about mucus because I am MUC5B. They grew two types of bacteria known to convinced it can help us find new strategies for compete in the mouth: Streptococcus mutans, protecting us from infections, in particular those which forms cavities, and Streptococcus sanguinis, that relate to an overgrowth of harmful microbes," a bacterium associated with healthy oral conditions. said Ribbeck. "My lab and others around the world They found that the harmful Streptococcus mutans have begun to engineer mucin-inspired polymers bacteria quickly outgrew Streptococcus sanguinis and [synthetic] mucus.
    [Show full text]
  • Science in a New Light Last Experiment on the DORIS Synchrotron, P-CUBE Draws to a Close, and the Story Behind a New Crystal Harvesting Technology
    The Newsletter of the European Molecular Biology Laboratory EMBL Issue 72 • December 2012 • www.embl.org/newsletter etcetera Science in a new light Last experiment on the DORIS synchrotron, P-CUBE draws to a close, and the story behind a new crystal harvesting technology Balancing act More than 300 scientists, journalists and members of the public convened at EMBL Heidelberg 9–10 November to discuss one of the most challenging DORIS retired, page 4 issues facing mankind: the increas- ing number of species of plants and animals under threat of extinction. The diverse programme for this year’s Science and Society conference brought together expertise from areas including research, policy, public health and philosophy. The event gave participants the opportunity to voice opinions, hopes and concerns in rela- Crystal harvesting, page 5 P-CUBE legacy, page 3 tion to biodiversity. See page 10 Reviews, rewards and renewals Important decisions made at Winter Council Meeting in November An eventful Winter Council Meeting took place in Hamburg, with delegates discussing and voting on a large number of lab-based issues. Highlights included the announcement of positive reviews of EMBL Heidelberg’s Genome Biology Unit and EMBL Monterotondo’s Mouse Biology Unit, a special contribution from the Luxembourg government to fund joint projects, agreement to take the next steps towards a new outstation, and the appointment of Claudio Sunkel as the new Chair of Council. Find out more on page 2 Meet the new John Kendrew The greatest story What sci-fi head of EMBL Award winner never told? stocking filler 7 Monterotondo 9 11 12 would you give? Winter Council Meeting: Reviews, rewards and renewals Delegates took part in an eventful Winter finance research projects jointly selected by Council Meeting in Hamburg, 27–28 Novem- EMBL and Luxembourg’s National Research ber, where they approved EMBL’s 2013 budget Fund (FNR).
    [Show full text]
  • Co Crouzier Ribbeck Advmatin
    DOI: 10.1002/ Article type: Full Paper Title: Probing the Role of Mucin-Bound Glycans in Bacterial Repulsion by Mucin Coatings Julia Y. Co†, Thomas Crouzier†, and Katharina Ribbeck* †These authors contributed equally to this work. J. Y. Co1,2, T. Crouzier1 PhD, and Assistant Professor K. Ribbeck1, PhD 1 Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, USA 2 Microbiology Graduate Program, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA, USA *E-mail: [email protected] Keywords: Mucin coatings, bacterial attachment, Streptococcus pneumoniae, Staphylococcus aureus, deglycosylation The original version of this manuscript is available at http://onlinelibrary.wiley.com/doi/10.1002/admi.201500179/abstract Copyright WILEY-VCH Verlag GmbH & Co. KGaA, 69469 Weinheim, Germany, 2013. 1 Table of Contents Excerpt Mucin coatings suppress surface attachment by the bacteria Streptococcus pneumoniae and Staphylococcus aureus. Bacterial repulsion by mucin coatings is dependent on the presence of mucin-bound glycans. Upon mucin deglycosylation, the coatings display measurable changes in coating thickness and softness, as well as antifouling capacity. This study highlights the structural and functional role of glycans in mucin coatings. J. Y. Co†, T. Crouzier†, and K. Ribbeck* Probing the Role of Mucin-Bound Glycans in Bacterial Repulsion by Mucin Coatings Abstract Microbial colonization of implanted medical devices in humans can lead to device failure and life-threatening infections. One strategy to prevent this unwanted colonization is to coat devices with polymers that reduce bacterial attachment. This study investigates how mucins, a class of biopolymers found in mucus, can be used as surface coatings to prevent attachment of selected respiratory pathogens to polystyrene surfaces.
    [Show full text]
  • Fueling Curiosity-Driven Research 2014 ANNUAL REPORT
    Fueling Curiosity-Driven Research 2014 ANNUAL REPORT 2014 Annual Report Contents About the Burroughs Wellcome Fund 4 President’s Message 6 Biomedical Sciences 11 Diversity in Science 15 Infectious Diseases 18 Interfaces in Science 23 Population and Laboratory Sciences 28 Regulatory Science 30 Reproductive Sciences 34 Science Education 36 Science and Philanthropy 45 Report on Finance 46 Grants Index 50 Advisory Committees 77 Board of Directors and Staff 79 Contact Information 79 Burroughs Wellcome Fund 21 T. W. Alexander Drive P. O. Box 13901 Research Triangle Park, NC 27709-3901 919.991.5100 www.bwfund.org Fueling Curiosity-Driven Research | 2014 Annual Report 3 About the Burroughs Wellcome Fund The Burroughs Wellcome Fund is an independent private foundation dedicated to advancing the biomedical sciences by supporting research and other scientific and educational activities. Within this broad mission, BWF seeks to accomplish two primary goals—to help scientists early in their careers develop as independent investigators and to advance fields in the biomedical sciences that are undervalued or in need of particular encouragement 4 Burroughs Wellcome Fund The importance of curiosity-driven research, as endorsed by Henry Wellcome, guides the mission of the Burroughs Wellcome Fund. Financial support is channeled primarily through The firm prospered. After Burroughs died in 1895, competitive peer-reviewed award programs. Grants Wellcome directed the growth of the company into are made primarily to degree-granting institutions an international network with subsidiaries in on behalf of individual researchers. To complement numerous countries on several continents. As the these competitive award programs, grants are also business grew, Wellcome held firm to his belief that made to nonprofit organizations conducting research was fundamental to the development of activities intended to improve the general excellent pharmaceutical products and established environment for science.
    [Show full text]
  • Mucins Trigger Dispersal of Pseudomonas Aeruginosa Biofilms
    www.nature.com/npjbiofilms ARTICLE OPEN Mucins trigger dispersal of Pseudomonas aeruginosa biofilms Julia Y. Co1,2, Gerardo Cárcamo-Oyarce3, Nicole Billings1, Kelsey M. Wheeler1,2, Scott C. Grindy4, Niels Holten-Andersen4 and Katharina Ribbeck1 Mucus is a biological gel that lines all wet epithelia in the body, including the mouth, lungs, and digestive tract, and has evolved to protect the body from pathogenic infection. However, microbial pathogenesis is often studied in mucus-free environments that lack the geometric constraints and microbial interactions in physiological three-dimensional mucus gels. We developed fluid-flow and static test systems based on purified mucin polymers, the major gel-forming constituents of the mucus barrier, to understand how the mucus barrier influences bacterial virulence, particularly the integrity of Pseudomonas aeruginosa biofilms, which can become resistant to immune clearance and antimicrobial agents. We found that mucins separate the cells in P. aeruginosa biofilms and disperse them into suspension. Other viscous polymer solutions did not match the biofilm disruption caused by mucins, suggesting that mucin-specific properties mediate the phenomenon. Cellular dispersion depended on functional flagella, indicating a role for swimming motility. Taken together, our observations support a model in which host mucins are key players in the regulation of microbial virulence. These mucins should be considered in studies of mucosal pathogenesis and during the development of novel strategies to treat biofilms. npj Biofilms
    [Show full text]
  • 1 Covalently-Crosslinked Mucin Biopolymer Hydrogels for Sustained Drug Delivery Connor V. Duffya, Laurent Davidb, Thomas Crouzie
    Covalently-Crosslinked Mucin Biopolymer Hydrogels for Sustained Drug Delivery Connor V. Duffya, Laurent Davidb, Thomas Crouziera,b,* a Department of Biological Engineering, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Building 56-341C, Cambridge, MA 02139 USA b Ingénierie des Matériaux Polymères, Université de Lyon, Université Claude Bernard Lyon 1, UMR CNRS 5223, 15 Boulevard Latarjet, 69622 Villeurbanne Cedex, France * Corresponding author: Email: [email protected] Phone: +1 617-324-5259 Original pdf file available at doi:10.1016/j.actbio.2015.03.024 1 Abstract The sustained delivery of both hydrophobic and hydrophilic drugs from hydrogels has remained a challenge requiring the design and scalable production of complex multifunctional synthetic polymers. Here, we demonstrate that mucin glycoproteins, the gel-forming constituents of native mucus, are suitable for assembly into robust hydrogels capable of facilitating the sustained release of hydrophobic and hydrophilic drugs. Covalently-crosslinked mucin hydrogels were generated via exposure of methacrylated mucin to ultraviolet light in the presence of a free radical photoinitiator. The hydrogels exhibited an elastic modulus similar to that of soft mammalian tissue and were sensitive to proteolytic degradation by pronase. Paclitaxel, a hydrophobic anti-cancer drug, and polymyxin B, a positively-charged hydrophilic antibacterial drug, were retained in the hydrogels and released linearly with time over seven days. After four weeks of drug release, the hydrogels continued to release sufficient amounts of active paclitaxel to reduce HeLa cell viability and sufficient amounts of active polymyxin B to prevent bacterial proliferation. Along with previously-established anti-inflammatory, anti-viral, and hydrocarbon- solubilizing properties of mucin, the results of this study establish mucin as a readily-available, chemically-versatile, naturally-biocompatible alternative to complex multifunctional synthetic polymers as building blocks in the design of biomaterials for sustained drug delivery.
    [Show full text]
  • Mucus and Mucin Environments Reduce the Efficacy of Polymyxin and Fluoroquinolone Antibiotics Against Pseudomonas Aeruginosa
    Letter Cite This: ACS Biomater. Sci. Eng. 2019, 5, 1189−1194 pubs.acs.org/journal/abseba Mucus and Mucin Environments Reduce the Efficacy of Polymyxin and Fluoroquinolone Antibiotics against Pseudomonas aeruginosa Tahoura Samad,† Julia Y Co,‡ Jacob Witten,§ and Katharina Ribbeck*,† † ‡ § Department of Biological Engineering, Microbiology Graduate Program, and Computational and Systems Biology Graduate Program, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States *S Supporting Information ABSTRACT: Mucus, a biopolymer hydrogel that covers all wet epithelia of the body, is a potential site for infection by pathogenic bacteria. Mucus can bind small molecules and influence bacterial physiology, two factors that may affect the efficacy of antibiotics. In spite of this, the impact of mucus on antibiotic activity has not been thoroughly characterized. We examined the activity of polymyxin and fluoroquinolone antibiotics against the opportunistic pathogen Pseudomonas aeruginosa in native mucus and purified mucin biopolymer environments. We found that mucus reduces the effectiveness of polymyxins and fluoroquinolones against P. aeruginosa. Mucin biopolymers MUC5AC, MUC2, and MUC5B are primary contributors to this reduction. Our findings highlight that the biomaterial environmental context should be considered when evaluating antibiotics in vitro. KEYWORDS: mucus, mucin, antibiotics, efficacy, Pseudomonas aeruginosa Treatment of antimicrobial-resistant infections is a major public binding sites for small molecules;11,12 mucin-antibiotic binding health challenge that makes accurate in vitro evaluation of may reduce the activity of antibiotics by sequestering them. − antibiotic activity critically important. Many studies have Mucin can also modulate the physiology of bacteria,13 16 which investigated how alterations in microbial genomes and tran- may alter their susceptibility to antibiotics (Figure 1C).
    [Show full text]
  • The Particle in the Spider's Web: Transport Through Biological Hydrogels
    The particle in the spider's web: transport through biological hydrogels The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Witten, Jacob, and Katharina Ribbeck. “The Particle in the Spider’s Web: Transport through Biological Hydrogels.” Nanoscale, vol. 9, no. 24, 2017, pp. 8080–95. © 2017 The Royal Society of Chemistry. As Published http://dx.doi.org/10.1039/C6NR09736G Publisher Royal Society of Chemistry (RSC) Version Author's final manuscript Accessed Wed Dec 05 21:35:58 EST 2018 Citable Link http://hdl.handle.net/1721.1/117712 Terms of Use Creative Commons Attribution-Noncommercial-Share Alike Detailed Terms http://creativecommons.org/licenses/by-nc-sa/4.0/ HHS Public Access Author manuscript Author ManuscriptAuthor Manuscript Author Nanoscale Manuscript Author . Author manuscript; Manuscript Author available in PMC 2018 June 22. Published in final edited form as: Nanoscale. 2017 June 22; 9(24): 8080–8095. doi:10.1039/c6nr09736g. The particle in the spider's web: transport through biological hydrogels Jacob Witten1,2 and Katharina Ribbeck1,a 1Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 2Computational and Systems Biology Initiative, Massachusetts Institute of Technology, Cambridge, MA 02139 Abstract Biological hydrogels such as mucus, extracellular matrix, biofilms, and the nuclear pore have diverse functions and compositions, but all act as selectively permeable barriers to the diffusion of particles. Each barrier has a crosslinked polymeric mesh that blocks penetration of large particles such as pathogens, nanotherapeutics, or macromolecules. These polymeric meshes also employ interactive filtering, in which affinity between solutes and the gel matrix controls permeability.
    [Show full text]
  • Salivary Mucins in Host Defense and Disease Prevention
    Salivary mucins in host defense and disease prevention The MIT Faculty has made this article openly available. Please share how this access benefits you. Your story matters. Citation Frenkel, Erica Shapiro, and Katharina Ribbeck. “Salivary Mucins in Host Defense and Disease Prevention.” Journal of Oral Microbiology 7, no. 0 (December 22, 2015). As Published http://dx.doi.org/10.3402/jom.v7.29759 Publisher Co-Action Publishing Version Final published version Citable link http://hdl.handle.net/1721.1/102597 Terms of Use Creative Commons Attribution Detailed Terms http://creativecommons.org/licenses/by-nc/4.0/ ournal of ralr æ icrobiologyi REVIEW ARTICLE Salivary mucins in host defense and disease prevention Erica Shapiro Frenkel1,2 and Katharina Ribbeck2* 1Biological Sciences in Dental Medicine, Harvard University, Cambridge, MA, USA; 2Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, USA Mucus forms a protective coating on wet epithelial surfaces throughout the body that houses the microbiota and plays a key role in host defense. Mucins, the primary structural components of mucus that creates its viscoelastic properties, are critical components of the gel layer that protect against invading pathogens. Altered mucin production has been implicated in diseases such as ulcerative colitis, asthma, and cystic fibrosis, which highlights the importance of mucins in maintaining homeostasis. Different types of mucins exist throughout the body in various locations such as the gastrointestinal tract, lungs, and female genital tract, but this review will focus on mucins in the oral cavity. Salivary mucin structure, localization within the oral cavity, and defense mechanisms will be discussed. These concepts will then be applied to present what is known about the protective function of mucins in oral diseases such as HIV/AIDS, oral candidiasis, and dental caries.
    [Show full text]
  • Iolabs· D Addgene 2018 Boston Bacterial Meeting - Schedule and Introduction
    SERES ~CCIDP THERAPEUTICS HARVARDIMIT Lea ding the Microbiome Revolution www.the<:oop.<om • f . Northeast Branch ~EWENGLAND Americmt Sociehj for Microbiologtj ioLabs· D addgene 2018 Boston Bacterial Meeting - Schedule and Introduction Thursday, May 31 8:00 AM Registration and Breakfast 9:00 AM Opening Remarks Session I: Motility Moderator: Becky Lamason 9:10 AM Shanice Webster The type IV pili alignment complex, surface sensing, and cyclic-di- GMP signaling in early biofilm formation 9:30 AM Marianne Grognot High throughput 3D tracking of bacterial chemotaxis in complex environments 9:50 AM Miles Duncan Vibrio cholerae motility exerts drag force to impede attack by the bacterial predator Bdellovibrio bacteriovorus 10:10 AM Sophie Robitaille Experimental directed evolution of a swarming motility-defective mutant of Pseudomonas aeruginosa leads to regained motility 10:30 AM Coffee Break Session II: Antibiotics and Resistance Moderator: Hesper Rego 11:00 AM Wilma Neumann The siderophore enterobactin targets ciprofloxacin to Gram-negative pathogens 11:20 AM Gleb Pishchany Amycomicin: an antibiotic that isn’t 11:40 AM Sylvie Manuse Phenotypic variation of intracellular ATP concentration impacts persister formation in E. coli at a single cell level 12:00 PM Cristina AlgR controls in vivo persistence of Pseudomonas aeruginosa Peñaranda 12:20 PM Lunch and Breakout Session 1 12:40 PM Breakout Sessions Begin 1:30 PM Networking Session III: Stress Response Mechanisms and Systems Biology Moderator: Cheryl Andam 1:40 PM Rilee Zeinert A legacy role
    [Show full text]
  • Fighting Bacteria with Mucus 8 November 2012, by Anne Trafton
    Fighting bacteria with mucus 8 November 2012, by Anne Trafton Slimy layers of bacterial growth, known as biofilms, Mucus normally lines most of the wet surfaces of pose a significant hazard in industrial and medical the body, including the respiratory and digestive settings. Once established, biofilms are very tracts. "The textbook view of mucus is that it forms difficult to remove, and a great deal of research a barrier to infection, but it's not at all clear how it has gone into figuring out how to prevent and does so," Ribbeck says. eradicate them. To investigate that question, Ribbeck and her Results from a recent MIT study suggest a colleagues observed the behavior of Pseudomonas possible new source of protection against biofilm aeruginosa bacteria in a growth medium that formation: polymers found in mucus. The MIT contained soluble purified mucins—long proteins biological engineers found that these polymers, with many sugar molecules attached. known as mucins, can trap bacteria and prevent them from clumping together on a surface, For bacteria to effectively penetrate the mucus rendering them harmless. layer and infect the tissues below, they need to form clusters that can adhere to the tissue surface. "Mucus is a material that has developed over Clumps of bacteria are much more difficult for the millions of years of evolution to manage our immune system to clear, because immune cells are interactions with the microbial world. I'm sure we specialized to attack individual bacterial cells. can find inspiration from it for new strategies to help prevent infections and bacterial colonization," "In general, you want to have bacteria around, you says Katharina Ribbeck, the Eugene Bell Career just don't want them to team up," Ribbeck says.
    [Show full text]
  • Microbes at Biomedical Interfaces 2020
    Microbes at Biomedical Interfaces 2020 Topical Conference at the 2020 AIChE Annual Meeting Online 16 – 20 November 2020 ISBN: 978-1-7138-2290-5 Printed from e-media with permission by: Curran Associates, Inc. 57 Morehouse Lane Red Hook, NY 12571 Some format issues inherent in the e-media version may also appear in this print version. Copyright© (2020) by AIChE All rights reserved. Printed with permission by Curran Associates, Inc. (2021) For permission requests, please contact AIChE at the address below. AIChE 120 Wall Street, FL 23 New York, NY 10005-4020 Phone: (800) 242-4363 Fax: (203) 775-5177 www.aiche.org Additional copies of this publication are available from: Curran Associates, Inc. 57 Morehouse Lane Red Hook, NY 12571 USA Phone: 845-758-0400 Fax: 845-758-2633 Email: [email protected] Web: www.proceedings.com TABLE OF CONTENTS (99A) PREVENTING BACTERIAL COLONIZATION OF SURFACES WITH LAYER-BY- LAYER COATINGS OF FLUORINATED POLYPHOSPHAZENES AND ANTIBIOTICS ........................... 1 Svetlana A. Sukhishvili, Victoria Albright, Alexander K. Andrianov (99B) TREATMENT OF GRAM-NEGATIVE BACTERIA USING STIMULI-RESPONSIVE NANOANTIBIOTICS ......................................................................................................................................... 2 Julius Edson, Young Jik Kwon (99C) NANOSUS (ULTRA FINE GRAINED STAINLESS-STEEL) FOR ORTHOPEDIC IMPLANTS .........................................................................................................................................................
    [Show full text]