The Global Need for Effective Antibiotics—Moving Towards
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A New Antibiotic Kills Pathogens Without Detectable Resistance
ARTICLE doi:10.1038/nature14098 A new antibiotic kills pathogens without detectable resistance Losee L. Ling1*, Tanja Schneider2,3*, Aaron J. Peoples1, Amy L. Spoering1, Ina Engels2,3, Brian P. Conlon4, Anna Mueller2,3, Till F. Scha¨berle3,5, Dallas E. Hughes1, Slava Epstein6, Michael Jones7, Linos Lazarides7, Victoria A. Steadman7, Douglas R. Cohen1, Cintia R. Felix1, K. Ashley Fetterman1, William P. Millett1, Anthony G. Nitti1, Ashley M. Zullo1, Chao Chen4 & Kim Lewis4 Antibiotic resistance is spreading faster than the introduction of new compounds into clinical practice, causing a public health crisis. Most antibiotics were produced by screening soil microorganisms, but this limited resource of cultivable bacteria was overmined by the 1960s. Synthetic approaches to produce antibiotics have been unable to replace this platform. Uncultured bacteria make up approximately 99% of all species in external environments, and are an untapped source of new antibiotics. We developed several methods to grow uncultured organisms by cultivation in situ or by using specific growth factors. Here we report a new antibiotic that we term teixobactin, discovered in a screen of uncultured bacteria. Teixobactin inhibits cell wall synthesis by binding to a highly conserved motif of lipid II (precursor of peptidoglycan) and lipid III (precursor of cell wall teichoic acid). We did not obtain any mutants of Staphylococcus aureus or Mycobacterium tuberculosis resistant to teixobactin. The properties of this compound suggest a path towards developing antibiotics that are likely to avoid development of resistance. Widespread introduction of antibiotics in the 1940s, beginning with factors through the chambers enables growth of uncultured bacteria in penicillin1,2 and streptomycin3, transformed medicine, providing effec- their natural environment. -
Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications
International Journal of Molecular Sciences Review Folic Acid Antagonists: Antimicrobial and Immunomodulating Mechanisms and Applications Daniel Fernández-Villa 1, Maria Rosa Aguilar 1,2 and Luis Rojo 1,2,* 1 Instituto de Ciencia y Tecnología de Polímeros, Consejo Superior de Investigaciones Científicas, CSIC, 28006 Madrid, Spain; [email protected] (D.F.-V.); [email protected] (M.R.A.) 2 Consorcio Centro de Investigación Biomédica en Red de Bioingeniería, Biomateriales y Nanomedicina, 28029 Madrid, Spain * Correspondence: [email protected]; Tel.: +34-915-622-900 Received: 18 September 2019; Accepted: 7 October 2019; Published: 9 October 2019 Abstract: Bacterial, protozoan and other microbial infections share an accelerated metabolic rate. In order to ensure a proper functioning of cell replication and proteins and nucleic acids synthesis processes, folate metabolism rate is also increased in these cases. For this reason, folic acid antagonists have been used since their discovery to treat different kinds of microbial infections, taking advantage of this metabolic difference when compared with human cells. However, resistances to these compounds have emerged since then and only combined therapies are currently used in clinic. In addition, some of these compounds have been found to have an immunomodulatory behavior that allows clinicians using them as anti-inflammatory or immunosuppressive drugs. Therefore, the aim of this review is to provide an updated state-of-the-art on the use of antifolates as antibacterial and immunomodulating agents in the clinical setting, as well as to present their action mechanisms and currently investigated biomedical applications. Keywords: folic acid antagonists; antifolates; antibiotics; antibacterials; immunomodulation; sulfonamides; antimalarial 1. -
Official Journal of AFSTAL, ECLAM, ESLAV, FELASA, GV-SOLAS, ILAF, LASA, NVP, SECAL, SGV, SPCAL
Volume 53 Number 2 April 2019 ISSN 0023-6772 Laboratory Animals THE INTERNATIONAL JOURNAL OF LABORATORY ANIMAL SCIENCE, MEDICINE, TECHNOLOGY AND WELFARE Official Journal of AFSTAL, ECLAM, ESLAV, FELASA, GV-SOLAS, ILAF, LASA, NVP, SECAL, SGV, SPCAL Published on behalf of Laboratory Animals Ltd. journals.sagepub.com/home/lan by SAGE Publications Ltd. Does your facility have all the right people with all the right skills? Your animal facilities can get the training, consulting, FDQKHOSƬOOWKHJDSVLQ\RXUSURJUDPPH:KHWKHU\RX DQGVWDƯQJVROXWLRQVWKH\QHHGZLWKInsourcing DUHORRNLQJIRUSHUPDQHQWRUWHPSRUDU\VWDƪZHFDQ SolutionsSM)URPUHJXODWRU\DQG&RQWLQXLQJ3URIHVVLRQDO TXLFNO\SURYLGHTXDOLƬHGSHUVRQQHOLQFOXGLQJEDFNJURXQG 'HYHORSPHQWWUDLQLQJWRSURYLGLQJIXOO\TXDOLƬHGDQLPDO FKHFNV7UDLQLQJDQGIXUWKHUHGXFDWLRQLVDYDLODEOHYLDRXU WHFKQLFLDQVYHWHULQDULDQVDQG3K'OHYHOVFLHQWLVWVZH classroom and eLearning solutions. Visit us at stand A15 at FELASA or at www.criver.com/insourcing Volume 53 Number 2 April 2019 Contents Review Article Guidelines for porcine models of human bacterial infections 125 LK Jensen, NL Henriksen and HE Jensen Working Party Report FELASA accreditation of education and training courses in laboratory animal science according to the Directive 2010/63/EU 137 M Gyger, M Berdoy, I Dontas, M Kolf-Clauw, AI Santos and M Sjo¨quist Original Articles Improved timed-mating, non-invasive method using fewer unproven female rats with pregnancy validation via early body mass increases 148 AK Stramek, ML Johnson and VJ Taylor A rat model of nerve stimulator-guided brachial -
Novel Antimicrobial Agents Inhibiting Lipid II Incorporation Into Peptidoglycan Essay MBB
27 -7-2019 Novel antimicrobial agents inhibiting lipid II incorporation into peptidoglycan Essay MBB Mark Nijland S3265978 Supervisor: Prof. Dr. Dirk-Jan Scheffers Molecular Microbiology University of Groningen Content Abstract..............................................................................................................................................2 1.0 Peptidoglycan biosynthesis of bacteria ........................................................................................3 2.0 Novel antimicrobial agents ...........................................................................................................4 2.1 Teixobactin ...............................................................................................................................4 2.2 tridecaptin A1............................................................................................................................7 2.3 Malacidins ................................................................................................................................8 2.4 Humimycins ..............................................................................................................................9 2.5 LysM ........................................................................................................................................ 10 3.0 Concluding remarks .................................................................................................................... 11 4.0 references ................................................................................................................................. -
Predictive QSAR Tools to Aid in Early Process Development of Monoclonal Antibodies
Predictive QSAR tools to aid in early process development of monoclonal antibodies John Micael Andreas Karlberg Published work submitted to Newcastle University for the degree of Doctor of Philosophy in the School of Engineering November 2019 Abstract Monoclonal antibodies (mAbs) have become one of the fastest growing markets for diagnostic and therapeutic treatments over the last 30 years with a global sales revenue around $89 billion reported in 2017. A popular framework widely used in pharmaceutical industries for designing manufacturing processes for mAbs is Quality by Design (QbD) due to providing a structured and systematic approach in investigation and screening process parameters that might influence the product quality. However, due to the large number of product quality attributes (CQAs) and process parameters that exist in an mAb process platform, extensive investigation is needed to characterise their impact on the product quality which makes the process development costly and time consuming. There is thus an urgent need for methods and tools that can be used for early risk-based selection of critical product properties and process factors to reduce the number of potential factors that have to be investigated, thereby aiding in speeding up the process development and reduce costs. In this study, a framework for predictive model development based on Quantitative Structure- Activity Relationship (QSAR) modelling was developed to link structural features and properties of mAbs to Hydrophobic Interaction Chromatography (HIC) retention times and expressed mAb yield from HEK cells. Model development was based on a structured approach for incremental model refinement and evaluation that aided in increasing model performance until becoming acceptable in accordance to the OECD guidelines for QSAR models. -
(12) United States Patent (10) Patent No.: US 9.468,689 B2 Zeng Et Al
USOO9468689B2 (12) United States Patent (10) Patent No.: US 9.468,689 B2 Zeng et al. (45) Date of Patent: *Oct. 18, 2016 (54) ULTRAFILTRATION CONCENTRATION OF (56) References Cited ALLOTYPE SELECTED ANTIBODES FOR SMALL-VOLUME ADMINISTRATION U.S. PATENT DOCUMENTS 5,429,746 A 7/1995 Shadle et al. (71) Applicant: Immunomedics, Inc., Morris Plains, NJ 5,789,554 A 8/1998 Leung et al. (US) 6,171,586 B1 1/2001 Lam et al. 6,187,287 B1 2/2001 Leung et al. (72) Inventors: Li Zeng, Edison, NJ (US); Rohini 6,252,055 B1 6/2001 Relton Mitra, Brigdewater, NJ (US); Edmund 6,676,924 B2 1/2004 Hansen et al. 6,870,034 B2 3/2005 Breece et al. A. Rossi, Woodland Park, NJ (US); 6,893,639 B2 5/2005 Levy et al. Hans J. Hansen, Picayune, MS (US); 6,991,790 B1 1/2006 Lam et al. David M. Goldenberg, Mendham, NJ 7,038,017 B2 5, 2006 Rinderknecht et al. (US) 7,074,403 B1 7/2006 Goldenberg et al. 7,109,304 B2 9, 2006 Hansen et al. 7,138,496 B2 11/2006 Hua et al. (73) Assignee: Immunomedics, Inc., Morris Plains, NJ 7,151,164 B2 * 12/2006 Hansen et al. ............. 530,387.3 (US) 7,238,785 B2 7/2007 Govindan et al. 7,251,164 B2 7/2007 Okhonin et al. (*) Notice: Subject to any disclaimer, the term of this 7.282,567 B2 10/2007 Goldenberg et al. patent is extended or adjusted under 35 7,300,655 B2 11/2007 Hansen et al. -
Treating Rare and Neglected Pediatric Diseases: Promoting the Development of New Treatments and Cures
S. HRG. 111–1147 TREATING RARE AND NEGLECTED PEDIATRIC DISEASES: PROMOTING THE DEVELOPMENT OF NEW TREATMENTS AND CURES HEARING OF THE COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS UNITED STATES SENATE ONE HUNDRED ELEVENTH CONGRESS SECOND SESSION ON EXAMINING TREATING RARE AND NEGLECTED PEDIATRIC DISEASES, FOCUSING ON PROMOTING THE DEVELOPMENT OF NEW TREAT- MENTS AND CURES JULY 21, 2010 Printed for the use of the Committee on Health, Education, Labor, and Pensions ( Available via the World Wide Web: http://www.gpo.gov/fdsys/ U.S. GOVERNMENT PRINTING OFFICE 76–592 PDF WASHINGTON : 2012 For sale by the Superintendent of Documents, U.S. Government Printing Office Internet: bookstore.gpo.gov Phone: toll free (866) 512–1800; DC area (202) 512–1800 Fax: (202) 512–2104 Mail: Stop IDCC, Washington, DC 20402–0001 COMMITTEE ON HEALTH, EDUCATION, LABOR, AND PENSIONS TOM HARKIN, Iowa, Chairman CHRISTOPHER J. DODD, Connecticut MICHAEL B. ENZI, Wyoming BARBARA A. MIKULSKI, Maryland JUDD GREGG, New Hampshire JEFF BINGAMAN, New Mexico LAMAR ALEXANDER, Tennessee PATTY MURRAY, Washington RICHARD BURR, North Carolina JACK REED, Rhode Island JOHNNY ISAKSON, Georgia BERNARD SANDERS (I), Vermont JOHN MCCAIN, Arizona SHERROD BROWN, Ohio ORRIN G. HATCH, Utah ROBERT P. CASEY, JR., Pennsylvania LISA MURKOWSKI, Alaska KAY R. HAGAN, North Carolina TOM COBURN, M.D., Oklahoma JEFF MERKLEY, Oregon PAT ROBERTS, Kansas AL FRANKEN, Minnesota MICHAEL F. BENNET, Colorado DANIEL SMITH, Staff Director PAMELA SMITH, Deputy Staff Director FRANK MACCHIAROLA, Republican Staff Director and Chief Counsel (II) CONTENTS STATEMENTS WEDNESDAY, JULY 21, 2010 Page Harkin, Hon. Tom, Chairman, Committee on Health, Education, Labor, and Pensions, opening statement .............................................................................. -
Annual Review 2004 Contents Contentsforeword
Annual Review 2004 Contents ContentsForeword ........................................................................................................................... 3 Editor’s Note ..................................................................................................................... 4 Organization Chart ............................................................................................................ 5 Administrative Board .......................................................................................................... 6 Special Events..................................................................................................................... 8 Consultants ...................................................................................................................... 13 Visiting Professors ............................................................................................................ 13 Faculty Board ...................................................................................................................13 Faculty Senate ..................................................................................................................14 Department of Clinical Tropical Medicine ........................................................................ 15 Department of Helminthology ......................................................................................... 22 Department of Medical Entomology ............................................................................... -
Private Equity Guide to Life Sciences Investing Under the Trump Administration: Food and Drug Administration (FDA) Developments
Debevoise In Depth Private Equity Guide to Life Sciences Investing Under the Trump Administration: Food and Drug Administration (FDA) Developments March 15, 2018 Overview As the Trump administration enters its second year, it is an ideal time for private equity funds and investors active in the life sciences arena to reflect on the impact of the new administration—and a new commissioner—on the Food and Drug Administration (“FDA”). Of all the potential Trump nominees to head the agency, Dr. Scott Gottlieb, a physician, was clearly the most mainstream choice. Commissioner Gottlieb previously served as FDA’s Deputy Commissioner for Medical and Scientific Affairs and, before that, as a senior advisor to the FDA Commissioner. As a cancer survivor, he also had first-hand experience as a patient— perhaps informing some of the regulatory strategies he has pursued. Those strategies have been significant. While many other federal regulatory agencies have been marginalized or victims of regulatory paralysis, FDA, under Scott Gottlieb’s leadership, has forged ahead with sweeping initiatives intended to accelerate drug and device approvals and clearances, embrace innovation and new technologies, lower regulatory burdens, and enhance therapeutic opportunities.1 This fast-moving regulatory landscape, combined with robust innovation in the life sciences sector, creates both opportunities and challenges for private equity sponsors. In recent years, private equity sponsors have continued to prioritize investments in both the healthcare and life sciences industries and 1 When Gottlieb took the reins at FDA, the agency was already focused on a number of ongoing initiatives such as the implementation of the 21st Century Cures Act, enacted at the end of 2016, and the passage of the FDA Reauthorization Act of 2017 (“FDARA”). -
WO 2015/028850 Al 5 March 2015 (05.03.2015) P O P C T
(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2015/028850 Al 5 March 2015 (05.03.2015) P O P C T (51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, C07D 519/00 (2006.01) A61P 39/00 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, C07D 487/04 (2006.01) A61P 35/00 (2006.01) DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 31/5517 (2006.01) A61P 37/00 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KN, KP, KR, A61K 47/48 (2006.01) KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, (21) International Application Number: OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, PCT/IB2013/058229 SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, (22) International Filing Date: TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, 2 September 2013 (02.09.2013) ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (26) Publication Language: English GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (71) Applicant: HANGZHOU DAC BIOTECH CO., LTD UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, [US/CN]; Room B2001-B2019, Building 2, No 452 Sixth TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, Street, Hangzhou Economy Development Area, Hangzhou EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, City, Zhejiang 310018 (CN). -
TMA-15 Humanized Monoclonal Antibody Specific for Shiga Toxin 2
toxins Article Efficacy of Urtoxazumab (TMA-15 Humanized Monoclonal Antibody Specific for Shiga Toxin 2) Against Post-Diarrheal Neurological Sequelae Caused by Escherichia coli O157:H7 Infection in the Neonatal Gnotobiotic Piglet Model Rodney A. Moxley 1,*, David H. Francis 2, Mizuho Tamura 3, David B. Marx 4, Kristina Santiago-Mateo 5 and Mojun Zhao 6 1 School of Veterinary Medicine and Biomedical Sciences, University of Nebraska-Lincoln, Lincoln, NE 68583, USA 2 Department of Veterinary and Biomedical Sciences, South Dakota State University, Brookings, SD 57007, USA; [email protected] 3 Teijin Pharma Limited, Pharmacology Research Department, 4-3-2 Asahigaoka, Hino, Tokyo 191-8512, Japan; [email protected] 4 Department of Statistics, University of Nebraska-Lincoln, Lincoln, NE 68583, USA; [email protected] 5 Canadian Food Inspection Agency, Lethbridge Laboratory, Box 640 TWP Rd 9-1, Lethbridge, AB T1J 3Z4, Canada; [email protected] 6 Valley Pathologists, Inc., 1100 South Main Street, Suite 308, Dayton, OH 45409, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-402-472-8460 Academic Editors: Gerald B. Koudelka and Steven A Mauro Received: 1 November 2016; Accepted: 19 January 2017; Published: 26 January 2017 Abstract: Enterohemorrhagic Escherichia coli (EHEC) is the most common cause of hemorrhagic colitis and hemolytic uremic syndrome in human patients, with brain damage and dysfunction the main cause of acute death. We evaluated the efficacy of urtoxazumab (TMA-15, Teijin Pharma Limited), a humanized monoclonal antibody against Shiga toxin (Stx) 2 for the prevention of brain damage, dysfunction, and death in a piglet EHEC infection model. -
Bioversys Announces First Subjects Dosed in Phase 1 Clinical Trial Of
PRESS RELEASE BioVersys Announces First Subjects Dosed in Phase 1 Clinical Trial of BVL-GSK098 BVL-GSK098 IS BEING DEVELOPED FOR THE TREATMENT OF MULTIDRUG- RESISTANT TUBERCULOSIS INFECTIONS Basel, Switzerland. January, 12th 2021. 09:00 CET BioVersys has reached another major milestone by moving a second program into clinical development with the start of Phase 1 testing for BVL-GSK098 in healthy volunteers. BioVersys AG, a privately owned, multi-asset Swiss phArmAceuticAl compAny focused on developing small molecules for multidrug-resistant bActeriAl infections with ApplicAtions in Anti- MicrobiAl ResistAnce (AMR) And tArgeted microbiome modulAtion, todAy Announced thAt the first heAlthy volunteers hAve received BVL-GSK098 in A PhAse 1 clinicAl trial designed to evaluate the safety, tolerability, and pharmacokinetics of BVL-GSK098 in heAlthy humAn volunteers through Single Ascending Dose (SAD) and Multiple Ascending Dose (MAD) studies. • BVL-GSK098 is a novel compound potentiating and overcoming the resistAnce AgAinst ethionAmide (Eto) or prothionamide (Pto) for the treAtment of tuberculosis (TB). BVL- GSK098 tArgets bActeriAl trAnscriptionAl regulAtors, A groundbreAking ApproAch thAt is being assessed globally for the first time in a clinical trial. BVL-GSK098 is developed in combinAtion with Eto or Pto for the treAtment of TB in collaboration with GSK. The program is supported by the IMI2 AMR AccelerAtor from the EU (TRIC-TB Project). The progrAm originAtes from BioVersys And its pArtners At the University of Lille And Pasteur Institute Lille, FrAnce. • BVL-GSK098 has completed GLP toxicology studies and shown excellent in vitro And in vivo efficAcy in AnimAl models against multidrug-resistant TB (MDR-TB), including overcoming pre-existing resistance mechanisms in Mycobacterium tuberculosis by employing novel bioactivAtion pAthwAys for Eto.