TECHNOLOGICAL CHALLENGES
IN ANTIBIOTIC DISCOVERY AND
DEVELOPMENT

A WORKSHOP SUMMARY

Douglas Friedman and Joe Alper, Rapporteurs

Chemical Sciences Roundtable

Board on Chemical Sciences and Technology

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL
              OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS

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Douglas Friedman and Joe Alper, Rapporteurs Chemical Sciences Roundtable Board on Chemical Sciences and Technology Division on Earth and Life Studies

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The National Academies Press   500 Fifth Street, NW   Washington, DC 20001 NOTICE: The project that is the subject of this report was approved by the Governing Board of the National Research Council, whose members are drawn from the councils of the National Academy of Sciences, the National Academy of Engineering, and the Institute of Medicine. The members of the committee responsible for the report were chosen for their special competences and with regard for appropriate balance. This study was supported by the U.S. Department of Energy under Grant DE-FG02-07ER15872, the National Institutes of Health under Contract HHSN263201200074I (Task Order 25), and the National Science Founda- tion under Grant CHE-1231459. This report was prepared as an account of work sponsored by an agency of the United States Government. Neither the United States Government nor any agency thereof, nor any of their employees, makes any warranty, express or implied, or assumes any legal liability or responsibility for the accuracy, completeness or useful- ness of any information, apparatus, product, or process disclosed, or represents that its use would not infringe privately owned rights. Reference herein to an specific commercial product, process, or service by trade name, trademark, manufacturer, or otherwise does not necessarily constitute or imply its endorsement, recommenda- tion, or favoring by the United States Government or any agency thereof. The views and opinions of authors expressed herein do not necessarily state or reflect those of the United States Government or agency thereof. International Standard Book Number-13:  978-0-309-29814-8 International Standard Book Number-10:  0-309-29814-8 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, N.W., Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. Cover Art: Image of Clostridium Difficule. Courtesy of the Centers for Disease Control and Prevention. Copyright 2014 by the National Academy of Sciences. All rights reserved. Printed in the United States of America

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The National Academy of Sciences is a private, nonprofit, self-perpetuating society of distinguished scholars engaged in scientific and engineering research, dedicated to the furtherance of science and technology and to their use for the general welfare. Upon the authority of the charter granted to it by the Congress in 1863, the Academy has a mandate that requires it to advise the federal government on scientific and technical matters. Dr. Ralph J. Cicerone is president of the National Academy of Sciences. The National Academy of Engineering was established in 1964, under the charter of the National Academy of ­Sciences, as a parallel organization of outstanding engineers. It is autonomous in its administration and in the selection of its members, sharing with the National Academy of Sciences the responsibility for advising the federal govern- ment. The National Academy of Engineering also sponsors engineering programs aimed at meeting national needs, encourages education and research, and recognizes the superior achievements of engineers. Dr. C. D. Mote, Jr., is president of the National Academy of Engineering. The Institute of Medicine was established in 1970 by the National Academy of Sciences to secure the services of eminent members of appropriate professions in the examination of policy matters pertaining to the health of the public. The Institute acts under the responsibility given to the National Academy of Sciences by its congressional charter to be an adviser to the federal government and, upon its own initiative, to identify issues of medical care, research, and education. Dr. Harvey V. Fineberg is president of the Institute of Medicine. The National Research Council was organized by the National Academy of Sciences in 1916 to associate the broad community of science and technology with the Academy’s purposes of furthering knowledge and advising the federal government. Functioning in accordance with general policies determined by the Academy, the Council has become the principal operating agency of both the National Academy of Sciences and the National Academy of Engineering in providing services to the government, the public, and the scientific and engineering communities. The Council is administered jointly by both Academies and the Institute of Medicine. Dr. Ralph J. Cicerone and Dr. C. D. Mote, Jr., are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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CHEMICAL SCIENCES ROUNDTABLE CO-CHAIRS WILLIAM F. CARROLL JR., Occidental Chemical Corporation, Dallas, Texas JENNIFER S. CURTIS, University of Florida MEMBERS MICHAEL R. BERMAN, Air Force Office of Scientific Research CAROLE BEWLEY,* National Institute of Diabetes and Digestive and Kidney Diseases DONNA G. BLACKMOND, Scripps Research Institute PAUL BRYAN, University of California, Berkeley EMILIO BUNEL, Argonne National Laboratory ALLISON CAMPBELL, Pacific Northwest National Laboratory A.WELFORD CASTLEMAN, JR., Pennsylvania State University RICHARD R. CAVANAGH, National Institute of Standards and Technology MIGUEL GARCIA-GARIBAY, University of California, Los Angeles JACQUELYN GERVAY-HAGUE, National Science Foundation JACK KAYE, National Aeronautics and Space Administration JOHN KOZARICH,* ActivX Biosciences, Inc. LUIS E. MARTINEZ,* Trinity University JOHN MILLER, U.S. Department of Energy KENNETH G. MOLOY,* DuPont Central Research and Development ROBERT PEOPLES, American Carpet Institute MICHAEL E. ROGERS, National Institute of General Medical Sciences JAMES M. SOLYST, Enviro International, Inc. KATHLEEN J. STEBE, University of Pennsylvania PATRICIA A. THIEL, Ames Laboratory and Iowa State University NATIONAL RESEARCH COUNCIL STAFF TERESA FRYBERGER, Director INDIA HOOK-BARNARD, Senior Program Officer KATHRYN HUGHES, Senior Program Officer DOUGLAS FRIEDMAN, Program Officer ELIZABETH FINKELMAN, Administrative Assistant NAWINA MATSHONA, Senior Program Assistant JOE ALPER, Consulting Science Writer * These members of the Chemical Sciences Roundtable oversaw the planning of the Workshop on Technological Challenges in Antibiotic Discovery and Development, but were not involved in the writing of this workshop summary. v

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BOARD ON CHEMICAL SCIENCES AND TECHNOLOGY CO-CHAIRS TIMOTHY SWAGER, Massachusetts Institute of Technology DAVID WALT, Tufts University MEMBERS MARK A. BARTEAU, University of Michigan DAVID BEM, Dow Chemical Company JOAN BRENNECKE, Notre Dame University ROBERT BERGMAN, University of California, Berkeley HENRY BRYNDZA, E. I. du Pont de Nemours & Company DAVID CHRISTIANSON, University of Pennsylvania RICHARD EISENBERG, University of Rochester MARY JANE HAGENSON, Chevron Phillips Chemical Company LLC (retired) CAROL J. HENRY, Independent Consultant JILL HRUBY, Sandia National Laboratories CHARLES E. KOLB, Aerodyne Research, Inc. SANDER G. MILLS, Merck, Sharp, & Dohme Corporation DAVID MORSE, Corning Inc. ROBERT E. ROBERTS, Institute for Defense Analyses DARLENE J. S. SOLOMON, Agilent Technologies JEAN TOM, Bristol-Myers Squibb NATIONAL RESEARCH COUNCIL STAFF TERESA FRYBERGER, Director KATHRYN HUGHES, Senior Program Officer DOUGLAS FRIEDMAN, Program Officer ELIZABETH FINKELMAN, Administrative Assistant NAWINA MATSHONA, Senior Program Assistant vi

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Preface The Chemical Sciences Roundtable (CSR) was established in 1997 by the National Research Council. It provides a science-oriented apolitical forum for leaders in the chemi- cal sciences to discuss chemistry-related issues affecting government, industry, and uni- versities. Organized by the National Research Council’s Board on Chemical Sciences and Technology, the CSR aims to strengthen the chemical sciences by fostering communication among the people and organizations—spanning industry, government, universities, and professional associations—involved with the chemical enterprise. One way it does this is by organizing workshops that address issues in chemical science and technology that require national or more widespread attention. On September 23, 2013, the CSR held a one-day workshop on the technical challenges in antibiotic discovery and development that explored the current state of antibiotic discov- ery, examined the technology available to facilitate development, discussed the technical challenges present, identified novel approaches to antibiotic discovery, and discussed the incentives and disincentives industry faces in antibiotic development. The workshop fea- tured both formal presentations and panel discussions among participants from academia, industry, and federal research agencies. The workshop program consisted of three themes: • The challenges and approaches in overcoming antibiotic resistance; • The challenges and approaches in screening for new chemical entities with anti- biotic properties; and • The challenges and approaches in delivering antibiotics to their intended site of action, particularly with regard to surmounting biophysical barriers. This document summarizes the presentations and discussions that took place at the workshop. In accordance with the policies of the NRC, the workshop did not attempt to establish any conclusions or recommendations about needs and future directions, focus- ing instead on issues identified by the speakers and workshop participants. In addition, the organizing committee’s role was limited to planning the workshop. The workshop summary has been prepared by workshop rapporteurs Douglas Friedman and Joe Alper as a factual summary of what occurred at the workshop. vii

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Acknowledgment of Reviewers This workshop summary has been reviewed in draft form by persons chosen for their diverse perspectives and technical expertise in accordance with procedures approved by the National Research Council’s Report Review Committee. The purpose of this independent review is to provide candid and critical comments that will assist the institution in making the published workshop summary as sound as possible and to ensure that it meets insti- tutional standards of objectivity, evidence, and responsiveness to the charge. The review comments and draft manuscript remain confidential to protect the integrity of the delibera- tive process. We wish to thank the following individuals for their review of this summary: Carole Bewley, National Institute of Diabetes and Digestive and Kidney Diseases Nicole Mahoney, The Pew Charitable Trusts Melinda Moore, RAND Corporation Douglas Weibel, University of Wisconsin, Madison Although the reviewers listed above provided many constructive comments and sug- gestions, they did not see the final draft of the workshop summary before its release. The review of this summary was overseen by Douglas Lauffenburger, Massachusetts Institute of Technology. Appointed by the National Research Council, he was responsible for mak- ing certain that an independent examination of this workshop summary was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of this workshop summary rests entirely with the authors and the institution. ix

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Contents 1 INTRODUCTION AND OVERVIEW 1 Organization of the Workshop Summary, 1 A View from the Antibiotic Resistance Battlefield, 2 References, 5 2 CHALLENGES IN OVERCOMING ANTIBIOTIC RESISTANCE 7 Selecting Antibacterial Targets to Avoid Resistance Selection, 7 The Complex Resistance Machineries for β-Lactam Antibiotics in Gram-Negative and Gram-Positive Bacteria, 10 Discussion, 11 References, 12 3 CHALLENGES IN SCREENING 13 Challenges in Discovering New Antibiotics Through Screening, 13 News Way of Looking at Old Antibiotics and Their Targets, 16 Discussion, 17 References, 18 4 CHALLENGES IN DRUG DELIVERY 19 Novel Approaches to Antimicrobial Therapeutic Design, 19 Overcoming Antibiotic Challenges in Biofilm-Associated Infection, 20 Discussion, 21 References, 22 5 GENERAL OBSERVATIONS 23 Appendixes A Statement of Task 25 B Workshop Agenda 27 C Biographical Information 29 D Workshop Attendees 33 xi

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Acronyms BARDA Biomedical Advanced Research and Development Authority CDC Centers for Disease Control and Prevention CRE carbapenem-resistant Enterobacteriaceae CSR Chemical Sciences Roundtable FDA U.S. Food and Drug Administration GyrB DNA gyrase B KPC Klebsiella pneumoniae carbapenemase MIC minimum inhibitory concentration MRSA methicillin-resistant Staphylococcus aureus NDM New Delhi metallo-β-lactamase NIAID National Institute of Allergy and Infectious Diseases NIH National Institutes of Health NRC National Research Council NSF National Science Foundation PBP2a penicillin-binding protein 2A PMMA poly(methyl methacrylate) TTSS type three secretion system VRE vancomycin-resistant Enterococcus xiii

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