TREATING INFECTIOUS DISEASES IN A MICROBIAL WORLD

Report of Two Workshops on Novel Antimicrobial Therapeutics

Committee on New Directions in the Study of Antimicrobial Therapeutics: New Classes of Antimicrobials

Committee on New Directions in the Study of Antimicrobial Therapeutics: Immunomodulation

Board on Life Sciences

Division on Earth and Life Studies

NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES

THE NATIONAL ACADEMIES PRESS
Washington, D.C.
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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics TREATING INFECTIOUS DISEASES IN A MICROBIAL WORLD Report of Two Workshops on Novel Antimicrobial Therapeutics Committee on New Directions in the Study of Antimicrobial Therapeutics: New Classes of Antimicrobials Committee on New Directions in the Study of Antimicrobial Therapeutics: Immunomodulation Board on Life Sciences Division on Earth and Life Studies NATIONAL RESEARCH COUNCIL OF THE NATIONAL ACADEMIES THE NATIONAL ACADEMIES PRESS Washington, D.C. www.nap.edu

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics 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 Contract No. N01-OD-4-2139 (Task Order #153) between the National Academy of Sciences and the National Institutes of Health. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the U.S. Government. International Standard Book Number 0-309-10056-9 Additional copies of this report are available from the National Academies Press, 500 Fifth Street, NW, Lockbox 285, Washington, DC 20055; (800) 624-6242 or (202) 334-3313 (in the Washington metropolitan area); Internet, http://www.nap.edu. Cover image: Confocal micrograph depicting a common behavior of bacteria (green) gathering in mucus shed by host epithelial cells (red). Such behavior has been noted in both beneficial and pathogenic associations with microbial partners. This image shows the gathering of the microbial symbiont Vibrio fischeri during its colonization of tissues of the host squid Euprymna scolopes. As described in the report, models such as the squid-vibrio system promise to provide insight into the mechanisms underlying the reciprocal dialogue between the hosts and their microbial partners, whether the relationship results in health or disease. Image courtesy of Laura Sycuro and Margaret McFall-Ngai. Copyright 2006 by the National Academy of Sciences. All rights reserved. Printed in the United States of America.

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics THE NATIONAL ACADEMIES Advisers to the Nation on Science, Engineering, and Medicine 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 government. 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. Wm. A. Wulf 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. Wm. A. Wulf are chair and vice chair, respectively, of the National Research Council. www.national-academies.org

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics COMMITTEE ON NEW DIRECTIONS IN THE STUDY OF ANTIMICROBIAL THERAPEUTICS: NEW CLASSES OF ANTIMICROBIALS CHRISTOPHER T. WALSH (Chair), Harvard Medical School, Boston, Massachusetts BONNIE L. BASSLER, Princeton University, Princeton, New Jersey CARL F. NATHAN, Weill Medical College of Cornell University, New York, New York THOMAS F. O’BRIEN, Brigham and Women’s Hospital, Boston, Massachusetts MARGARET RILEY, University of Massachusetts, Amherst, Massachusetts RICHARD J. WHITE, Vicuron Pharmaceuticals, Fremont, California GERARD D. WRIGHT, McMaster University, Hamilton, Ontario, Canada Staff ADAM P. FAGEN, Study Director ANN H. REID, Program Officer ROBERT T. YUAN, Senior Program Officer JOSEPH C. LARSEN, Postdoctoral Research Associate MATTHEW D. McDONOUGH, Program Assistant (through August 2005) ANNE F. JURKOWSKI, Program Assistant (since September 2005) NORMAN GROSSBLATT, Senior Editor

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics COMMITTEE ON NEW DIRECTIONS IN THE STUDY OF ANTIMICROBIAL THERAPEUTICS: IMMUNOMODULATION ARTURO CASADEVALL (Chair), Albert Einstein College of Medicine, New York, New York RITA R. COLWELL, University of Maryland, College Park, Maryland; Johns Hopkins University, Baltimore, Maryland; and Canon U.S. Life Sciences, Arlington, Virginia R.E.W. (BOB) HANCOCK, University of British Columbia, Vancouver, British Columbia, Canada MARGARET JEAN McFALL-NGAI, University of Wisconsin, Madison, Wisconsin CARL F. NATHAN, Weill Medical College of Cornell University, New York, New York LIISE-ANNE PIROFSKI, Albert Einstein College of Medicine, New York, New York ARTHUR TZIANABOS, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts DENNIS M. ZALLER, Merck Research Laboratories, Rahway, New Jersey Staff ANN H. REID, Study Director ADAM P. FAGEN, Program Officer ROBERT T. YUAN, Senior Program Officer JOSEPH C. LARSEN, Postdoctoral Research Associate MATTHEW D. McDONOUGH, Program Assistant (through August 2005) ANNE F. JURKOWSKI, Program Assistant (since September 2005) NORMAN GROSSBLATT, Senior Editor

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics BOARD ON LIFE SCIENCES COREY S. GOODMAN (Chair), Renovis, Inc., South San Francisco, California ANN M. ARVIN, Stanford University School of Medicine, Stanford, California JEFFREY L. BENNETZEN, University of Georgia, Athens, Georgia RUTH BERKELMAN, Emory University, Atlanta, Georgia DEBORAH BLUM, University of Wisconsin, Madison, Wisconsin R. ALTA CHARO, University of Wisconsin, Madison, Wisconsin DENNIS CHOI, Merck Research Laboratories, West Point, Pennsylvania JEFFREY L. DANGL, University of North Carolina, Chapel Hill, North Carolina PAUL R. EHRLICH, Stanford University, Stanford, California JAMES M. GENTILE, Research Corporation, Tucson, Arizona JO HANDELSMAN, University of Wisconsin, Madison, Wisconsin ED HARLOW, Harvard Medical School, Boston, Massachusetts DAVID HILLIS, University of Texas, Austin, Texas KENNETH H. KELLER, University of Minnesota, Minneapolis, Minnesota RANDALL MURCH, Virginia Polytechnic Institute and State University, Alexandria, Virginia GREGORY A. PETSKO, Brandeis University, Waltham, Massachusetts STUART L. PIMM, Duke University, Durham, North Carolina JAMES TIEDJE, Michigan State University, East Lansing, Michigan KEITH YAMAMOTO, University of California, San Francisco, California Staff FRANCES E. SHARPLES, Director KERRY A. BRENNER, Senior Program Officer MARILEE K. SHELTON-DAVENPORT, Senior Program Officer ROBERT T. YUAN, Senior Program Officer ADAM P. FAGEN, Program Officer ANN H. REID, Program Officer EVONNE P. Y. TANG, Program Officer DENISE GROSSHANS, Financial Associate ANNE F. JURKOWSKI, Program Assistant

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics Acknowledgments Each report benefited from the contribution of the speakers and participants in the respective workshops. The agenda, speakers, and participant list for each workshop are provided as an appendix to each report. The immunomodulation committee would also like to acknowledge David Schneider, Stanford University, for preparing the figure highlighting the complexity of the immune system, and Fiona Roche, Simon Fraser University, for preparing the Cytoscape figure of the TLR4 pathway. These reports have 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 reports as sound as possible and to ensure that the reports meet institutional standards of objectivity, evidence, and responsiveness to the study charge. The review comments and draft manuscript remain confidential to protect the integrity of the deliberative process. We wish to thank the following individuals for their review of these reports: Christine A. Biron, Brown University Richard A. Flavell, Yale University Emil C. Gotschlich, The Rockefeller University Lora Hooper, University of Texas Southwestern Medical Center at Dallas

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics Harry F. Noller, University of California, Santa Cruz John H. Rex, AstraZeneca Pharmaceuticals Jerome S. Schultz, University of California, Riverside Peter M. Small, Bill and Melinda Gates Foundation Elaine Tuomanen, St. Jude Children’s Research Hospital H. Boyd Woodruff, Soil Microbiology Associates Although the reviewers listed above have provided constructive comments and suggestions, they were not asked to endorse the conclusions or recommendations, nor did they see the final drafts of the reports before their release. The review of these reports was overseen by Elaine L. Larson, Columbia University, and Leslie Z. Benet, University of California, San Francisco. Appointed by the National Research Council, they were responsible for making certain that an independent examination of these reports was carried out in accordance with institutional procedures and that all review comments were carefully considered. Responsibility for the final content of these reports rests entirely with the authoring committees and the institution.

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics Contents     Summary   1     Challenges for the Development of New Antimicrobials—Rethinking the Approaches: Report of a Workshop   7      Introduction   7      Antibiotic Resistance   10      A Microbial Community Approach to New Antibacterials   15      Understanding Biological Processes to Devise New Antibiotics   19      Need for New Molecules   25      How Can This Work Be Carried Out?   32      References   32     Promising Approaches to the Development of Immunomodulation for the Treatment of Infectious Diseases: Report of a Workshop   37      Introduction   37      Modulating Innate Immunity   43      Modulating Acquired Immunity   50      Taking Advantage of the Resident Microbiota   53      Cross-cutting Research Needs for the Development of Immunotherapy   57      The Near and Far Horizon   59      References   59

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Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics     Appendixes     A   Statement of Task   63 B   New Classes of Antimicrobials Committee Biographical Sketches   65 C   New Classes of Antimicrobials Workshop   69 D   Immunomodulation Committee Biographical Sketches   79 E   Immunomodulation Workshop   85