Treating Infectious Diseases in a Microbial World: Report of Two Workshops on Novel Antimicrobial Therapeutics, March, 2006

103 Pages·2006·0.65 MB·English

by  Christopher T. Walsh

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
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This study was supported by Contract No. N01-OD-4-2139 (Task Order #153) be-
tween the National Academy of Sciences and the National Institutes of Health. The
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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 rela-
tionship 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.
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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
iv
Copyright © National Academy of Sciences. All rights reserved.
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
v
Copyright © National Academy of Sciences. All rights reserved.
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
vi
Copyright © National Academy of Sciences. All rights reserved.
Acknowledgments
Each report benefited from the contribution of the speakers and par-
ticipants in the respective workshops. The agenda, speakers, and partici-
pant 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 proce-
dures approved by the National Research Council’s Report Review Com-
mittee. 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 institu-
tional 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 fol-
lowing 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
vii
Copyright © National Academy of Sciences. All rights reserved.
viii ACKNOWLEDGMENTS
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 com-
ments 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 respon-
sible 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.
Copyright © National Academy of Sciences. All rights reserved.
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
ix
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