Abstract

Research priorities for controlling antibiotic resistance

First and foremost, additional basic information is required in order to direct strategic efforts towards control of the crisis. Increasing lines of evidence identify the principal reservoirs of resistance genes to be bacteria that live in and on humans and animals as well as those found in the environment (soil, water, etc). However there is insufficient information on the conditions and factors that lead to their mobilization, selection and movement into and between animal and human populations.

The key questions for researchers to address are therefore:

• What and where are the critical stages in the process of development of clinically significant antibiotic resistance from microbes in the environment and how can the chain of events be intercepted?

• When reliable information on the above is available, will it enable the prediction of the emergence of new mechanisms of resistance? If so, what actions should be taken?

• Modern diagnostic technology is critical for accurate and efficient use of antibiotics. Can the methodology be improved to facilitate decision-making in individual, point-of-care settings requiring rapid action?

• Containment of outbreaks of antibiotic resistance is dependent on an early warning system. The establishment and maintenance of reliable city-wide, country-wide and international surveillance is essential to ensure the prescription of the most appropriate antibiotics and treatment (including isolation) of infected people. How can such a world-wide network be created?

• Dormant persister bacterial cells are produced by all pathogens and may serve as a potential source of antibiotic-resistant bacteria, although further studies are required to define the correlation. Better understanding of persisters and ways to eliminate them is needed.

These questions are priorities for the prevention of antibiotic resistance development worldwide; in order to support the research necessary to track new threats on a global scale, international funding is indispensable. In cases of influenza outbreaks, WHO and associated agencies have moved rapidly to isolate and eliminate new outbreaks of infection. The same approach should be applied to antibiotic resistance; a new generation of physician/scientists with modern approaches to diagnostic/predictive medicine needs to be trained.

Urgent actions needed to tackle resistance

It is indisputable that antibiotic resistance is life-threatening in the same sense as cancer, both in numbers of cases and likely outcome; thus the following actions can and must be taken as matters of extreme urgency.

A collaborative approach

It is essential that antibiotic discovery and production be maintained on a scale that is appropriate to our increasing requirements. The Infectious Diseases Society of America has proposed a goal of “10 new antibiotics for 2020” (Ref 9). This will be difficult, given that industry’s search for novel chemical agents acting on new biological targets has become non-productive. However, it is now clear that natural-product drug discovery efforts to date have generally focused on readily accessible sources (Ref 10). These are only the tip of the iceberg in terms of the vast reservoir of bioactive compounds available in nature. For example, in 2008, over 1000 novel compounds were isolated from marine micro-organisms (Ref 11). With such a treasure trove to mine and the active involvement and wealth of experience of the established pharmaceutical industry (which was in fact founded on natural product development in the 1950s – 70s) the IDSA target would be attainable. Without such collaboration, the antibiotic discovery commitment becomes the responsibility of government agencies, academia and small biotech companies, entailing significant federal investments.

The cost of the undertaking that we propose will be infinitesimally small in comparison to the economic and human cost of doing nothing. The late Joshua Lederberg observed that “barring geno-suicide, human domination is challenged only by pathogenic microbes, for which we are the prey, they are the predators. In natural evolutionary competition there is no guarantee that we will find ourselves the survivors.” (Ref 12). The Banbury participants believe that if the appropriate actions are taken on a worldwide scale, the odds can be changed.

Acknowledgements

Contributor Information

Karen Bush, Department of Biology, 1001 E. Third Street, Indiana University, Bloomington, Indiana 47405, USA.

Patrice Courvalin, Unité des Agents Antibactériens, Institut Pasteur, 25 rue du Docteur Roux, 75724 Paris cedex 15, France.

Gautam Dantas, Department of Pathology & Immunology, Washington University School of Medicine, 4444 Forest Park Ave., St Louis, Missouri 63108, USA.

Julian Davies, Department of Microbiology and Immunology, University of British Columbia, 2350 Health Sciences Mall, Vancouver, BC V6T 1Z3, Canada.

Barry Eisenstein, Cubist Pharmaceuticals, 65 Hayden Avenue, Lexington, Massachusetts 02421, USA.

Pentti Huovinen, Department of Medical Microbiology and Immunology, University of Turku, Kiinamyllynkatu 13, 20520 Turku, Finland.

George A. Jacoby, Lahey Clinic, 41 Mall Road, Burlington, Massachusetts 01805, USA.

Roy Kishony, Harvard Medical School, Department of Systems Biology, 200 Longwood Avenue, Boston, Massachusetts 02115, USA.

Barry N. Kreiswirth, Public Health Research Institute, University of Medicine and Dentistry of New Jersey, Warren Street, Newark, New Jersey 07103, USA.

Elizabeth Kutter, Phage Biology, The Evergreen State College, 2700 Evergreen Parkway NW, Olympia, Washington 98505, USA.

Stephen A. Lerner, Division of Infectious Diseases, Wayne State University School of Medicine, Harper University Hospital, 3990 John R, Detroit, Michigan 48201, USA.

Stuart Levy, Tufts University School of Medicine, Department of Molecular Biology and Microbiology, Harrison Avenue, Boston, Massachusetts 02111, USA.

Kim Lewis, Antimicrobial Discovery Center, Department of Biology, Northeastern University Huntington Avenue, Mugar 306C, Boston, Massachusetts 02115, USA.

Olga Lomovskaya, Rempex Pharmaceuticals, Inc., 11535 Sorrento Valley Road, San Diego, California 92121, USA.

Jeffrey H. Miller, Department of Microbiology, Immunology, and Molecular Genetics, UCLA, 1602 Molecular Sciences Building, 405 Hilgard Avenue, Los Angeles, California 90095-1489, USA.

Shahriar Mobashery, Department of Chemistry and Biochemistry, University of Notre Dame, 423 Nieuwland Science Hall, Notre Dame, Indiana 46556, USA.

Laura J. V. Piddock, Antimicrobial Agents Research Group, Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Steven Projan, Innovative Medicines Head of Infectious Diseases and Vaccines, MedImmune, 3001 Red Lion Road,(Philadelphia, Pennsylvania 19114, USA.

Christopher M. Thomas, Professor of Molecular Genetics, School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Alexander Tomasz, Laboratory of Microbiology and Infectious Diseases, The Rockefeller University, 1230 York Avenue, New York, New York 10021, USA.

Paul M. Tulkens, Unité de Pharmacologie cellulaire et moléculaire, Université catholique de Louvain, UCL 73.70, Avenue E. Mounier 73, B-1200 Brussels, Belgium.

Timothy R. Walsh, Section of Medical Microbiology,(IIB, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK.

James D. Watson, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.

Jan Witkowski, Banbury Center, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.

Wolfgang Witte, Robert Koch Institute, Wernigerode Branch, D-38855 Wernigerode, Germany.

Gerry Wright, M.G. DeGroote Institute for Infectious Disease Research, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada.

Pamela Yeh, Department of Biology, Portland State University, Portland, Oregon 97201, USA.

Helen I. Zgurskaya, University of Oklahoma, Department of Chemistry and Biochemistry, Stephenson Life Sciences Research Center, 101 Stephenson Parkway, Norman, Oklahoma 73019-5251, USA.

References