At the request of the National Institute of Allergy and Infectious Diseases, two committees established by the National Research Council organized workshops to identify promising new approaches to the development of antimicrobial therapeutics (Appendix A). One workshop focused on potential new classes of antibiotics, while the other explored the possibility of treating infectious diseases by modulating the immune system. The need for new antimicrobial therapeutics is acute because of growing resistance to available antibiotics, the emergence of new infectious diseases like SARS and West Nile virus, and the risk of bioterrorist attacks using infectious agents that may not be immediately identifiable. From one point of view, these are all manifestations of a single problem—human vulnerability to microbial disease—and therefore subject to one solution—a single drug that can protect against any infectious agent. Attractive as the idea of a “gorillacillin” superdrug might be in the abstract, discussions at both workshops made it clear that a point of view pitting human against microorganism is at best limited and at worst seriously flawed.
Through research in fields as diverse as evolutionary biology, bacteriology, ecology, immunology and developmental biology, a much more complex viewpoint is emerging—a perspective recognizing that humans exist as part of an environment full of microorganisms and that these microorganisms have been evolving, coexisting, and competing with each other for millions of years. Most of the antimicrobial agents that have revolutionized
the treatment of infectious diseases in the past several decades are derived from bacterial products that have been used as weapons against other bacteria for millions of years, and the ability of bacteria to develop resistance to them is an ancient evolutionary defense tactic. Similarly, the human immune system has evolved in the midst of this microbial world to provide highly nuanced and carefully regulated responses to the myriad microorganisms it encounters. Perhaps most discordant with the “human versus microorganism” point of view is the increasing realization that all humans live in intimate community with thousands of microbial species—the natural microbiota of our skins, guts and oral cavities—and that these microorganisms affect human health in many positive ways from development, to nutrition, to susceptibility to disease. In short, humans have evolved in and exist now in a world overwhelmingly dominated by microorganisms, the vast majority of which do not cause disease.
In such a world, the idea of developing a “gorillacillin” becomes hopelessly complicated. How would such a drug distinguish microbial friend from foe? How would it simultaneously outwit the varied defense tactics developed over millions of years by thousands of microorganisms? How could a single drug improve the performance of the highly complicated and already extremely effective human immune system? These questions are daunting, even discouraging. At the same time, antibiotics have saved millions of lives and interventions exploiting the human immune system—especially immunization—have vastly reduced human vulnerability to infectious disease. If “gorillacillin” is an unrealistic—perhaps even an undesirable—goal, it is nevertheless clear that effective antimicrobial therapeutics have been and can again be developed.
Both workshops focused on generating ideas for innovative research approaches that would contribute to the development of new antimicrobial therapeutics. There was widespread recognition, however, that the road from a brilliant idea to a clinically available treatment is long and full of pitfalls. Differing approaches to antibiotic use in different countries, declining investment in antimicrobials by large pharmaceutical companies, increasing costs of clinical trials, and complicated regulatory and legal environments, are just a few of the obstacles to bringing new compounds rapidly from the laboratory to the clinic. Interesting and important as these issues are, the workshops were not designed to address them because the committees were specifically charged to focus on the scientific possibilities. The interested reader is referred to a recent report by the Infectious Diseases Society of America, Bad Bugs, No Drugs: As Antibiotic Discovery Stag-
nates … A Public Health Crisis Brews,1 for a useful description of these challenges specifically as they affect antibiotic development. Several reports issued by the National Academies have also addressed some of these issues, including Discovery of Antivirals Against Smallpox: Executive Summary by the Committee on Transforming Biological Information into New Therapies: A Strategy for Developing Antiviral Drugs for Smallpox (2004), Saving Lives, Buying Time: Economics of Malaria Drugs in an Age of Resistance by the Committee on the Economics of Antimalarial Drugs (2004), and Making Better Drugs for Children with Cancer by the Committee on Shortening the Time Line for New Cancer Treatments (2005).
The two workshops held for this report approached the challenge by looking at the current state of knowledge, identifying the approaches that have been successful in the past, and brainstorming about ways in which new areas of research could revolutionize the treatment of infectious disease. The recommendations put forward by each committee emerged independently from their respective workshop discussions and are organized according to the topics that emerged as most promising. An overview of the recommendations of both committees, however, suggests that they are of three types.
Some of the recommendations reflect ways in which current approaches to developing antibiotics and immunomodulators could be improved. Implementation of recommendations of this type is most likely to provide improved therapeutics in the short term. For example,
Many successful antibiotics have been discovered by studying natural products. The field of metagenomics offers the possibility of discovering gene products with antibiotic activity without having to culture individual organisms. (Antimicrobial workshop recommendation A-6.2)
Generating slight chemical variations of compounds with promising activity frequently results in more effective drugs; new chemical synthesis approaches that allow the rapid synthesis of more varied structures could speed this process. (Antimicrobial workshop recommendations A-7.1, A-7.2, A-7.3)
Immunization, both passive and active, has been hugely successful, but could be improved with enhanced understanding of exactly how different antibody isotypes function and how they interact with the innate immune system. (Immunomodulation workshop recommendation I-3.1)
Other recommendations reflect the committees’ judgments as to which areas of basic research are most likely to lead to genuinely novel approaches to infectious disease treatment. Since the outcome of basic research is difficult to predict, these approaches might be labeled “high-risk,” but have the potential also to reap great reward in the long term.
Current antibiotic development concentrates on targets that are essential for bacterial metabolism; research into how bacteria communicate with each other may allow the development of drugs that confuse rather than kill—drugs that might be less likely to provoke resistance. (Antimicrobial workshop recommendations A-3.1, A-3.2, A-3.3)
The human immune system is constantly interacting with the thousands of bacterial species comprising the natural microbiota; understanding how the natural microbiota communicates with the immune system and how the immune system singles out harmful microorganisms could lead to drugs that help the natural microbiota outcompete pathogens. (Immunomodulation workshop recommendations I-6.1, I-6.2, I-6.3 and Antimicrobial workshop recommendation A-3.2)
Once considered primitive, the innate immune system is increasingly being shown to be highly complex, regulated and intimately intertwined with the acquired immune system and the nervous system. Understanding innate immune system regulatory pathways and active molecules may lead to drugs that are effective against a wide array of infectious agents. (Immunomodulation workshop recommendations I-1.1, I-1.2, I-1.3, I-1.4)
A third group of recommendations reflects cross-cutting issues. In particular, both workshops highlighted the value of improved diagnostics.
Rapid diagnostic tools to allow identification of the disease-causing agent and its resistance profile would make it possible for physicians to reduce the use of broad-spectrum antibiotics and encourage the development of narrowly-targeted therapeutics. (Antimicrobial workshop recommendation A-1.2)
Diagnostic profiles that describe the immune status of the patient could make it possible to predict how effective different treatments will be and target immunomodulatory drugs to the right patients at the right time. (Immunomodulation workshop recommendation I-7.2)
Both workshops also suggested that many of the techniques currently used to evaluate antimicrobial compounds are imperfect. Testing antimicrobial compounds against pure cultures under ideal laboratory growth conditions does not reflect the reality of pathogens competing against the natural microbiota in human tissue and under pressure from the immune system. Mice are imperfect models of humans, but developing and validating alternative animal models is difficult and expensive. It is also difficult to design and evaluate clinical trials of compounds that affect the highly complex and individually variable immune system.
Finally, both committees recognized that dividing the task into antimicrobial versus immunomodulatory approaches made it difficult to discuss some very promising ideas. For example, the immunomodulation committee noted that many immunomodulators may not be able to cure disease directly, but could be effective in combination with traditional antimicrobials. Participants in the antimicrobial workshop explored the idea of developing antibiotics that would be selectively activated through interaction with the compounds used by the immune system to signal damage. Future discussions of infectious disease treatments that target the disease-causing agent and enhance the immune response at the same time could generate even more promising ideas.