Treating Infectious Diseases in a Microbial World Report of Two Workshops on Novel Antimicrobial Therapeutics (2006) / Chapter Skim
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Challenges for the Development of New Antimicrobials— Rethinking the Approaches: Report of a Workshop
Challenges for the Development of New Antimicrobials— Rethinking the Approaches: Report of a Workshop
Pages 7-36
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From page 7... ...
To do so, the mechanisms of infectious disease must be better understood, based on a deeper appreciation of microbial physiology, a comprehensive understanding of antibiotic resistance, and a renewed commitment to the discovery of novel antimicrobial molecules and therapies. There are several indications that new approaches are required to combat emerging infections and the global spread of drug-resistant bacterial pathogens.
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. A technology gap is developing and widening, as research on and development of new antimicrobial agents are being de-emphasized or abandoned by many pharmaceutical companies.
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This report has four major sections: a discussion of the challenge of antibiotic resistance at the population and molecular levels, the importance of understanding bacterial communities and resident microbiota for the discovery of new antimicrobial therapies, consideration of biological processes that can guide strategic approaches to antibiotic development, and
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ANTIBIOTIC RESISTANCE Antibiotic Resistance Is Inevitable The goal of the workshop was to identify novel approaches to the development of antimicrobial therapeutics. However, workshop discussions made it clear that even the most innovative antibiotics will be made obsolete, at some point, by the inevitable emergence of resistance.
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Antibiotic Resistance Is Manageable 1. Predicting Resistance The inevitability of resistance is well accepted by researchers in the field, but there are barriers to collecting and sharing data on resistance among diverse geographic centers and among individual health-care settings within a single geographic region.
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Clinicians and developers of diagnostics would then be aware of resistance mechanisms that may be encountered in the clinic. Such an integrated database would greatly enhance the ability to develop predictive diagnostics that could be rapidly brought on line as resistance elements move around the globe.
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Development of such tests may be difficult but could lead to significant advancement in the treatment of infectious disease. To effect the greatest reduction in inappropriate antibiotic use, such tests would need to be so rapid and reliable that clinicians would be comfortable waiting for the results before beginning antibiotic treatment.
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Understanding the fundamental principles underlying how pathogenic organisms and normal microbiota communicate and exchange genetic information is a key to the ability to manage the spread of resistance. Research on the molecular mechanisms that facilitate resistance is also warranted.
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· A-1.6 Exploration of the effect of antibiotic usage, alone and in combination, on the development of resistance. A MICROBIAL COMMUNITY APPROACH TO NEW ANTIBACTERIALS Characterization of Communities of Microbiota There is growing evidence of the important role played by resident microbiota in offering protection from infectious disease.
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. Precise definition of these associations in human health and in disease will allow the development of nontraditional therapeutics aimed at manipulating bacteria and their environment to enhance the maintenance and proliferation of the normal microbiota and inhibit the growth of pathogens.
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. Enhancing growth-promotion signals of the normal microbiota at the expense of non-indigenous species might restore the normal microbial balanced state.
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Probiotic Therapies Anecdotal information suggests that the microbiota plays an active role in defense against pathogens. For example, treatment of Salmonella infections with antibiotics that kill both salmonellae and the normal microbiota increases the longevity of the carrier state.
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. Such probiotic therapies could extend the lifespan of traditional broad-spectrum antibiotics because their use in the healthy community essentially converts broadspectrum drugs into narrow-spectrum ones.
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Which genes are essential to the pathogen in specific host environments, including polymicrobial communities on epithelial surfaces, where the microorganism of interest may represent a relatively minor planktonic population; in monomicrobial populations deep in tissues, where the pathogen may attain high population densities; and in biofilms in either kind of site? (If genes expressed in a pathogen only when it is the sole microbial species yield products that are needed for pathogenesis, targeting their products could spare the normal microbiota.)
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Tools needed to study these questions include in vitro culture systems with pathophysiologically-relevant concentrations of oxygen, iron, and carbon sources; biologically-relevant growth surfaces; and, in some cases, mixed microbial populations with systems-biological approaches to the analysis of prokaryotes in microbial communities. Alternatives to Direct Killing of Microorganisms The standard goal of eliminating disease-causing microorganisms without harming the host can be complemented by an alternative goal of simply suppressing their pathogenic behavior.
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Protein-synthesis inhibitors are generally bacteriostatic but might be selectively bactericidal to a species whose proliferative program is induced. Combating infectious disease by interfering with microbial signaling mimics a major strategy used by the immune system.
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A striking example was recently reported in Mycobacterium tuberculosis through the joint disruption of two isocitrate lyases (Muñoz-Elías and McKinney 2005)
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· A-5.4 Exploring inhibition of host targets to thwart infectious disease.
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Natural and synthetic molecules are both likely to remain important sources for new antibiotics but offer distinct challenges. Mining the Natural World: Discover, Diversify, and Deliver Microorganisms themselves have been the richest source of antibiotics; with 99% of the known microbial species as yet uncultured, these clearly are untapped sources of novel molecules.
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are a predominant strategy in natural microbial communities for killing neighboring strains; for example, bacteriocidic microcins secreted by one strain of E coli kill neighboring strains selectively but have minimal effect on the microbial community.
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· A-6.5 Increased research on bacterial cell death, including investigation of programmed cell death and how antibacterials kill to exploit new strategies for the elimination of pathogens. Developing Synthetic Molecules: Diversity, Bioactivity, and Specificity In addition to discovering and elaborating on the bioactive compounds made by bacteria themselves, the design of synthetic antibiotic molecules should also be pursued.
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Another promising direction for antimicrobial chemical libraries is genetically programmable small molecules (Li and Liu 2004; Halpin et al. 2004; Halpin and Harbury 2004a,b)
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Such a historical and biographical approach is unusual in drug development and in biomedical research, but may reinvigorate now-ignored research that showed promise. Screening Issues: How to Find Functional Properties in Candidate Molecules If it becomes possible to generate a multitude of diverse molecules, the next challenge is to improve the ability to screen them for antibiotic potential.
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A few hundred antimicrobial small molecules would become standard probes to provide response patterns with which new candidate molecules could be compared. In target-based screens, greater emphasis needs to be placed on increasing the likelihood of success in cell penetration and persistence of active molecules.
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To improve the identification and characterization of bioactive compounds, the committee recommends the following: · A-8.1 Development of cell-based screening techniques that collect detailed information on cell metabolism through gene arrays, metabolome profiling, and other measurements. · A-8.2 Increased research on the chemical properties necessary for cell permeability and retention.
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(1999) Trends in infectious disease mortality in the United States during the 20th century.
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(2003) Quorum sensing and its relevance to infectious diseases.
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(2005) Mycobacterium tuberculosis isocitrate lyases 1 and 2 are jointly required for in vivo growth and virulence.
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(2001) Using Internet discussion of antimicrobial susceptibility databases for continuous quality improvement of the testing and management of antimicrobial resistance.
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(2005) Integrating Escherichia coli antimicrobial susceptibility data from multiple surveillance programs.
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