Evolution of Stress-Induced Bacterial Toxins

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DESCRIPTION (provided by applicant): Bacteriocins comprise a large, functionally diverse family of toxins often described as the microbial world's first choice in defense strategies. In contrast to the limited taxonomic distribution of classical antibiotic production, bacteriocins are produced by all bacterial lineages surveyed to date. Bacteriocins display a unique form of expression that is confined to stressful conditions and is lethal to the producing cell. Little is known about the mechanisms involved in this expression system. The goal of this proposal is to experimentally identify environmental biotic and a-biotic factors that play a role in colicin induction and to assess the impact of such production on the producing and target bacterial populations. The proposed combination of empirical and theoretical studies will provide the first comprehensive investigation into the ecological role and dynamics of bacteriocin production and the resulting impact of toxin expression on the population dynamics of the target bacteria. These data are both timely and critical from a human health perspective. If we have learned anything from our overuse of classical antibiotics, it is that as we artificially increase the presence of these naturally occurring antimicrobials, the bacterial communities rapidly respond with the evolution of antibiotic resistance. Drugs that required 10+ years of research and up to a billion dollars investment are rendered useless in short order. If we had invested in a thorough investigation into the natural roles played by classical antibiotics and the resulting responses of the microbial community to their presence, we might have designed therapeutic approaches that would have limited the rate and the scope of resistance evolution and thus extended the lifespan of these critical drugs. Bacteriocins are already used as preservatives in certain meats and cheeses and are currently being tested for use in the treatment of a variety of bacterial infections. The widespread use of these potent, narrow spectrum drugs is rapidly approaching. We need to know NOW how to advise pharmaceutical companies and clinicians how best to deploy these potent toxins in a manner that will retain their utility for as long as is possible. The experiments proposed here will provide exactly the sort of information required to make informed decisions about how and when to employ bacteriocins in therapeutic treatment and will allow us to make predictions as to the likely response by the bacterial community.