Grant: Discovery Grants Program - Individual

Natural products have a well-documented track record of providing new active ingredients with a wide range of applications. Historically, one primary target area has been the pharmaceutical industry. As one example, the 2015 Novel Prize in Physiology or Medicine was jointly awarded to Campbell and Omura for the discovery of avermectins for the treatment of river blindness, and Tu for the discovery of the anti-malaria drug artemisinin. Natural products are also of great importance to the agriculture industry as over one third of all pesticides are natural products. Bacteria and fungi are prolific sources of bioactive agents and are particularly attractive as they provide a renewable resource. While numerous discoveries of natural products have been made, the rate of discovery of new natural products has declined in recent years. This could have a far-reaching effect on our daily lives as, for one example, the rate of discovery of new antibiotics has declined sharply and we may be facing the possibility of the world entering a "post-antibiotic era". The general aim of this proposal is to conduct basic research in natural products chemistry and associated microbiology to develop innovative tools/methods to invigorate natural product discovery. Research will proceed along two fronts. One focus will address the Great Plate Count Anomaly which describes the observation that only 1 % of microbes in an environmental sample can be cultured. The critical step in this process is a `domestication period' of individual bacterial cultures in the environment from which the bacteria were isolated. We will develop and test a tool that we believe will facilitate the culture of a greatly increased percentage of microbes. The second focus will address the issue of "silent" natural products in bacteria and fungi. These are defined as natural products that are encoded in a microbe's DNA but are not produced under standard conditions. We will investigate a number of approaches individually and in combination to develop tools to induce production of silent natural products. While there has been substantial effort in natural product discovery for applications in human health, there has been much less effort in veterinary medicine. This project will test new natural products identified in this research program for applications as antimicrobial agents for use in companion animals. For ethical reasons, `last resort' antimicrobials such as vancomycin are reserved solely for the treatment of infections in humans and are not to be used in animals; therefore, a pressing need exists in veterinary medicine for the discovery of novel antibiotics to treat infections caused by drug-resistant pathogens. Overall, if successful, the proposed research will develop tools/methods that will greatly enhance the rate of discovery of new natural products. Given the diverse applications of natural products, completion of the scientific goals could have a significant impact.