Grant: Foundation Grant

<html> <body> <p>My research group is exploring largely uncharted aspects of complex biology in bacteria that underlie bacterial survival. The ultimate goal is to contribute fresh directions for new antibacterial therapies. This stage 2 foundation application follows a stage 1 application that was ranked 53 out of a total of 1366 applications.<br> <br> Antibiotic drug resistance has reached crisis proportions, principally because modern industrial drug discovery efforts have failed to provide new antibiotics. The reasons for failure are manifold, however, a lack of understanding of the basic biology has played a large part. Where modern drug discovery emphasizes reductionist efforts on validated targets and lead chemicals, there is a profound risk of failure if the complexity of the target, indeed the system, is underestimated.<br> <br> Hence the proposed program includes on-going investigations of enigmatic antibacterial targets such as Gram-positive wall teichoic acid synthesis and ribosome biogenesis. It also includes plans to continue developing chemical biology platforms to enable the discovery and characterization of new chemical probes of bacterial cell systems. We pride ourselves on creative screening approaches that yield novel chemical probes with utility as tool compounds in exploring the biology. Occasionally these probes have potential as leads for new antibiotics. With routine success in pilot scale screens, e.g., ~30,000 diverse synthetic compounds, we propose now to expand our efforts more than ten-fold and to screen natural product extracts. The goal is to discover many more new chemical probes of bacteria with a better chance of identifying compounds with the potential for drug development.<br> <br> Expertise within my group spans chemistry, biology and computation. Our efforts to date have resulted in new knowledge, platforms, chemical probes and lead compounds for antibacterial research. We have made key advances in projects focused on enigmatic aspects of bacterial physiology and on platforms for the discovery of new chemical probes of bacterial cell systems. These projects have characteristically involved the development of innovative genetic or chemical screens that have yielded new targets and antibacterial chemical matter. Indeed, chemical and high throughput biology are hallmark approaches for my group. I will continue to build a diverse multidisciplinary team that is capable of addressing gaps in knowledge and technology in antibacterial drug discovery. Further, I propose continued collaboration with a complementary cadre of investigators that encompass expertise in structural biology, animal models, natural products, medicinal chemistry and preclinical drug development.<br> <br> In training young scientists, I stress creative thinking, technical skills, communication, independence and career development. The context for this academic training environment is unusual, however, in that it emphasizes drug discovery. Exposure to the thinking and paradigms of modern drug discovery is a unique benefit as are the interactions that my group has with the pharmaceutical sector through collaborations and sponsored research. These can be life-changing, in my experience, when it comes to alternate career paths in the private sector. With first-rate infrastructure, technical assistance and critical mass, my trainees expect to make ground-breaking contributions to the field. This will be the currency of their success and is an overriding goal for all my trainees.</p> </body> </html>