Presented By: Center for the Discovery of New Medicines - CDNM
Drug Discovery Lecture Series: "Antibiotic Discovery for Tuberculosis: Returning to a “Golden Target”, RNA Polymerase"
George Garcia, Ph.D, Professor and Chair of Medicinal Chemistry, College of Pharmacy
Tuberculosis is one of the most important world health problems, responsible for 9.6 million new cases, 1.2 million TB-associated deaths (400,000 of those among HIV-positive people) in 2014 (WHO). Increases in the occurrence of multidrug-resistant TB (MDR-TB) and extensively drug-resistant TB (XDR-TB) have become an increasingly problematic health crisis. Clearly there is a critical unmet need for the development of novel antibiotics against M. tuberculosis (MTB) to overcome resistance to current therapeutics. However, only one new drug (bedaquiline) with a novel target, the mycobacterial ATP synthase, has been approved for the treatment of tuberculosis in the last ~45 years. The lack of success in inhibiting novel targets suggests that the reinvestigation of targets of previously effective drugs (i.e., “Golden Targets”) is a worthy approach.
The MTB RNA polymerase (RNAP) is a proven and attractive target because it is essential for bacterial survival, and there is low similarity between prokaryotic and eukaryotic RNAPs. The rifamycins (RIFs) are very potent inhibitors of MTB RNAP; however, these agents suffer from resistance (RIFR) via mutation of the target RNAP and drug-drug interactions that result from RIF activation of the human pregnane X receptor (hPXR) (particularly problematic in TB/HIV co-infection).
Dr. Garcia is conducting a multi-disciplinary and comprehensive program that involves high-throughput screening (HTS), X-ray crystal structure determinations of inhibitor•RNAP complexes, structure-based analogue synthesis, in vitro RNAP inhibition evaluation, microbiological assessments against M. tuberculosis, and studies to minimize hPXR activation towards uncovering novel agents to address current MTB treatment limitations. The first set of RIF analogues exhibit enhanced activity against RIFR RNAP, reduced hPXR activation for one compound, and binding to RNAP in the designed mode as shown by our X-ray crystal structures. A second approach to novel small molecule inhibitors involves development of an efficient in vitro RNAP assay, which has been scaled for HTS. The seminar will focus on this latter campaign and subsequent follow-up studies.
The MTB RNA polymerase (RNAP) is a proven and attractive target because it is essential for bacterial survival, and there is low similarity between prokaryotic and eukaryotic RNAPs. The rifamycins (RIFs) are very potent inhibitors of MTB RNAP; however, these agents suffer from resistance (RIFR) via mutation of the target RNAP and drug-drug interactions that result from RIF activation of the human pregnane X receptor (hPXR) (particularly problematic in TB/HIV co-infection).
Dr. Garcia is conducting a multi-disciplinary and comprehensive program that involves high-throughput screening (HTS), X-ray crystal structure determinations of inhibitor•RNAP complexes, structure-based analogue synthesis, in vitro RNAP inhibition evaluation, microbiological assessments against M. tuberculosis, and studies to minimize hPXR activation towards uncovering novel agents to address current MTB treatment limitations. The first set of RIF analogues exhibit enhanced activity against RIFR RNAP, reduced hPXR activation for one compound, and binding to RNAP in the designed mode as shown by our X-ray crystal structures. A second approach to novel small molecule inhibitors involves development of an efficient in vitro RNAP assay, which has been scaled for HTS. The seminar will focus on this latter campaign and subsequent follow-up studies.
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