Speaker: Dr. Paul Blount from the University of Texas Southwestern Medical Center
Title: Quest for the Next Generation of Antibiotics: A Bacterial Mechanosensor, MscL, as a Novel Drug Target
Abstract: MscL is a highly conserved bacterial mechanosensitive channel found in the vast majority of bacterial species including most pathogens. It normally serves as a biological emergency release valve: upon osmotic downshock it opens a huge 30Å pore that allows for the rapid release of many accumulated cytoplasmic components, including potassium and glutamate, thus preventing cell lysis. When the channel gates inappropriately, it leads to slowed growth or even cell death. MscL may therefore serve as a pharmacological target for novel antibiotics. From a High Throughput Screen (HTS), 22 chemical compounds that inhibit the growth of E. coli in a MscL-dependent and specific manner have been identified. Among these were four known antibiotics including Dihydrostreptomycin (DHS). We have found that DHS, and perhaps other antibiotics, use MscL as a pathway into the bacterial cell; thus, expression of the channel increases drug potency. Recently, we have begun to characterize a handful of the 18 novel compounds that were identified in the HTS. Preliminary findings indicate that the majority of these compounds do indeed modify MscL and increase its activity, and thus may serve as the seeds for deriving novel anti-bacterial agents.