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4178123
Solid-phase synthesis of des-hydroxy pseudouridimycin analogs | Poster Board #918
Date
March 24, 2025
The emergence of drug-resistant pathogens has led to increased demand for the discovery and development of new antibiotics that mitigate resistance mechanisms. Bacterial RNA polymerase (RNAP) is an enzyme that is essential for bacterial survival and is a target of several FDA-approved drugs. However, resistance to these drugs emerges rapidly through mutations in RNAP that alter binding sites but not enzymatic function. Pseudouridimycin (PUM) is a naturally occurring C-nucleoside antibiotic isolated from Streptomyces albus. In contrast to currently available RNAP-targeting drugs, PUM binds to the RNAP active site. As a result, mutations that might weaken PUM binding would also compromise RNAP function. PUM exhibits greater than 10-fold selectivity for bacterial RNAP over human RNAP and is not cytotoxic to mammalian cells. PUM displays antibacterial activity against drug-resistant and multidrug-resistant Streptococci pyogenes in vitro and in vivo. These properties make PUM a promising drug candidate for further development. Our research group identified two intramolecular decomposition pathways of PUM which greatly compromise its antimicrobial activity and clinical potential. At physiological pH, scission of the hydroxamate bond causes complete loss of activity and modifications to the hydroxamate bond have been found to considerably enhance its stability. Here, we describe the synthesis and biological evaluation of des-hydroxy PUM analogs on solid support. These analogs feature modified dipeptide tails in search of lead compounds with enhanced stability and RNAP inhibitory activity. Our solid-phase approach enables the rapid generation of PUM analog libraries for structure-activity relationship studies. To date we have synthesized des-hydroxy analogs which exhibit antimicrobial activity in the low to sub-micromolar ranges with greatly enhanced stability relative to the natural product.
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