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- W3105279918 abstract "Abstract Antibiotic resistance is a worldwide challenge. A potential approach to block resistance is to simultaneously inhibit WT and known escape variants of the target bacterial protein. Here we applied an integrated computational and experimental approach to discover compounds that inhibit both WT and trimethoprim (TMP) resistant mutants of E. coli dihydrofolate reductase (DHFR). We identified a novel compound (CD15-3) that inhibits WT DHFR and its TMP resistant variants L28R, P21L and A26T with IC 50 50-75 µM against WT and TMP-resistant strains. Resistance to CD15-3 was dramatically delayed compared to TMP in in vitro evolution. Whole genome sequencing of CD15-3 resistant strains showed no mutations in the target folA locus. Rather, gene duplication of several efflux pumps gave rise to weak (about twofold increase in IC 50 ) resistance against CD15-3. Altogether, our results demonstrate the promise of strategy to develop evolution drugs - compounds which block evolutionary escape routes in pathogens." @default.
- W3105279918 created "2020-11-23" @default.
- W3105279918 creator A5003188309 @default.
- W3105279918 creator A5011258863 @default.
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- W3105279918 creator A5076972352 @default.
- W3105279918 date "2020-10-31" @default.
- W3105279918 modified "2023-09-22" @default.
- W3105279918 title "Development of antibacterial compounds that block evolutionary pathways to resistance" @default.
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- W3105279918 doi "https://doi.org/10.1101/2020.10.30.362582" @default.
- W3105279918 hasPublicationYear "2020" @default.
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