Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy.

ABSTRACT: The mechanism of efflux is a tour-de-force in the bacterial armoury that has thwarted the development of novel antibiotics. We report the discovery of a novel chemical series with potent antibacterial properties that was engineered to overcome efflux liability. Compounds liable to efflux specifically via the Resistance Nodulation and cell Division (RND) pump, AcrAB-TolC were chosen for a hit to lead progression. Using structure-based design, the compounds were optimised to lose their binding to the efflux pump, thereby making them potent on wild-type bacteria. We discovered these compounds to be pro-drugs that require activation in E. coli by specific bacterial nitroreductases NfsA and NfsB. Hit to lead chemistry led to the generation of compounds that were potent on wild-type and multi-dr

SUBMITTER: Hameed P S 

PROVIDER: S-EPMC5940854 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature