In:
Scientific Reports, Springer Science and Business Media LLC, Vol. 8, No. 1 ( 2018-05-08)
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-drug resistant clinical isolates of E. coli , Shigella spp ., and Salmonella spp . These compounds are bactericidal and efficacious in a mouse thigh infection model.
Type of Medium:
Online Resource
ISSN:
2045-2322
DOI:
10.1038/s41598-018-25407-7
Language:
English
Publisher:
Springer Science and Business Media LLC
Publication Date:
2018
detail.hit.zdb_id:
2615211-3
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