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Sci Rep. 2018 May 8;8(1):7263. doi: 10.1038/s41598-018-25407-7.

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

Author information

1
BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India.
2
Centre for Cellular and Molecular Platforms (C-CAMP), National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India.
3
St. John's Research Institute, 100 Feet Rd, John Nagar, Koramangala, Bengaluru, Karnataka, 560034, India.
4
TheraIndx Lifesciences Pvt. Ltd., Sy No. 27, Deganahalli, Budihal Post, Nelamangala, Karnataka, 562123, India.
5
Syngene International Ltd., Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka, 560099, India.
6
BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India. santanu@bugworksresearch.com.

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.

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