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

Autor:	Hameed P S; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Bharatham N; Centre for Cellular and Molecular Platforms (C-CAMP), National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Katagihallimath N; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Sharma S; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Nandishaiah R; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Shanbhag AP; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Thomas T; St. John's Research Institute, 100 Feet Rd, John Nagar, Koramangala, Bengaluru, Karnataka, 560034, India., Narjari R; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Sarma M; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Bhowmik P; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Amar P; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Ravishankar R; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Jayaraman R; TheraIndx Lifesciences Pvt. Ltd., Sy No. 27, Deganahalli, Budihal Post, Nelamangala, Karnataka, 562123, India., Muthan K; Syngene International Ltd., Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka, 560099, India., Subbiah R; Syngene International Ltd., Plot 2 & 3, Bommasandra Industrial Estate - Phase-IV, Bommasandra-Jigani Link Road, Bengaluru, Karnataka, 560099, India., Ramachandran V; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Balasubramanian V; BUGWORKS Research India Pvt. Ltd., Centre for Cellular & Molecular Platforms, National Centre for Biological Sciences, GKVK, Bellary Rd, Bengaluru, Karnataka, 560065, India., Datta S; 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.
Jazyk:	angličtina
Zdroj:	Scientific reports [Sci Rep] 2018 May 08; Vol. 8 (1), pp. 7263. Date of Electronic Publication: 2018 May 08.
DOI:	10.1038/s41598-018-25407-7
Abstrakt:	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.
Databáze:	MEDLINE
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