Scientific Reports (May 2018)

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

  • Shahul Hameed P,
  • Nagakumar Bharatham,
  • Nainesh Katagihallimath,
  • Sreevalli Sharma,
  • Radha Nandishaiah,
  • Anirudh P. Shanbhag,
  • Teby Thomas,
  • Riya Narjari,
  • Maitrayee Sarma,
  • Purnendu Bhowmik,
  • Prakruthi Amar,
  • Rajani Ravishankar,
  • Ramesh Jayaraman,
  • Kubendran Muthan,
  • Ramesh Subbiah,
  • Vasanthi Ramachandran,
  • V. Balasubramanian,
  • Santanu Datta

DOI
https://doi.org/10.1038/s41598-018-25407-7
Journal volume & issue
Vol. 8, no. 1
pp. 1 – 18

Abstract

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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.