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 sp...
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oai:doaj.org-article:7ea9439734d44af0a1b4d9b9699003a22021-12-02T11:41:24ZNitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy10.1038/s41598-018-25407-72045-2322https://doaj.org/article/7ea9439734d44af0a1b4d9b9699003a22018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-25407-7https://doaj.org/toc/2045-2322Abstract 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.Shahul Hameed PNagakumar BharathamNainesh KatagihallimathSreevalli SharmaRadha NandishaiahAnirudh P. ShanbhagTeby ThomasRiya NarjariMaitrayee SarmaPurnendu BhowmikPrakruthi AmarRajani RavishankarRamesh JayaramanKubendran MuthanRamesh SubbiahVasanthi RamachandranV. BalasubramanianSantanu DattaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-18 (2018) |
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Medicine R Science Q 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 Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy |
| description |
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. |
| format |
article |
| author |
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 |
| author_facet |
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 |
| author_sort |
Shahul Hameed P |
| title |
Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy |
| title_short |
Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy |
| title_full |
Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy |
| title_fullStr |
Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy |
| title_full_unstemmed |
Nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: Mechanism of action and Efficacy |
| title_sort |
nitrothiophene carboxamides, a novel narrow spectrum antibacterial series: mechanism of action and efficacy |
| publisher |
Nature Portfolio |
| publishDate |
2018 |
| url |
https://doaj.org/article/7ea9439734d44af0a1b4d9b9699003a2 |
| work_keys_str_mv |
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1718395407275393024 |