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12th International Conference on STRUCTURAL AND MOLECULAR BIOLOGY

Osaka, Japan

Santanu Datta

Santanu Datta

Bugworks Research, India

Title: Novel antibacterial series identified through integrated drug discovery technology platform


Biography: Santanu Datta


The mechanism of efflux is a tour de force in bacterial armoury that has thwarted discovery of novel antibiotics. We reported the discovery of a novel series of compounds with potent antibacterial properties that is devoid of efflux liability. Starting from a phenotypic screen with a library diverse molecule on a panel of efflux deficient E. coli strains, we progressed a nitro-thiophene carboxamide derivative that effluxed selectively via the efflux pump AcrAB-TolC. Binding of these molecules to AcrB was evaluated by fluorescent thermal shift and Nile red dye-based assays. Prospective in silico modeling using computational methodologies viz. molecular docking and MD simulations were done. Iterative design and synthesis based on binding potency by in vitro assays and in silico prediction led to the generation of a series of molecules that were potent on wild type and multi-drug resistant clinical isolates of E. coliShigella spp. and Salmonella spp. Using a novel system biology reverse MOA (mechanism of action) protocol that measures the synergistic sensitivity on library of specially curated single gene knockout sub-library from the KIEO strains we identified these molecules to be pro-drugs that are activated inside E. coli by specific bacterial nitro reductases NfsA and NfsB. The conversion of these pro-drugs was characterized by in vitro enzymatic assay of purified NfsA and NfsB. Furthermore, these molecules were shown to be bactericidal and efficacious in a mouse thigh infection model.