Antibacterial agent 7af (Indian Institute of Technology Bombay)

Antimicrobial resistance is perceived as a silent pandemic with dire predictions for humanity. S. aureus and its methicillin- and vancomycin-resistant variants have been identified as some of the leading pathogens for deaths associated with resistance. The quest to discover novel agents against these pathogens has proven difficult. Compounds with novel chemotype and/or novel mechanism of action have been put forth as one of the innovation criteria. In search for novel chemotypes with potential bioactivity, Pseudo-Natural product hypothesis relies on designing hitherto unknown scaffolds by combining natural product fragments in a biologically pre-validated and synthetically tractable ways. Herein, we report the discovery of a novel antibacterial chemotype, derived from indotropane pseudo natural products, with potent activity against both susceptible and resistant strains of S. aureus. The hit compound, 7af possesses potent bactericidal nature, shows synergy with FDA-approved Gentamicin and doesn't induce resistance up to the 28th passage. It eradicates pre-formed biofilm by up to 5% and displays good in vivo efficacy in murine skin infection model. Despite the presence of nitro-group, 7af does not act as substrate of nitro-reductase enzyme in both S.aureus and M. smegmatis, thereby, hinting towards a different mechanism of action. Excellent structural features (sp³-rich, presence of H-bond donors and acceptors, polarity etc.) combined with a compelling antibacterial activity profile make 7af a validated lead compound for further development against resistant strains.