Kumar Gautam, Akhir Abdul, Srivatsav Aswin T, Saxena Deepanshi, Maitra Rahul, Gaonkar Deepak Datta, Kapoor Shobhna, Chopra Sidharth, Narayan Rishikesh
Department of Chemistry, Indian Institute of Technology Bombay, Powai, Maharashtra, 400076, India.
Department of Molecular Microbiology and Immunology, CSIR-Central Drug Research Institute, Lucknow, Uttar Pradesh, 226031, India.
Eur J Med Chem. 2025 Oct 15;296:117805. doi: 10.1016/j.ejmech.2025.117805. Epub 2025 May 25.
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 (sp-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.
抗菌耐药性被视为一场无声的大流行，对人类有着可怕的预测。金黄色葡萄球菌及其耐甲氧西林和耐万古霉素的变体已被确定为与耐药性相关死亡的一些主要病原体。事实证明，寻找针对这些病原体的新型药物非常困难。具有新型化学类型和/或新型作用机制的化合物已被提出作为创新标准之一。为了寻找具有潜在生物活性的新型化学类型，伪天然产物假说依赖于通过以生物学上预先验证且合成上易于处理的方式组合天然产物片段来设计迄今未知的骨架。在此，我们报告了一种源自吲哚托烷伪天然产物的新型抗菌化学类型的发现，它对金黄色葡萄球菌的敏感菌株和耐药菌株均具有强效活性。命中化合物7af具有强大的杀菌性质，与FDA批准的庆大霉素显示出协同作用，并且在第28代之前不会诱导耐药性。它能消除高达5%的预先形成的生物膜，并在小鼠皮肤感染模型中显示出良好的体内疗效。尽管存在硝基，但7af在金黄色葡萄球菌和耻垢分枝杆菌中均不作为硝基还原酶的底物，因此，暗示了一种不同的作用机制。出色的结构特征（富含sp、存在氢键供体和受体、极性等）与引人注目的抗菌活性谱相结合，使7af成为针对耐药菌株进一步开发的经过验证的先导化合物。
