Singh Atamjit, Kaur Kirandeep, Mohana Pallvi, Singh Karanvir, Sharma Aman, Prajapati Jignesh, Goswami Dweipayan, Khosla Neha, Kaur Uttam, Kaur Rajanbir, Kaur Rajinder, Rana Abhineet, Kour Sandeep, Ohri Puja, Arora Saroj, Chadha Renu, Singh Bedi Preet Mohinder
Department of Pharmaceutical Sciences, Guru Nanak Dev University Amritsar Punjab 143005 India
Department of Botanical and Environmental Sciences, Guru Nanak Dev University Amritsar Punjab 143005 India.
RSC Med Chem. 2023 Nov 20;15(1):234-253. doi: 10.1039/d3md00580a. eCollection 2024 Jan 25.
Bacterial resistance toward available therapeutic agents has become a nightmare for the healthcare system, causing significant mortality as well as prolonged hospitalization, thereby needing the urgent attention of research groups working on antimicrobial drug development worldwide. Molecular hybridization is a well-established tool for developing multifunctional compounds to tackle drug resistance. Inspired by the antibacterial profiles of isatin and thymol, along with the efficiency of a triazole linker in molecular hybridization, herein, we report the design, synthesis and antibacterial activity of a novel series of triazole tethered thymol-isatin hybrids. Most of the hybrids exhibited a broad-spectrum antibacterial efficacy against standard human pathogenic as well as clinically isolated multidrug-resistant bacterial strains listed in the WHO's 'priority pathogen' list and also in the ESKAPE group. Among them, hybrid compound AS8 was the most effective against methicillin-resistant (MIC = 1.9 μM and MBC = 3.9 μM), exhibiting biofilm inhibitory potential. AS8 exhibited dehydrosqualene synthase (CrtM) inhibitory potential in MRSA and decreased the production of virulence factor staphyloxanthin, which is one of the key mechanisms of its anti-MRSA efficacy, which was further supported by molecular docking and simulation studies. Moreover, AS8 was found to be non-toxic and showed a potent antibacterial efficacy (90% survival at 10 mg kg) as well as a modulated immune response in the larva-based () model of systemic infections. Overall findings confirmed that AS8 can be a promising candidate or take the lead in the treatment and further drug development against drug-resistant infectious diseases, especially against MRSA infections.
细菌对现有治疗药物的耐药性已成为医疗系统的噩梦，导致大量死亡以及住院时间延长，因此需要全球致力于抗菌药物研发的研究团队予以紧急关注。分子杂交是开发多功能化合物以应对耐药性的成熟工具。受异吲哚酮和百里酚的抗菌特性以及三唑连接子在分子杂交中的效率启发，在此，我们报告了一系列新型三唑连接的百里酚-异吲哚酮杂化物的设计、合成及抗菌活性。大多数杂化物对世界卫生组织“重点病原体”清单及ESKAPE组中列出的标准人类致病以及临床分离的多重耐药菌株均表现出广谱抗菌效果。其中，杂化化合物AS8对耐甲氧西林金黄色葡萄球菌最有效（MIC = 1.9 μM，MBC = 3.9 μM），具有生物膜抑制潜力。AS8在耐甲氧西林金黄色葡萄球菌中表现出对脱氢鲨烯合酶（CrtM）的抑制潜力，并降低了毒力因子金黄色色素的产生，这是其抗耐甲氧西林金黄色葡萄球菌功效的关键机制之一，分子对接和模拟研究进一步支持了这一点。此外，发现AS8无毒，在基于幼虫的全身感染模型中显示出强效抗菌效果（10 mg/kg时存活率为90%）以及调节的免疫反应。总体研究结果证实，AS8有望成为治疗耐药性传染病尤其是耐甲氧西林金黄色葡萄球菌感染的候选药物或引领进一步的药物开发。
