P.G. Department of Genetics, Ashok and Rita Patel Institute of Integrated Study and Research in Biotechnology and Allied Sciences (ARIBAS), Sardar Patel University, Anand, India.
Dr. Vikram Sarabhai Institute of Cell and Molecular Biology, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, India.
Microb Drug Resist. 2021 May;27(5):602-615. doi: 10.1089/mdr.2020.0196. Epub 2020 Oct 13.
Incidence of drug resistance in clinical isolates of methicillin-resistant (MRSA) is attributed to its diverse repertoire of virulence factors. Of these virulence determinants, Panton-Valentine Leukocidin (PVL) has been experimentally validated as a prospective drug target due to its conspicuous and comprehensive role in nosocomial infections. This study encompassed an approach to elucidate the antimicrobial potentiality of human cathelicidin LL-37 against PVL toxin of MRSA. Molecular docking studies of LL-37 and its segments with the PVL toxin subunits LukS and LukF were carried out using PatchDock server and the results were refined using FireDock server. The paramount ligand-receptor combination was selected and analyzed based on diverse parametric attributes and compared with the commercial inhibitors of PVL viz. Andrimid, Beclobrate, Beta-sitosterol, Diathymosulfone, and Probucol to determine the most potent inhibitor among them. Our results elucidated that the interaction of LL-37 with the LukS subunit of PVL toxin (minimum global energy of -61.82 kcal/mol) depicted 34 molecular interactions, while the commercial PVL inhibitors depicted fewer and insubstantial interactions. SWISS-ADME (Absorption, Distribution, Metabolism, and Excretion) and ToxinPred analysis of LL-37 further corroborated its null potency of toxicity in systemic milieu. The results obtained may credit this study as basis for the development of LL-37 as a potential inhibitor against virulent MRSA toxins, thereby exalting the treatment regimes for nosocomial infections in health care facilities worldwide.
耐甲氧西林金黄色葡萄球菌（MRSA）临床分离株的耐药性的产生归因于其丰富多样的毒力因子。在这些毒力决定因素中，Panton-Valentine 白细胞素（PVL）已被实验验证为一个有前途的药物靶点，因为它在医院感染中具有显著和全面的作用。本研究采用一种方法来阐明人源抗菌肽 LL-37 对 MRSA 的 PVL 毒素的抗菌潜力。使用 PatchDock 服务器对 LL-37 及其与 PVL 毒素亚基 LukS 和 LukF 的片段进行分子对接研究，并用 FireDock 服务器对结果进行细化。根据不同的参数属性选择并分析最重要的配体-受体组合，并与 PVL 的商业抑制剂（如 Andrimid、Beclobrate、Beta-sitosterol、Diathymosulfone 和 Probucol）进行比较，以确定其中最有效的抑制剂。我们的研究结果表明，LL-37 与 PVL 毒素的 LukS 亚基的相互作用（最低总能量为-61.82 kcal/mol）描述了 34 个分子相互作用，而商业 PVL 抑制剂则描述了较少且微不足道的相互作用。SWISS-ADME（吸收、分布、代谢和排泄）和 ToxinPred 对 LL-37 的分析进一步证实了它在全身环境中没有毒性。这项研究的结果可能使它成为开发 LL-37 作为潜在抑制剂对抗毒力 MRSA 毒素的基础，从而提高世界各地医疗机构医院感染的治疗方案。
