Alanzi Abdullah R, Alanazi Ahmad Z, Alhazzani Khalid, Abbas Munawar
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
Sci Rep. 2025 Jul 3;15(1):23776. doi: 10.1038/s41598-025-08107-x.
Klebsiella michiganensis, an emerging multidrug-resistant pathogen, poses a significant public health threat. This study employed subtractive genomics to identify potential therapeutic targets in K. michiganensis THO-011. From 4,024 predicted open reading frames, we identified non-redundant, human non-homologous proteins and analyzed them for essentiality, subcellular localization, and metabolic pathway involvement. Two promising druggable targets, WP_004097788.1 and WP_219541799, vital for bacterial survival, were identified. Using AlphaFold-predicted structures, virtual screening of 10,000 natural compounds from the LOTUS database, alongside DrugBank controls, identified LTS0037797 and LTS0037810 as top inhibitors. Glide Gscores ranked these compounds, with validation via MM-GBSA binding energy and molecular dynamics simulations confirming their stability and binding efficacy. These findings highlight novel therapeutic strategies against K. michiganensis, with further in vitro studies necessary to advance these inhibitors to clinical application.
密歇根克雷伯菌是一种新出现的多重耐药病原体，对公众健康构成重大威胁。本研究采用消减基因组学方法来鉴定密歇根克雷伯菌THO - 011中的潜在治疗靶点。从4024个预测的开放阅读框中，我们鉴定出非冗余的、与人类无同源性的蛋白质，并对其进行必需性、亚细胞定位和代谢途径参与情况分析。确定了两个对细菌存活至关重要的有前景的可成药靶点，即WP_004097788.1和WP_219541799。利用AlphaFold预测的结构，对来自LOTUS数据库的10000种天然化合物以及DrugBank对照进行虚拟筛选，确定LTS0037797和LTS0037810为顶级抑制剂。Glide G分数对这些化合物进行了排名，通过MM - GBSA结合能和分子动力学模拟进行验证，证实了它们的稳定性和结合效力。这些发现突出了针对密歇根克雷伯菌的新型治疗策略，还需要进一步的体外研究将这些抑制剂推进到临床应用阶段。
