In silico analysis of zosurabalpin-LptB2FG binding in Acinetobacter spp., Klebsiella pneumoniae, and Shigella flexneri: mechanisms underlying its differential efficacy.

In silico pharmacology Pub Date : 2025-04-16 eCollection Date: 2025-01-01 DOI:10.1007/s40203-025-00343-3

Meryam Magri, Rachid Eljaoudi, Lahcen Belyamani, Azeddine Ibrahimi, El Mehdi Bouricha

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Abstract

Zosurabalpin, a novel tethered macrocyclic peptide antibiotic, exhibits potent activity against Acinetobacter spp., particularly carbapenem-resistant Acinetobacter baumannii (CRAB). Zosurabalpin inhibits lipopolysaccharide (LPS) transport by targeting the LptB2FG protein complex, resulting in toxic LPS accumulation and bacterialdeath. This study investigates zosurabalpin's molecular specificity against Acinetobacter spp., its ineffectiveness against Klebsiella pneumoniae, and its potential efficacy against Shigella flexneri. Comparative analysis of LptB2FG sequences and structures, revealed significant differences in LptB2FG protein conformations, pocket geometry and electrostatic surface surrounding the binding pocket among the three species, which may influence zosurabalpin binding. Docking results for zosurabalpin showed lower binding affinities for K. pneumoniae and S. flexneri compared to Acinetobacter baylyi. Additionally, other zosurabalpin derivatives were tested showing improved binding affinities for K. pneumoniae but not for S. flexneri. These findings underscore the need for tailored zosurabalpin derivatives to enhance efficacy against a broader spectrum of Gram-negative bacteria.

Supplementary information: The online version contains supplementary material available at 10.1007/s40203-025-00343-3.

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zosurabalpin-LptB2FG在不动杆菌、肺炎克雷伯菌和福氏志贺氏菌中的结合：其不同疗效的机制。

Zosurabalpin是一种新型栓系大环肽抗生素，对不动杆菌，特别是耐碳青霉烯鲍曼不动杆菌（CRAB）具有较强的抗药活性。Zosurabalpin通过靶向LptB2FG蛋白复合物抑制脂多糖（LPS）运输，导致毒性LPS积累和细菌死亡。本研究探讨zosurabalpin对不动杆菌的分子特异性、对肺炎克雷伯菌的无效性以及对福氏志贺氏菌的潜在药效。通过对LptB2FG序列和结构的比较分析，发现三种LptB2FG蛋白构象、结合袋几何形状和结合袋周围的静电表面存在显著差异，这可能会影响zosurabalpin的结合。zosurabalpin的对接结果显示，与baylyi不动杆菌相比，zosurabalpin对肺炎克雷伯菌和flexneri的结合亲和力较低。此外，对其他zosurabalpin衍生物进行了测试，显示出对肺炎克雷伯菌的结合亲和力，但对弗氏沙门氏菌没有亲和力。这些发现强调需要定制zosurabalpin衍生物，以增强对更广泛的革兰氏阴性细菌的功效。补充资料：在线版本提供补充资料，网址为10.1007/s40203-025-00343-3。

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In silico pharmacology

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