Medical and Biological Computing Laboratory, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Tamil Nadu, Vellore, 632014, India.
Department of Bio-Medical Sciences, School of Bio-Sciences and Technology, Vellore Institute of Technology (VIT), Tamil Nadu, Vellore, 632014, India.
Probiotics Antimicrob Proteins. 2024 Apr;16(2):459-473. doi: 10.1007/s12602-023-10067-5. Epub 2023 Mar 27.
The production of extended spectrum β-lactamases (ESBLs) in extensively drug-resistant (XDR) strains of Acinetobacter baumannii has created havoc amongst clinicians making the treatment procedure challenging. Carbapenem-resistant strains have displayed total ineffectiveness towards newer combinations of β-lactam-β-lactamase inhibitors (βL-βLI) in tertiary healthcare settings. Therefore, the present study was aimed to design potential β-lactamase antimicrobial peptide (AMP) inhibitors against ESBLs produced by the strains. We have constructed an AMP mutant library with higher antimicrobial efficacy (range: ~ 15 to 27%) than their parent peptides. The mutants were thoroughly screened based on different physicochemical and immunogenic properties revealing three peptides, namely SAAP-148, HFIAP-1, myticalin-C6 and their mutants with safe pharmacokinetics profile. Molecular docking highlighted SAAP-148_M15 displaying maximum inhibitory potential with lowest binding energies against NDM1 (- 1148.7 kcal/mol), followed by OXA23 (- 1032.5 kcal/mol) and OXA58 (- 925.3 kcal/mol). The intermolecular interaction profiles displayed SAAP-148_M15 exhibiting hydrogen bonds and van der Waals hydrophobic interactions with the crucial residues of metallo β-lactamase [IPR001279] and penicillin-binding transpeptidase [IPR001460] domains. Coarse-grained clustering and molecular dynamics simulations (MDS) further validated the stable backbone profile and minimal residue-level fluctuations of the protein-peptide complex that were maintained throughout the simulation timeframe. The present study hypothesised that the combination of sulbactam (βL) with SAAP-148_M15 (βLI) holds immense potential in inhibiting the ESBLs alongside restoration of sulbactam activity. The current in silico findings upon further experimental validations can pave path towards designing of successful therapeutic strategy against XDR strains of A. baumannii.
广泛耐药（XDR）鲍曼不动杆菌中产生的扩展谱β-内酰胺酶（ESBLs）给临床医生带来了极大的困扰，使治疗过程变得极具挑战性。碳青霉烯类耐药菌株对三级医疗机构中新型β-内酰胺-β-内酰胺酶抑制剂（βL-βLI）组合完全无效。因此，本研究旨在设计针对该菌株产生的 ESBL 的潜在β-内酰胺酶抗菌肽（AMP）抑制剂。我们构建了一个 AMP 突变体文库，其抗菌功效比亲本肽高（范围：~15 至 27%）。根据不同的理化性质和免疫原性对突变体进行了全面筛选，揭示了三种肽，即 SAAP-148、HFIAP-1、myticalin-C6 及其具有安全药代动力学特征的突变体。分子对接突出显示 SAAP-148_M15 对 NDM1（-1148.7 kcal/mol）显示出最大的抑制潜力，具有最低的结合能，其次是 OXA23（-1032.5 kcal/mol）和 OXA58（-925.3 kcal/mol）。分子间相互作用谱显示，SAAP-148_M15 与金属β-内酰胺酶 [IPR001279] 和青霉素结合转肽酶 [IPR001460] 结构域的关键残基形成氢键和范德华疏水相互作用。粗粒聚类和分子动力学模拟（MDS）进一步验证了蛋白质-肽复合物的稳定骨架构象和最小的残基水平波动，这些在整个模拟时间内都得到了保持。本研究假设，舒巴坦（βL）与 SAAP-148_M15（βLI）的联合使用具有抑制 ESBLs 并恢复舒巴坦活性的巨大潜力。进一步实验验证后的当前计算结果可以为设计针对 XDR 鲍曼不动杆菌的成功治疗策略铺平道路。
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