Sreenithya K H, Manoharadas Salim, Sugumar Shobana
Department of Genetic Engineering, School of Bioengineering, College of Engineering and Technology, SRM Institute of Science and Technology, Kattankulathur, India.
Department of Botany and Microbiology, College of Science 5, King Saud University, Riyadh, 11451, Saudi Arabia.
BMC Microbiol. 2025 May 6;25(1):268. doi: 10.1186/s12866-025-03994-6.
Antibiotic resistance caused by pathogenic microbes have become a serious issue in health field as most of the antibiotics discovered are rendered ineffective for the treatment of numerous microbial infections. Stenotrophomonas maltophilia is such a type of pathogen and the treatment of this bacterial infection is extremely difficult due to its intrinsic multi-drug resistance property. Production of β-lactamases (L1 and L2) by the organism is one of the main causes of resistance to a broad spectrum of antibiotics. β -lactamase inhibitor and β-lactam drug combination can be a promising alternative.
In the current study, approximately 500,000 compounds from ZINC15 database were subjected to virtual High Throughput screening (vHTS). Compounds with binding energies in the range of - 8.1 kcal/mol to - 7.2 kcal/mol were shortlisted for further analysis After molecular docking and ADMET analysis, ZINC393032 (-7.3 kcal/mol) and ZINC616394 (-7.6 kcal/mol) were selected for 300 ns Molecular Dynamics (MD) simulation. Analysis of RMSD, RMSF and Hydrogen bond concluded ZINC393032 as the best compound. In vitro validation assays with the screened inhibitor on recombinant Metallo-L1 β-lactamase like enzyme inhibition (IC obtained at 22.96 µM), MIC (Minimum inhibitory concentration), checkerboard synergy assay and time kill assay showed good inhibitory property. Five different concentration combinations of the inhibitor with imipenem were tested against the bacteria and found to have bactericidal effects.
The study validates a promising compound for overcoming resistance caused by L1 β-lactamase in Stenotrophomonas maltiphilia. These results highlight the potential of combining computational and experimental approaches to develop novel therapies. The findings provide a foundation for future strategies targeting β-lactamase-mediated resistance in Stenotrophomonas maltophilia.
致病微生物引起的抗生素耐药性已成为健康领域的一个严重问题，因为发现的大多数抗生素对许多微生物感染的治疗均无效。嗜麦芽窄食单胞菌就是这样一种病原体，由于其固有的多重耐药特性，这种细菌感染的治疗极其困难。该生物体产生β-内酰胺酶（L1和L2）是对多种抗生素耐药的主要原因之一。β-内酰胺酶抑制剂与β-内酰胺类药物联合使用可能是一种有前景的替代方法。
在当前研究中，对ZINC15数据库中的约500,000种化合物进行了虚拟高通量筛选（vHTS）。结合能在-8.1千卡/摩尔至-7.2千卡/摩尔范围内的化合物被入围进行进一步分析。经过分子对接和ADMET分析后，选择了ZINC393032（-7.3千卡/摩尔）和ZINC616394（-7.6千卡/摩尔）进行300纳秒的分子动力学（MD）模拟。均方根偏差（RMSD）、均方根波动（RMSF）和氢键分析得出ZINC393032是最佳化合物。用筛选出的抑制剂对重组金属L1β-内酰胺酶样酶抑制（IC为22.96微摩尔）、最低抑菌浓度（MIC）、棋盘协同试验和时间杀菌试验进行体外验证试验，结果显示出良好的抑制特性。测试了抑制剂与亚胺培南的五种不同浓度组合对该细菌的作用，发现具有杀菌效果。
该研究验证了一种有前景的化合物，可克服嗜麦芽窄食单胞菌中L1β-内酰胺酶引起的耐药性。这些结果突出了结合计算和实验方法开发新疗法的潜力。这些发现为未来针对嗜麦芽窄食单胞菌中β-内酰胺酶介导的耐药性的策略奠定了基础。
