Ramachandran Balajee, Muthupandian Saravanan, Jeyaraman Jeyakanthan, Lopes Bruno Silvester
Structural Biology and Bio-Computing Lab, Department of Bioinformatics, Alagappa University, Karaikudi, Tamil Nadu, India.
Department of Pharmacology, Saveetha Institute of Medical and Technical Sciences (SIMATS), Chennai, Tamil Nadu, India.
Front Chem. 2023 Feb 23;11:1090630. doi: 10.3389/fchem.2023.1090630. eCollection 2023.
Carbapenem-resistant is an opportunistic pathogen responsible for nosocomial infections and is one of the biggest global threats according to the World Health Organization (WHO), particularly causing substantial morbidity and mortality. This study aimed at using computational approaches to screen meropenem and its analogs against OXA-23-positive analyzing the correlations between kinetic and phenotypic characteristics. A total of 5,450 compounds were screened using virtual screening workflow (HTVS, Glide-SP, and Glide-XP) to identify the best compounds based on their binding energy and interactions against OXA-23 and OXA-27 as they had phenotypic data available. Molecular dynamics simulation and density functional theory (DFT) studies were performed from the outcome of molecular docking analysis. During simulations, meropenem and its analogs exhibited high-level stable interactions with Ser79, Ser126, Thr217, Trp219, and Arg259 of OXA-23. Meropenem displayed a CovDock energy of about -3.5 and -1.9 kcal mol against OXA-23 and OXA-27, respectively. Among the 5,450 compounds, Pubchem_10645796, Pubchem_25224737, and ChEMBL_14 recorded CovDock energy between -6.0 and -9.0 kcal mol. Moreover, the infra-red (IR) spectrophotometric analysis revealed C=O and C-N atoms showing bands at 1,800 and 1,125 cm, respectively. These observed data are in congruence with the experimental observations. The identified compounds showed good agreement with the spectrophotometric analysis using DFT methods. In the earlier studies, meropenem's MIC value was 32 μg mL in OXA-23-positive isolate A2265 compared to the MIC of 1 μg mL in Δ A2265. Comparing the CovDock energy and hydrogen-bonding interactions, the predicted results are in good agreement with the experimental data reported earlier. Our results highlight the importance of OXA-23 molecular docking studies and their compliance with the phenotypic results. It will help further in developing newer antibiotics for treating severe infections associated with carbapenem-resistant .
耐碳青霉烯类是一种导致医院感染的机会致病菌，根据世界卫生组织（WHO）的说法，它是全球最大的威胁之一，尤其会造成大量发病和死亡。本研究旨在使用计算方法筛选美罗培南及其类似物对OXA - 23阳性菌株的作用，分析动力学和表型特征之间的相关性。使用虚拟筛选工作流程（高通量虚拟筛选、Glide - SP和Glide - XP）对总共5450种化合物进行筛选，以根据它们与OXA - 23和OXA - 27的结合能和相互作用来确定最佳化合物，因为它们有可用的表型数据。根据分子对接分析的结果进行分子动力学模拟和密度泛函理论（DFT）研究。在模拟过程中，美罗培南及其类似物与OXA - 23的Ser79、Ser126、Thr217、Trp219和Arg259表现出高水平的稳定相互作用。美罗培南对OXA - 23和OXA - 27的CovDock能量分别约为 - 3.5和 - 1.9千卡/摩尔。在这5450种化合物中，Pubchem_10645796、Pubchem_25224737和ChEMBL_14的CovDock能量在 - 6.0至 - 9.0千卡/摩尔之间。此外，红外（IR）分光光度分析显示C = O和C - N原子分别在1800和1125厘米处出现谱带。这些观察到的数据与实验观察结果一致。所鉴定的化合物与使用DFT方法的分光光度分析结果吻合良好。在早期研究中，美罗培南在OXA - 23阳性分离株A2265中的MIC值为32微克/毫升，而在ΔA2265中的MIC为1微克/毫升。比较CovDock能量和氢键相互作用，预测结果与早期报道的实验数据吻合良好。我们的结果突出了OXA - 23分子对接研究的重要性及其与表型结果的一致性。这将有助于进一步开发用于治疗与耐碳青霉烯类相关严重感染的新型抗生素。
