COMPUTATIONAL INSIGHTS INTO ANTIBIOTIC RESISTANCE

对抗生素耐药性的计算见解

• 批准号: 6119208
• 负责人: IRINA MASSOVA
• 金额: $ 0.54万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6119208
• 关键词: bacteria; biological products; biomedical resource; computers; drug /agent; enzymes; infection; model design /development; technology /technique

We are studying mechanisms of beta-lactam antibiotic resistance. We are using new methodologies in the area combining quantum mechanics and molecular mechanics calculations, free energy perturbations, and continuum electrostatics models to examine the hydrolytic activity against beta- lactam antibiotics displayed by the bacterial defensive enzymes which render bacterial resistance--TEM-1 from E. coli and E. cloacae P99 beta- lactamases which are common in clinical pathogens. We are investigating the mechanism of catalysis on simple models of methanol-mediated hydrolysis of small beta-lactam molecules in the gas phase and in the solution followed by the modeling for the methanol-mediated hydrolysis of benzylpenicillin--a typical beta-lactam antibiotic. We have just completed a part of the project on calculation titration curves for the representative beta-lactamases. The results of this work helped to elucidate mechanisms of activation of the critical active-site residues in these enzymes. This data will be used in combination with the study of the entire mechanism of the beta-lactam antibiotic hydrolysis by beta-lactamases on a higher level of theory. The detailed knowledge gained from the science disclosed in this research project should ultimately be a driving force in designing novel potent antimicrobials that overcome the problem of bacterial resistance.

我们正在研究β-内酰胺类抗生素耐药性的机制。 我们正在使用结合量子力学的新方法 分子力学计算，自由能扰动， 连续静电模型，以检查水解活性 对β-内酰胺类抗生素的抵抗力 产生细菌抗性的酶--来自E. coli和E. 在临床病原体中常见的大肠杆菌P99 β-内酰胺酶。 我们正在研究简单模型上的催化机制， 甲醇介导的气体中小β-内酰胺分子的水解 阶段和解决方案中，然后是 甲醇介导的苄青霉素水解--典型的 β-内酰胺抗生素 我们刚刚完成了项目的一部分 计算代表性的滴定曲线 β-内酰胺酶。 这项工作的结果有助于阐明 这些关键活性位点残基的活化机制 内切酶 这些数据将与研究结合使用， β-内酰胺抗生素水解的整个机制， β-内酰胺酶在更高的理论水平上。 详细的知识 从这个研究项目中披露的科学中获得的信息应该 最终成为设计新型强效抗菌剂的驱动力 克服了细菌耐药性的问题。