COMPUTATIONAL INSIGHTS INTO ANTIBIOTIC RESISTANCE

对抗生素耐药性的计算见解

• 批准号: 2517162
• 负责人: IRINA MASSOVA
• 金额: $ 2.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-06-30 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2517162
• 关键词: beta lactam antibiotic; beta lactamase; chemical models; drug resistance; model design /development; pharmacokinetics

Mechanisms of beta-lactam antibiotics resistance will be investigated. New methodologies in the area combining quantum mechanics and molecular mechanics calculations, free energy perturbations, and continuum electrostatics models will be applied 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. The mechanism of catalysis will be first studied 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. Titration curves will be calculated for the representative beta-lactamases in order to elucidate mechanisms of activation of the critical active-site residues in these enzymes. Ultimately, the entire mechanism of the beta-lactam antibiotic hydrolysis by beta-lactamases will be studied. The detailed knowledge gained from the science disclosed in this proposal should ultimately be a driving force in designing novel potent antimicrobials that overcome the problem of bacterial resistance.

将研究β-内酰胺抗生素耐药性的机制。 结合量子力学和分子领域的新方法 力学计算、自由能扰动和连续介质 静电模型将用于检查水解活性 对抗细菌防御所表现出的β-内酰胺抗生素 赋予大肠杆菌和大肠杆菌细菌耐药性的酶-TEM-1。 泄殖腔 P99 β-内酰胺酶，在临床病原体中常见。 首先将在简单的模型上研究催化机制 甲醇介导的气体中小β-内酰胺分子的水解 相和溶液中，然后对甲醇进行建模 苄青霉素介导的水解——一种典型的β-内酰胺 抗生素。 将计算代表性的滴定曲线 β-内酰胺酶，以阐明其激活机制 这些酶中的关键活性位点残基。 最终，整个 β-内酰胺酶水解β-内酰胺抗生素的机制 将被研究。从科学中获得的详细知识 本提案中披露的内容最终应成为推动 设计新型有效的抗菌药物来克服以下问题 细菌耐药性。