COMPUTATIONAL INSIGHTS INTO ANTIBIOTIC RESISTANCE

将研究β-内酰胺类抗生素耐药的机制。 量子力学与分子生物学相结合的新方法论 力学计算、自由能扰动和连续介质 静电模型将被应用于检测水解活性 针对细菌防御系统显示的β-内酰胺抗生素， 产生细菌抗性的酶-来自E. coli和E. Clobacillus P99 β-内酰胺酶，其在临床病原体中常见。 催化机理将首先在简单的模型上进行研究， 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-一种典型的β-内酰胺的介导水解 抗生素 将计算代表性的滴定曲线 β-内酰胺酶，以阐明激活的机制， 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-内酰胺类抗生素的机理 将被研究。从科学中获得的详细知识 本提案中披露的信息最终应成为 设计新的强效抗菌剂， 细菌耐药性

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.