COMPUTATIONAL INSIGHTS INTO ANTIBIOTIC RESISTANCE

将对β-内酰胺类抗生素的耐药机制进行研究。 量子力学与分子相结合的新方法 力学计算、自由能微扰和连续体 将应用静电学模型来考察其水解性 对抗细菌防御性表现出的β-内酰胺类抗生素 使细菌产生耐药性的酶--E.Coli和E. 阴沟肠杆菌P99β-内酰胺酶，临床常见。 催化机理将首先在简单的模型上进行研究。 甲醇催化气体中β-内酰胺小分子的水解 相中和溶液中，然后对甲醇进行建模- 典型β-内酰胺类青霉素的介导性水解 抗生素。将为代表计算滴定曲线 为了阐明β-内酰胺酶的激活机制 这些酶中的关键活性部位残基。最终，整个 β-内酰胺酶降解抗生素的机理研究 将会被研究。从科学中获得的详细知识 这项提案中披露的最终应该是 设计新的有效抗菌剂，以克服 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.