COMPUTATIONAL INSIGHTS INTO ANTIBIOTIC RESISTANCE

我们正在研究β-内酰胺类抗生素耐药的机制。 我们正在结合量子力学的领域使用新的方法 和分子力学计算，自由能微扰，以及 测定水解性的连续介质静电模型 对抗细菌防御性表现出的β-内酰胺类抗生素 引起细菌耐药性的酶--来自大肠杆菌和E. 阴沟肠杆菌P99β-内酰胺酶是临床常见病原菌。 我们正在用简单的模型研究催化作用的机理。 甲醇催化气体中β-内酰胺小分子的水解 阶段，然后在解决方案中为 典型的青霉素--甲醇催化的青霉素水解 β-内酰胺抗生素。我们刚刚完成了这项工程的一部分 关于代表性滴定曲线的计算 β-内酰胺酶。这项工作的结果有助于阐明 这些关键活性中心残基的活化机制 酵素。这些数据将结合对 β-内酰胺类抗生素水解酶的完整机制 更高层次的理论上的β-内酰胺酶。详细的知识 从这项研究项目中披露的科学中获得的应该是 最终成为设计新型高效抗菌剂的推动力 这克服了细菌耐药性的问题。

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.