COMPUTATIONAL INSIGHTS INTO ANTIBIOTIC RESISTANCE

对抗生素耐药性的计算见解

• 批准号: 6280229
• 负责人: IRINA MASSOVA
• 金额: $ 4.04万
• 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: 1998-07-01 至 1999-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6280229
• 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。