Molecular basis of antibiotic resistance and β-lactamase inhibition by mechanism-based inactivators:: perspectives and future directions

被引:87
作者
Therrien, C [1 ]
Levesque, RC [1 ]
机构
[1] Univ Laval, Fac Med, Ste Foy, PQ G1K 7P4, Canada
关键词
antibiotic resistance; beta-lactam; beta-lactamase;
D O I
10.1111/j.1574-6976.2000.tb00541.x
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
Antibacterial chemotherapy is particularly striking in the family of penicillins and cephalosporins. Over 40 structurally different beta-lactam molecules are available in 73 formulations and the majority of them are currently prescribed for medical use in hospitals. beta-Lactams are well tolerated by humans with few side effects. They interact very specifically with their bacterial target, the D-alanyl-D-alanine carboxypeptidase-transpeptidase usually referred to as DD-peptidase. The outstanding number of beta-lactamases produced by bacteria represent a serious threat to the clinical utility of beta-lactams. The discovery of beta-lactamase inhibitors was thought to solve,in part, the problem of resistance. Unfortunately, bacteria have evolved new mechanisms of resistance to overcome the inhibitory effects of beta-lactamase inactivators. Here, we summarize the diversified mechanistic features of class A beta-lactamases interactions with mechanism-based inhibitors using available microbiological, kinetic and structural data for the prototype TEM beta-lactamases. A brief historical overview of the strategies developed to counteract beta-lactamases will be presented followed by a short description of the chemical events which lead to the inactivation of TEM beta-lactamase by inhibitors from different classes. Finally, an update on the clinical prevalence of natural and inhibitor-resistant enzyme mutants, the total chemical synthesis to design and synthesize a new structure and produced a broad spectrum beta-lactamase inhibitor that mimics the beta-lactam ring, but does not contain it is discussed. (C) 2000 Federation of European Microbiological Societies: Published by Elsevier Science B.V. All rights reserved.
引用
收藏
页码:251 / 262
页数:12
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