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Resistance to β-Lactam Antibiotics: Structure and Mechanism Based Design of β-Lactamase Inhibitors

[ Vol. 9 , Issue. 12 ]

Author(s):

Vincent P. Sandanayaka and Amar S. Prashad   Pages 1145 - 1165 ( 21 )

Abstract:


Resistance to antibiotics is currently a major health concern in treating infectious diseases. The most common mechanism of resistance to β-lactam antibiotics is the production of β-lactamases, which destroy β-lactam antibiotics before they reach the bacterial target. Combination therapy, which involves treatment with a β-lactam antibiotic and a β-lactamase inhibitor, has been successfully used to control resistance during last two decades. Due to the lack of effectiveness of the currently available β-lactamase inhibitors against class C enzymes and new variants of β-lactamases, there is a need to develop an inhibitor with broad-spectrum activity. Since the discovery of clavulanic acid, there has been an enormous research effort in this area to identify better antibiotic / inhibitor combinations and to understand the molecular bases for interactions between β-lactam antibiotics, β-lactamases, and β-lactamase inhibitors. This review describes some of the structure- and mechanism-based approaches to design of new β-lactamase inhibitors and the study of probable mechanisms of inhibition using X-ray, electrospray ionization mass spectrometry, and molecular modeling techniques.

Keywords:

beta-lactam antibioties, beta-lactamase, c enzymes, clavulanic acid

Affiliation:

AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, MA 02451, USA



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