Resistance to beta-lactam antibiotics: structure and mechanism based design of beta-lactamase inhibitors.
Resistance to antibiotics is currently a major health concern in treating infectious diseases. The most common mechanism of resistance to beta-lactam antibiotics is the production of beta-lactamases, which destroy beta-lactam antibiotics before they reach the bacterial target. Combination therapy, which involves treatment with a beta-lactam antibiotic and a beta-lactamase inhibitor, has been successfully used to control resistance during last two decades. Due to the lack of effectiveness of the currently available beta-lactamase inhibitors against class C enzymes and new variants of beta-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 beta-lactam antibiotics, beta-lactamases, and beta-lactamase inhibitors. This review describes some of the structure- and mechanism-based approaches to design of new beta-lactamase inhibitors and the study of probable mechanisms of inhibition using X-ray, electrospray ionization mass spectrometry, and molecular modeling techniques.
Sandanayaka
Vincent P
VP
Chemical Sciences, Wyeth-Ayerst Research, 401 North Middletown Road, Pearl River, New York 10965, USA. vincent.sandanayaka@astrazeneca.com
Prashad
Amar S
AS
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001897:Boronic Acids / Q000737:chemistry / Q000494:pharmacology; D002511:Cephalosporins / Q000737:chemistry / Q000494:pharmacology; D002969:Clavulanic Acids / Q000737:chemistry / Q000494:pharmacology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008997:Monobactams / Q000737:chemistry / Q000494:pharmacology; D010397:Penicillanic Acid / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D018440:beta-Lactam Resistance; D065093:beta-Lactamase Inhibitors; D001618:beta-Lactamases / Q000145:classification
D000900:Anti-Bacterial Agents; D001897:Boronic Acids; D002511:Cephalosporins; D002969:Clavulanic Acids; D004791:Enzyme Inhibitors; D008997:Monobactams; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D001618:beta-Lactamases