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

Abstract

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.

Resistance to ?-lactam antibiotics

“…Inactivation of blactamases is also a proven approach, with b-lactam/blactamase inhibitor combinations often effective in treating infections caused by b-lactamase-producing organisms [346]. Thus, targeting these enzymes, particularly the broad-spectrum class C serine and class B metalloenzymes, will remain an active area of investigation [342,347]. Indeed, recent reports highlight a number of novel inhibitors, some of which are themselves b-lactams [348][349][350][351], of class C [348][349][350][351][352][353][354][355][356] and class B [357][358][359][360][361][362][363] enzymes (see also several references in [342]).…”

In Vitro and In Vivo Properties of BAL30376, a β-Lactam and Dual β-Lactamase Inhibitor Combination with Enhanced Activity against Gram-Negative Bacilli That Express Multiple β-Lactamases

“…Resistance toward ␤-lactams in Gram-negative bacteria is frequently caused by the expression of one or more ␤-lactamases, which destroy the antibiotic (12,19,20,22). It can be exacerbated by mutation or altered expression of outer membrane proteins responsible for the influx of the antibiotics and by increased expression of efflux pumps that remove the antibiotics from the periplasm, where they act against their lethal target, the penicillin-binding proteins (19,22).…”

“…Combinations comprising a ␤-lactam antibiotic and a ␤-lactamase inhibitor have proved clinically useful for overcoming some types of ␤-lactamase-mediated resistance (3,6,17,20). There are six such combinations, based around three ␤-lactamase inhibitors, currently available for clinical use in various parts of the world.…”

“…Tazobactam is a more recent extension of the penam sulfone class of inhibitors that has more potent activity than sulbactam, but it is still active against only a few class C ␤-lactamases (2). Many experimental ␤-lactamase inhibitors have been described, representing attempts to extend activity toward class C and D ␤-lactamases (3,6,17,20), but most have encountered difficulty in obtaining significant improvement in activity against Pseudomonas aeruginosa because of limited stability, restricted penetration, or efflux (6,17). An alternative strategy is represented by the bridged monobactams such as BAL29880, which are specific class C ␤-lactamase inhibitors that could be optimized independently for their penetration properties (9).…”

Design, synthesis and biological evaluation of sulfenimine cephalosporin analogues as β-lactamase inhibitors

“…In order to overcome this resistance, several β-lactamase inhibitor/β-lactam antibiotic combinations are currently being used clinically [3] . However, single point mutations within these β-lactamases have made them relatively resistant to inactivation [4,5] . According to Ambler's classification, β-lactamases can be divided into four classes(A to D) based on amino acid sequence homology.…”