Beta-lactamase inhibitors: evolving compounds for evolving resistance targets.
The many and diverse beta-lactamases produced by bacteria, particularly by Gram-negative pathogens, are increasingly posing a serious threat to the clinical utility of beta-lactams. First-generation inhibitors (clavulanic acid, sulbactam, tazobactam) focus on Ambler class A enzymes. However, recent structural upgrades of class A beta-lactamases (e.g. TEM, SHV) have extended their spectrum (extended-spectrum beta-lactamases and carbapenemases [Sme, NMC-A, IMI-1]) and have brought about the possibility of beta-lactamase-inhibitor resistance. Furthermore, the mobilisation and spread of originally chromosomal class C enzymes (CMY, MIR), the growing clinical importance of class B enzymes (IMP, VIM), the emergence of inhibitor-resistant, broad spectrum class D (OXA) enzymes and the co-existence of different classes of beta-lactamases in the same pathogen have spurred research toward universal inhibitors. A complicating issue is target accessibility in Gram-negative bacteria, particularly in Enterobacter, Acinetobacter, Pseudomonas, Stenotrophomonas and other organisms, which is necessary in order for the inhibitor to synergise with vulnerable beta-lactam antibiotics. Several new, broad-spectrum inhibitors have emerged: cephem sulfones and oxapenems are upgrades of penam sulfones and oxapenams, respectively, with cephem sulfones possibly extending their inhibition to class B metallo-enzymes; and boronates and phosphonates are designed de novo, based on common structural and mechanistic features of serine beta-lactamases.
MethylGene, Inc., 7220 Rue Frederick-Banting, Bureau 200, Montreal, PQ H4S 2A1, Canada. nafsikag@aol.com
Nafsika H
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Georgopapadakou
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D010397:Penicillanic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D013407:Sulbactam / Q000494:pharmacology; D000078142:Tazobactam; D018440:beta-Lactam Resistance / Q000502:physiology*; D065093:beta-Lactamase Inhibitors
D004791:Enzyme Inhibitors; D065093:beta-Lactamase Inhibitors; D010397:Penicillanic Acid; D013407:Sulbactam; D000078142:Tazobactam