Providing β-lactams a helping hand: targeting the AmpC β-lactamase induction pathway

A major cause of the clinical failure of broad-spectrum beta-lactam antibiotics against Pseudomonas aeruginosa and many Enterobacteriaceae species are chromosomal mutations that lead to the hyperproduction of AmpC beta-lactamase. These mutations typically affect proteins within the peptidoglycan (PG) recycling pathway, as well as proteins that are modulated by metabolic intermediates of this pathway. Blocking PG recycling and associated sensing mechanisms with small-molecule inhibitors holds promise as a strategy for overcoming AmpC-mediated resistance that results from the selection of mutations during beta-lactam therapy, or from the direct acquisition of infections by AmpC-producing mutants. Here we report on the structural and functional biology of potential drug targets within the Gram-negative PG recycling pathway and the utility of blocking PG recycling as a means of attenuating AmpC-mediated resistance in P. aeruginosa.