Abstract
Pseudomonas aeruginosa is a major opportunistic pathogen, causing a wide range of acute and chronic infections. beta-lactam antibiotics including penicillins, carbapenems, monobactams, and cephalosporins play a key role in the treatment of P. aeruginosa infections. However, a significant number of isolates of these bacteria are resistant to beta-lactams, complicating treatment of infections and leading to worse outcomes for patients. In this review, we summarize studies demonstrating the health and economic impacts associated with beta-lactam-resistant P. aeruginosa. We then describe how beta-lactams bind to and inhibit P. aeruginosa penicillin-binding proteins that are required for synthesis and remodelling of peptidoglycan. Resistance to beta-lactams is multifactorial and can involve changes to a key target protein, penicillin-binding protein 3, that is essential for cell division; reduced uptake or increased efflux of beta-lactams; degradation of beta-lactam antibiotics by increased expression or altered substrate specificity of an AmpC beta-lactamase, or by the acquisition of beta-lactamases through horizontal gene transfer; and changes to biofilm formation and metabolism. The current understanding of these mechanisms is discussed. Lastly, important knowledge gaps are identified, and possible strategies for enhancing the effectiveness of beta-lactam antibiotics in treating P. aeruginosa infections are considered.