Efflux pumps of Pseudomonas aeruginosa and their regulatory mechanisms underlying multidrug resistance

Pseudomonas aeruginosa, an opportunistic gram-negative bacterial pathogen, is a significant threat in hospital intensive care units due to its ability to cause various human infections. Its large genome enables remarkable adaptability to environmental changes, resulting in the development of antibiotic and multidrug resistance (MDR). The chromosomes of P. aeruginosa strains harbor numerous resistance genes, the majority of which are related to efflux pumps (EPs). These genes are primarily responsible for antibiotic and MDR. Efflux systems are pivotal in P. aeruginosa MDR, comprising six major EP protein families: ATP-binding cassette, major facilitator, multidrug and toxin extrusion, small MDR, proteobacterial antimicrobial compound efflux, and resistance nodulation cell division (RND) superfamilies. Among these, RND EPs are the most critical, displaying the broadest substrate spectrum and the strongest correlation with MDR. The P. aeruginosa genome encodes twelve RND EPs, which exhibit overlapping but distinct substrate ranges. Notably, MexAB, MexXY, MexCD, and MexEF EPs contribute significantly to MDR. EP systems in P. aeruginosa are unique, with gene sequences distinct from those of EP systems in other gram-negative and gram-positive bacteria, making interspecific gene transfer of EP resistance genes uncommon. EP inhibitors (EPIs) possess the potential to promote the clinical efficacy of antibiotics against P. aeruginosa infections. However, no EPIs have been applied in clinical anti-infective treatment to date. Consequently, there is an urgent need for in-depth exploration of the molecular structures, functions, and mechanisms of P. aeruginosa EP systems. Developing low-toxicity, high-efficacy, and broad-spectrum EPIs is crucial to drive and accelerate their clinical application.