Role of Efflux Pumps on Antimicrobial Resistance in Pseudomonas aeruginosa

Abstract

Antimicrobial resistance is an old and silent pandemic. Resistant organisms emerge in parallel with new antibiotics, leading to a major global public health crisis over time. Antibiotic resistance may be due to different mechanisms and against different classes of drugs. These mechanisms are usually found in the same organism, giving rise to multidrug-resistant (MDR) and extensively drug-resistant (XDR) bacteria. One resistance mechanism that is closely associated with the emergence of MDR and XDR bacteria is the efflux of drugs since the same pump can transport different classes of drugs. In Gram-negative bacteria, efflux pumps are present in two configurations: a transmembrane protein anchored in the inner membrane and a complex formed by three proteins. The tripartite complex has a transmembrane protein present in the inner membrane, a periplasmic protein, and a porin associated with the outer membrane. In Pseudomonas aeruginosa, one of the main pathogens associated with respiratory tract infections, four main sets of efflux pumps have been associated with antibiotic resistance: MexAB-OprM, MexXY, MexCD-OprJ, and MexEF-OprN. In this review, the function, structure, and regulation of these efflux pumps in P. aeruginosa and their actions as resistance mechanisms are discussed. Finally, a brief discussion on the potential of efflux pumps in P. aeruginosa as a target for new drugs is presented.

Keywords: Pseudomonas aeruginosa; antimicrobial resistance; efflux pumps.

Figure 1

Multidrug efflux pumps in P. aeruginosa. (a) Schematic structures of the four main efflux pumps involved in antibiotic resistance in P. aeruginosa, showing the resistance-nodulation-cell division transporters (MexB, MexY, MexD and MexF) on the inner membrane; the periplasmic membrane fusion proteins (MexA, MexX, MexC and MexE) on the periplasm; and the channel-forming outer membrane factors (OprM, OprJ and OprN) on the outer membrane. Protein representations based on the Protein Databank (PDB) structures: 2V50, 4DK1 and 3D5K. (b) Organization of the Mex operons and upstream regulatory genes in the P. aeruginosa genome. Regulatory genes are represented in white, and the Mex coding sequences follow the same color patterns of the protein structures shown in (a). Created with BioRender.com.