Bacterial multidrug efflux pumps and regulators (MDR efflux systems)

Bacterial multidrug transporters and regulators are a diverse class of proteins that facilitate the active extrusion of various antibiotics, detergents, and toxins from the bacterial cell, thereby mediating multidrug resistance (MDR) [1, 3]. These transporters are categorized into several superfamilies, including the Resistance-Nodulation-Division (RND), Major Facilitator Superfamily (MFS), and ATP-Binding Cassette (ABC) families, which utilize either the proton motive force or ATP hydrolysis as an energy source [2, 5]. Their expression is tightly controlled by transcriptional regulators, such as the TetR and MarR families, which sense environmental stresses or the presence of antimicrobial agents [7, 8]. In clinical settings, the overexpression of these systems is a primary driver of treatment failure in infections caused by pathogens like Pseudomonas aeruginosa and Acinetobacter baumannii [11, 12]. Consequently, these proteins are significant therapeutic targets for efflux pump inhibitors (EPIs), which aim to restore the efficacy of existing antibiotics by preventing their removal from the cell [13, 14]. However, developing safe and effective EPIs remains challenging due to potential cross-reactivity with human transporters and the inherent complexity of bacterial membrane structures [4, 15].

Other names

Bacterial multidrug transportersAntibiotic efflux pumpsMDR transportersXenobiotic efflux systems

Efflux pump inhibitors (EPIs) work by competitively or non-competitively binding to the transporter's substrate-binding pockets, blocking the exit channel, or dissipating the energy source (e.g., proton motive force) required for transport [3, 11]. Additionally, targeting transcriptional regulators can prevent the up-regulation of these pumps in response to antibiotic stress [6, 9].