Efflux Pump Inhibitors: Revisiting an Old Strategy in the Era of Antimicrobial Resistance.

Antimicrobial resistance (AMR) is a growing global threat that undermines the effectiveness of existing antibiotics and complicates the treatment of infectious diseases. Among the multiple mechanisms driving resistance, bacterial efflux pumps play a critical but often underappreciated role by actively expelling antibiotics from the cell and reducing intracellular drug concentrations. These pumps are widely distributed across gram-positive and gram-negative bacteria and contribute to multidrug resistance against several major antibiotic classes. Importantly, efflux-mediated resistance is frequently an early and reversible step, allowing bacteria to survive initial antimicrobial exposure and acquire additional resistance mechanisms. Efflux pump inhibitors (EPIs) have therefore long been explored as adjuncts to antibiotic therapy. Experimental studies, particularly with natural compounds, have shown that EPIs can restore antibiotic susceptibility and enhance drug efficacy despite having little intrinsic antibacterial activity. However, clinical translation has been limited by issues related to toxicity, selectivity, pharmacokinetics, and redundancy of efflux systems. Recent advances in molecular and structural biology have renewed interest in this strategy by enabling more rational, mechanism-based EPI design. In the context of a shrinking antibiotic pipeline, revisiting efflux pump inhibition offers a promising complementary approach to prolong the usefulness of existing antibiotics and combat multidrug-resistant infections.