Fighting back against bacterial resistance: Harnessing nanocarrier strategies to counter antibiotic efflux pumps

The global rise of multidrug-resistant (MDR) bacterial infections poses a significant threat to public health, mainly driven by antibiotic efflux pumps that actively expel drugs from bacterial cells and lower intracellular antibiotic concentrations below therapeutic levels. Efflux pumps, including the resistance-nodulation-division (RND), major facilitator superfamily (MFS), ATP-binding cassette (ABC), small multidrug resistance (SMR), multidrug and toxic compound extrusion (MATE), and proteobacterial antimicrobial compounds efflux pumps (PACE) families, confer broad-spectrum resistance and play a critical role in biofilm formation, persistence, and tolerance to antibiotic treatment. Currently available efflux pump inhibitors (EPIs) encompass a wide range of synthetic molecules, plant-derived compounds, seaweed-derived components, and microbe-derived inhibitors. Nanocarrier-based drug delivery systems have emerged as a viable approach to circumvent efflux-mediated resistance and restore antibiotic efficacy. Metallic, polymeric, and lipid nanocarriers potentiate antibiotic efficacy, decrease the minimum inhibitory concentrations (MICs), and reduce bacterial efflux pumps gene expression. Early preclinical and clinical studies demonstrate the feasibility of this approach, though challenges remain regarding safety, scale-up, and potential bacterial adaptation. This review discusses the mechanisms of antibiotic resistance, focusing on bacterial efflux systems and the specific mechanisms that contribute to antibiotic resistance. Finally, the review examined the diverse strategies involving nanocarriers in inhibiting bacterial efflux pumps, surface engineering of nanocarriers to inhibit efflux pumps, as well as a discussion of the limitations and future perspectives regarding the use of such nanocarriers for this purpose.