MexB‐Mediated Efflux Pumps in <i>Pseudomonas aeruginosa</i> : Mechanistic Insights, Inhibition Strategies, and Future Perspectives

Abstract The rise of multidrug‐resistant (MDR) Pseudomonas aeruginosa poses a serious global health threat, largely driven by the overexpression of efflux pumps, particularly the MexAB‐OprM system, which actively expels antibiotics and reduces their efficacy. This review provides molecular insights into the MexB efflux pump and explores the potential of MexB‐specific efflux pump inhibitors (EPIs) to restore the effectiveness of conventional antibiotics. Several natural and synthetic EPIs are from various sources that were examined for their ability to interact with MexB and potentially inhibit the efflux of antibiotics. Natural EPIs, derived from medicinal plants such as Curcuma longa (curcumin) and Holarrhena antidysentrica (conessine), have demonstrated the ability to inhibit MexB function, thereby enhancing antibiotic susceptibility. Synthetic EPIs, including phenylalanyl arginyl β‐naphthylamide (PAβN) and quinolone derivatives, target key components of the efflux pump. This review also highlights the structural and functional characteristics of MexB inhibitors from various sources. To combat antibiotic resistance effectively, it advocates for a multidisciplinary strategy integrating natural product research, synthetic chemistry, and drug repurposing approaches. Finally, it provides insights into the future development of novel EPIs as a promising strategy to enhance antibiotic efficacy and address the growing threat of P. aeruginosa MDR infections.