Membrane-Transporter Therapeutic Strategies Against Drug-Resistant Pseudomonas aeruginosa

Abstract Background: Pneumonia caused by Pseudomonas aeruginosa is increasingly difficult to treat due to Meropenem resistance, largely driven by the overexpression of the efflux pump MexAB-OprM, which expels the antibiotic from the bacterial cell before it reaches its target, allowing the pathogen to overcome Meropenem activity. Meropenem is crucial for managing multidrug-resistant (MDR) infections caused by Pseudomonas aeruginosa due to its broad-spectrum antibacterial activity. However, the emergence and accumulation of carbapenem-resistant mechanisms have elevated minimum inhibitory concentrations ( MICs ), significantly limiting therapeutic options. Among these resistance mechanisms, the overexpression of efflux pump systems is a major contributor. Notably, MexAB-OprM, the first efflux pump identified from the Resistance-Nodulation-Cell Division ( RND ) family, is constitutively expressed at high levels in P. aeruginosa , contributing substantially to both intrinsic and acquired resistance. Given their critical role as last-resort agents against increasingly difficult-to-treat Gram-negative pathogens, including P. aeruginosa , the prudent use of carbapenems is essential. Aim: The study aims to overcome efflux pump-mediated resistance in Pseudomonas aeruginosa through the synergistic effect of α-Bisabolol (a plant metabolite) and Meropenem (an antibiotic). Objective: To investigate the ability of the combination of Meropenem and the α-Bisabolol plant metabolite to resensitize the clinical Meropenem-resistant Pseudomonas aeruginosa by inhibiting the MexB efflux pump in vitro studies. Results: The combination of Meropenem and α-Bisabolol reduced the MIC of Meropenem by fourfold and significantly inhibited bacterial growth in time-kill assays. Ethidium bromide accumulation confirmed efflux inhibition, as evidenced by increased fluorescence in treated cells. These results suggest that α-Bisabolol effectively restores Meropenem activity and offers a promising strategy against resistant P. aeruginosa infections.