The emergence of multidrug-resistant Pseudomonas aeruginosa possesses a significant public health concern. Constitutively expressed MexAB-OprM efflux pumps in P. aeruginosa significantly contribute to its resistance to a variety of antibiotics. The development of efflux pump inhibitors (EPIs) has emerged as an attractive strategy in reversing antibiotic resistance. In this study, structure-based virtual screening techniques were used for the identification of new MexAB-OprM efflux inhibitors. The predicted poses were thoroughly filtered by induced fit docking procedures followed by in vitro microbiological assays for the validation of in silico results. Two compounds, NSC-147850 and NSC-112703, were able to restore tetracycline susceptibility in MexAB-OprM overexpressing Pseudomonas aeruginosa ATCC® 27853™ strain. This correlation observed between in silico screening and positive efflux inhibitory activity in vitro suggests that NSC-147850 and NSC-112703 have potential as EPIs and may be effective in combination therapy against drug-resistant strains of P. aeruginosa.
Keywords: MDR; MexAB; OprM; P. aeruginosa; efflux pumps inhibitors; in vitro synergy assay; molecular docking; virtual high-throughput screening.