In Silico Screening and Experimental Validation of Novel MexAB–OprM Efflux Pump Inhibitors of Pseudomonas aeruginosa

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.