Unveiling the potential of a novel drug efflux pump inhibitor to combat multidrug resistance in ESKAPEE pathogens, with a focus on Acinetobacter baumannii.

ESKAPEE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter spp. and Escherichia coli) is a group of nosocomial pathogens with alarming antibiotic resistance, representing a paramount public health menace. Their multidrug resistance (MDR) is often due to hyperactive drug efflux transporters (DETs) exporting antibiotics from bacterial cells. Fortunately, a breakthrough has been made by the synthetic molecule KSA5_1 (8,10-dimethyl-1,6,11-triazatetracene-5,12-dione). In vitro combination assays of KSA5_1 with antibiotics (colistin, ciprofloxacin, gentamicin) showed excellent reductions in minimum inhibitory concentrations (MICs), as much as 512-fold, against clinical MDR isolates such as Enterococcus faecium, Staphylococcus aureus and Acinetobacter baumannii. Surprisingly, KSA5_1 was more effective than the standard efflux pump inhibitor PAβN in inhibiting ciprofloxacin efflux from A. baumannii, primarily targeting the overexpressed AdeG gene, a key DET protein. Molecular docking and simulations indicated the improved binding of KSA5_1 to AdeG with a suggestion of tight DET inhibition. KSA5_1 also possessed good drug-like profiles. The improved physicochemical profile of the compound and the potential to increase the efficacy of antibiotics by inhibiting DETs offer KSA5_1 an exciting lead to combat antimicrobial resistance (AMR). The new approach promises to address the challenging issue of MDR among ESKAPEE pathogens and has the potential to restore the efficacy of existing antibiotics to combat the AMR crisis.