In vitro synergistic activity of NCL195 in combination with colistin against Gram-negative bacterial pathogens

Abstract

In this study, the potential of using the novel antibiotic NCL195 combined with subinhibitory concentrations of colistin against Gram-negative bacteria (GNB) infections was investigated. We showed synergistic activity of the NCL195+colistin combination against clinical multidrug-resistant GNB pathogens, with MICs for NCL195 ranging from 0.5-4 µg/mL for Acinetobacter baumannii, Escherichia coli, Klebsiella pneumoniae and Pseudomonas aeruginosa, whereas NCL195 alone had no activity. Transmission electron microscopy of the membrane morphology of E. coli and P. aeruginosa after single or combination drug treatment showed marked ultrastructural changes most frequently in the cell envelope. Exposure to NCL195 alone did not show any change compared to untreated control cells whereas the NCL195+colistin combination treatment caused more damage than colistin alone. Direct evidence for this interaction was demonstrated by fluorescence-based membrane potential measurements. We conclude that the synergistic antimicrobial activity of the NCL195+colistin combination against GNB pathogens warrants further exploration for specific treatment of acute GNB infections.