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

• NCL195 synergises with low colistin concentrations to kill Gram-negative bacteria (GNB). • The dual action of NCL195 + colistin against GNB is time- and concentration-dependent. • NCL195 + colistin combination also kills colistin-resistant GNB. • NCL195 represents a new chemical class against infections by GNB. • NCL195 + colistin could represent a good example of antimicrobial stewardship. In this study, the potential of using the novel antibiotic NCL195 combined with subinhibitory concentrations of colistin against infections caused by Gram-negative bacteria (GNB) was investigated. We showed synergistic activity of the combination NCL195 + colistin against clinical multidrug-resistant GNB pathogens with minimum inhibitory concentrations (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 colistin or combination drug treatment showed marked ultrastructural changes most frequently in the cell envelope. Exposure to NCL195 alone did not show any change compared with untreated control cells, whereas treatment with the NCL195 + colistin combination 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 combination NCL195 + colistin against GNB pathogens warrants further exploration for specific treatment of acute GNB infections. [ABSTRACT FROM AUTHOR]