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

Hang Thi Nguyen; Henrietta Venter; Tania Veltman; Ruth Williams; Lisa Anne O'Donovan; Cecilia C Russell; Adam McCluskey; Stephen W Page; Abiodun David Ogunniyi; Darren J Trott

doi:10.1016/j.ijantimicag.2021.106323

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

Int J Antimicrob Agents. 2021 May;57(5):106323. doi: 10.1016/j.ijantimicag.2021.106323. Epub 2021 Mar 19.

Authors

Affiliations

¹ Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, Australia; Department of Pharmacology, Toxicology, Internal Medicine and Diagnostics, Faculty of Veterinary Medicine, Vietnam National University of Agriculture, Hanoi, Vietnam.
² Health and Biomedical Innovation, Clinical and Health Sciences, University of South Australia, Adelaide, SA, Australia.
³ Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, Australia.
⁴ Adelaide Microscopy, University of Adelaide, Adelaide, SA, Australia.
⁵ ARC Centre of Excellence in Plant Energy Biology, School of Agriculture, Food & Wine, University of Adelaide, SA, Australia.
⁶ Chemistry, School of Environmental & Life Sciences, University of Newcastle, Callaghan, NSW, Australia.
⁷ Neoculi Pty Ltd., Burwood, VIC, Australia.
⁸ Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, Australia. Electronic address: david.ogunniyi@adelaide.edu.au.
⁹ Australian Centre for Antimicrobial Resistance Ecology, School of Animal and Veterinary Sciences, The University of Adelaide, Roseworthy, SA, Australia. Electronic address: darren.trott@adelaide.edu.au.

PMID: 33746046
DOI: 10.1016/j.ijantimicag.2021.106323

Abstract

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.

Keywords: Colistin; Gram-negative bacteria; Multidrug resistance; NCL195; Synergy; Transmission electron microscopy.

MeSH terms

Animals
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Colistin / pharmacology*
Dose-Response Relationship, Drug
Drug Resistance, Multiple, Bacterial
Drug Synergism
Drug Therapy, Combination
Gram-Negative Bacteria / drug effects*
Gram-Negative Bacterial Infections / drug therapy
Gram-Negative Bacterial Infections / microbiology
HEK293 Cells
Hep G2 Cells
Humans
Male
Mice
Microbial Sensitivity Tests
Models, Animal
Robenidine / analogs & derivatives*
Robenidine / pharmacology*

Substances

Anti-Bacterial Agents
Robenidine
Colistin