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. 2019 Jul 11:12:2031-2038.
doi: 10.2147/IDR.S207844. eCollection 2019.

Efficacy of combinations of colistin with other antimicrobials involves membrane fluidity and efflux machinery

E Armengol  1 , O Domenech  2 , E Fusté  1   3 , I Pérez-Guillén  1 , J H Borrell  2 , J M Sierra  1 , M Vinas  1
Affiliations

Efficacy of combinations of colistin with other antimicrobials involves membrane fluidity and efflux machinery

E Armengol et al. Infect Drug Resist. .

Abstract

Objective: Despite its use was abandoned several decades ago, the polycationic peptide colistin has become the last hope to treat severe infections caused by multidrug-resistant Gram-negative bacteria. Thus, the development of colistin resistance may seriously compromise the efficacy of treatment. Moreover, colistin has high toxicity being dose dependent. A potentially effective strategy to avoid resistance may be to combine colistin with other antimicrobials. This may help in the rescue of old antimicrobials and in reducing toxic undesired effects.

Methods: Antimicrobial susceptibility determination, efflux machinery function measurements in different conditions and measurement of inhibition of the extrusion by colistin were performed. Moreover, modifications of anisotropy of the membranes by using fluorescent dyes was accomplished.

Results: Sub-inhibitory concentrations of colistin have a synergistic effect with several antimicrobials that act intracellularly (targeting protein synthesis and DNA replication). This effect was demonstrated through the uptake increases of acridine orange. in Pseudomonas aeruginosa, Escherichia coli and Acinetobacter baumanii but also in an intrinsically colistin-resistant species as Serratia marcescens. Measurements of the anisotropy of bacterial membranes, as a measure of membrane fluidity, showed significant changes indicative of colistin activity.

Conclusion: The alterations in the cellular efflux machinery that resulted in higher intracellular concentrations of acridine orange, and likely of other antimicrobials combined with data of membrane fluidity and measured synergism in vitro allow us to envisage the use of these combinations to fight infections caused by multidrug-resistant bacteria.

Keywords: cationic antimicrobial peptides; efflux pumps; membrane fluidity; synergism.

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Conflict of interest statement

The authors have no conflicts of interest to declare in this work.

Figures

Figure 1
Figure 1
Average acridine orange (AO) accumulation in the presence of the efflux inhibitor PaβN and sub-inhibitory concentrations of colistin. (A–C) colistin-sensitive strains; (D) a species intrinsically resistant to colistin.
Figure 2
Figure 2
Confocal light microscopy imaging after Live/Dead staining of Pseudomonas aeruginosa. (A) Untreated cells; (B) cells treated with colistin at 0.25 μg/mL and (C) cells treated with colistin at bactericidal concentration. Similar images were obtained for Acinetobacter baumanii and E. coli (not shown). TEM of thin sections of S. marcescens after treatment with colistin. Blebs formed by the outer membrane are easily visualized.
See this image and copyright information in PMC

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