Combining Colistin and Fluconazole Synergistically Increases Fungal Membrane Permeability and Antifungal Cidality

The increasing emergence of drug-resistant fungal pathogens, together with the limited number available antifungal drugs, presents serious clinical challenges to treating systemic, life-threatening infections. Repurposing existing drugs augment activity well-tolerated antifungals is a promising strategy potential be implemented rapidly. Here, we explored mechanism by which colistin, positively charged lipopeptide antibiotic, enhances fluconazole, most widely used orally antifungal. In range susceptible and isolates species, colistin was primarily effective at reducing fluconazole tolerance, property subpopulations cells that grow slowly in presence drug may promote persistent infections resistance. Clinically relevant concentrations synergized minimum inhibitory concentration 4-fold. Combining also increased survival C. albicans Galleria mellonella infection, especially for highly fluconazole-tolerant isolate. Mechanistically, permeability fluorescent azole probes intracellular dyes, accompanied an increase cell death dependent upon pharmacological or genetic inhibition ergosterol biosynthesis pathway. positive charge critical its antifungal, antibacterial, activity: directly binds several eukaryotic membrane lipids (i.e., l-α-phosphatidylinositol, l-α-phosphatidyl-l-serine, l-α-phosphatidylethanolamine) are enriched membranes ergosterol-depleted cells. These results support idea permeabilizes manner depends degree depletion.