Imidazole Type Antifungal Drugs Are Effective Colistin Adjuvants That Resensitize Colistin-ResistantEnterobacteriaceae

The clinical value of the last-line antibiotic colistin is limited by its toxicity and the increasing prevalence of drug resistance in recent years. These two issues can be tackled by searching for adjuvant compounds that enhance colistin activity and facilitate reduction of treatment dosage. This study identifies a Food and Drug Administration (FDA)-approved drug, econazole, which can act synergistically with colistin to effectively eradicate colistin-resistant bacteria both in vitro and in a mouse infection model, and treat infections caused by colistin-susceptible bacteria in lower doses. Structural analysis shows that econazole exhibits high lipid affinity and acts as an ionophore. Functional assays and microscopy analysis confirm that econazole causes dissipation of transmembrane proton motive force (PMF) and damage to the bacterial cell membrane. Its synergistic effect with colistin might be due to the combination of these two compounds causing further collapse of PMF, arrest of various cellular functions, and eventually cell death. These findings suggest that the econazole and colistin drug combination is highly effective in eradicating colistin-resistant Gram negative bacterial pathogens regardless of their mechanism of colistin resistance.