Erythromycin, an inhibitor of mitoribosomal protein biosynthesis, alters the amphotericin B susceptibility of Candida albicans

Exposure of the yeast Candida albicans to the macrolide antibiotic erythromycin (C₃₇H₆₇NO₁₃) results in elevated tolerance to the polyene antifungal amphotericin B. Erythromycin displays no fungistatic activity against C. albicans but inhibits the synthesis of cytochromes, particularly cytochrome aa₃. Consequently there is a reduction in aerobic respiration by up to 90% when cells are exposed to 10 mg mL^-1 erythromycin. Cellular ergosterol levels are also severely reduced. Erythromycin inhibits protein biosynthesis in ribosomes (mitoribosomes) located within the mitochondrion of the yeast cell, which results in a disruption of cytochrome biosynthesis with an adverse effect on respiration. The synthesis of ergosterol is oxygen dependent and consequently ergosterol levels are depleted in erythromycin-treated C. albicans. Ergosterol is the target for amphotericin B and since there is less of this sterol in erythromycin-treated cells, there is an increase in tolerance of the antifungal agent. Our work indicates that co-administration of erythromycin and amphotericin B to control bacterial and fungal infections, respectively, may inadvertently lead to an elevation in the tolerance of C. albicans for this antifungal agent.