Metal complexes of 1,10-phenanthroline-5,6-dione alter the susceptibility of the yeast Candida albicans to Amphotericin B and Miconazole

Growth of the pathogenic yeast Candida albicans in sub-MIC (minimum inhibitory concentration) levels of Cu(ClO4)2 6H2O and [Cu(phendio)3](ClO4)2 4H2O (phendio = 1,10-phenanthroline-5,6-dione) increased the concentration of miconazole and amphotericin B required to achieve the MIC90 whereas pre-growth in AgClO4 and [Ag(phendio)2]ClO4 resulted in a small decrease in the relevant MIC90 values. The copper complexes reduce the oxygen consumption of C. albicans while the silver complexes increase oxygen consumption. In addition, pre-growth of cells in the copper complexes resulted in a lower ergosterol content while the silver complexes induced an elevation in ergosterol synthesis. The ability of copper and silver complexes to alter the susceptibility of C. albicans to miconazole and amphotericin B may be influenced by their action on respiration, since reduced respiration rates correlate with reduced cellular ergosterol which is the target for amphotericin B. Lower levels of ergosterol have previously been associated with elevated tolerance to this drug. In the case of reduced sensitivity to miconazole, tolerance may be mediated by lower ergosterol synthesis giving rise to fewer toxic side products once biosynthesis is inhibited by miconazole.