The mode of action of the anti-fungal compounds, 1,10-phenanthroline (phen), [Cu(phen)2(mal)] x 2H2O, [Mn(phen)2(mal)] x 2H2O and [Ag2(phen)3(mal)] x 2H2O (malH2 = malonic acid), was examined using the pathogenic yeast Candida albicans. The compounds have minimum inhibitory concentrations (MIC's) in the range 1.25-5.0 microg cm(-3) and at a concentration of 10 microg cm(-3) display some fungicidal activity. Yeast cells exposed to these drugs show a diminished ability to reduce 2,3,5-triphenyltetrazolium chloride (TTC), indicating a reduction in respiratory function. Treating exponential and stationary phase yeast cells with phen and the Cu(II) and Mn(II) complexes causes a dramatic increase in oxygen consumption. All of the drugs promote reductions in the levels of cytochromes b and c in the cells, whilst the Ag(I) complex also lowers the amount of cytochrome aa3. Cells treated with phen and the Cu(II) and Ag(I) species show reduced levels of ergosterol whilst the Mn(II) complex induces an increase in the sterol concentration. The general conclusion is that the drugs damage mitochondrial function and uncouple respiration. That the drugs are not uniformly active suggests their bioactivity has a degree of metal-ion dependency. Phen and metal-phen complexes represent a novel set of highly active anti-fungal agents whose mode of action is significantly different to that of the polyene and azole prescription drugs.

Metal complexes of malonie acid (metal Mn(II), Co(II), Ni(II), Cu(II), Zn(II), Ag(I)) were prepared and only the Ag(I) complex inhibited the growth of Candida albicans. Malonate complexes incorporating the chelating 1,10-phenanthroline (1,10-phen) ligand showed a range of activities: good (Mn(II), Cu(lI), Ag(I)); moderate (Zn(II)); poor (Co(II), Ni(II)). Metal-free 1,10-phen and Ag(CH3CO2) were also highly active. The metal-free non-chelating ligands 1,7-phenanthroline and 4,7-phenanthroline were inactive and the Cu(II), Mn(II) and Zn(II) complexs of 1,7-phen displayed only marginal activity. Whereas the Cu(II) malonate/1,10-phen complex induces significant cellular oxidative stress the Zn(II) analogue does not.

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Copper(II) alpha,omega-dicarboxylate complexes of general formulae, [Cu(O2C(CH2)nCO2)].xH2O, [Cu(O2C(CH2)nCO2) (phen)2].xH2O and [Cu(O2C(CH2),CO2)(bipy)y].xH2O (n = 1-8; y = 1, 2; phen = 1,10-phenanthroline; bipy = 2,2'-bipyridine) were synthesised. These copper complexes, some related manganese(II) complexes and the metal-free ligands were screened in vitro for their ability to inhibit the growth of Candida albicans. Metal-free 1,10-phenanthroline and all of the copper(II) and manganese(II) phenanthroline complexes were potent growth inhibitors, with only one bipyridine complex, [Cu(O2C(CH2)CO2)(bipy)2].2H2O, having moderate activity. The remaining substances were effectively inactive. Complexes which were active against C. albicans also proved effective against C. glabratta, C. tropicalis and C. kreusi with the manganese complexes retaining superior activity. For the phenanthroline complexes the active drug species is thought to be the dication [M(phen)2(H2O)n]2+ (M = Cu, Mn). Escherichia coli and Staphylococcus aureus were resistant to all of the metal complexes and also to metal-free 1,10-phenanthroline. Only the copper phenanthroline complexes showed intermediate activity against Pseudomonas aeruginosa.