Synergistic fungicidal activities of amphotericin B and N-methyl-N"-dodecylguanidine: a constituent of polyol macrolide antibiotic niphimycin.
The synergy between the alkylguanidinium chain of niphimycin (NM), a polyol macrolide antibiotic, and polyene macrolide amphotericin B (AmB) without such an alkyl side chain was examined using N-methyl-N"-alkylguanidines as its synthetic analogs. Among the analogs, N-methyl-N"-dodecylguanidine (MC12) most strongly inhibited the growth of Saccharomyces cerevisiae cells and those of other fungal strains in synergy with AmB. MC12 itself was not lethal but the analog could be a cause of a rapid cell death progression of yeast cells in the presence of AmB at a nonlethal concentration. Their combined actions resulted in the generation of NM-like fungicidal activity that depended on plasma membrane disability and cellular reactive oxygen species production. We also found an aberrant vacuolar morphogenesis and an associated vacuolar membrane disability in cells treated simultaneously with MC12 and AmB, as in the case of NM-treated cells. These findings support the idea that the alkylguanidinium chain plays a major role in the fungicidal activity of NM in cooperation with the polyol lactone ring as its enhancer.
Ogita
Akira
A
Research Center for Urban Health and Sports, Osaka City University, 3-3-138 Sugimoto, Sumiyoshi-ku, Osaka 558-8585, Japan.
Matsumoto
Keiji
K
Fujita
Ken-ichi
K
Usuki
Yoshinosuke
Y
Hatanaka
Yoshiro
Y
Tanaka
Toshio
T
D000666:Amphotericin B / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology*; D002462:Cell Membrane / Q000187:drug effects; D002463:Cell Membrane Permeability / Q000187:drug effects; D004357:Drug Synergism; D006146:Guanidines / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D050296:Microbial Viability; D046529:Microscopy, Electron, Transmission; D008856:Microscopy, Fluorescence; D015394:Molecular Structure; D017382:Reactive Oxygen Species / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000254:growth & development / Q000648:ultrastructure; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
D000935:Antifungal Agents; D006146:Guanidines; C518890:N-methyl-N''-dodecylguanidine; D017382:Reactive Oxygen Species; D000666:Amphotericin B