The mechanism of overcoming multidrug resistance (MDR) of fungi by amphotericin B and its derivatives.
Comparative studies were performed to determine the activity and cytotoxicity of amphotericin B (AmB) and its derivatives on standard strain of Saccharomyces cerevisiae and its transformants with cloned genes from Candida albicans encoding multidrug resistance (MDR) pumps of ATP-binding cassette and major facilitator superfamilies. The AmB derivatives: amphotericin B 3-dimethylaminopropyl amide and N-methyl-N-D-fructopyranosylamphotericin B methyl ester were shown to be fungistatic and fungicidal towards MDR strains, by membrane permeabilization mechanism. Antibiotic-cell interaction monitored by energy transfer method indicates similar membrane affinity in parent strain and its MDR transformants. Experiments with fungal cells loaded with rhodamine 6G point to lack of competition between this dye and AmB and its derivatives for efflux driven by CDR2p. It can be thus assumed that AmB and its derivatives overcome fungal MDR by not being substrates of the multidrug exporting pumps, presumably due to their large molecular volumes.
Slisz
Magdalena
M
Department of Pharmaceutical Technology and Biochemistry, Gdansk University of Technology, Poland.
Cybulska
Barbara
B
Grzybowska
Jolanta
J
Czub
Jacek
J
Prasad
Rajendra
R
Borowski
Edward
E
D018528:ATP-Binding Cassette Transporters; D000666:Amphotericin B / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology*; D000935:Antifungal Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics; D026141:Drug Resistance, Multiple, Fungal / Q000235:genetics; D005658:Fungi; D005800:Genes, Fungal / Q000187:drug effects; D019450:Genes, MDR / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000235:genetics; D014170:Transformation, Genetic
D018528:ATP-Binding Cassette Transporters; D000935:Antifungal Agents; D000666:Amphotericin B