Unexpected link between iron and drug resistance of Candida spp.: iron depletion enhances membrane fluidity and drug diffusion, leading to drug-susceptible cells.
Inthis study, we show that iron depletion in Candida albicans with bathophenanthrolene disulfonic acid and ferrozine as chelators enhanced its sensitivity to several drugs, including the most common antifungal, fluconazole (FLC). Several other species of Candida also displayed increased sensitivity to FLC because of iron restriction. Iron uptake mutations, namely, Deltaftr1 and Deltaftr2, as well as the copper transporter mutation Deltaccc2, which affects high-affinity iron uptake in Candida, produced increased sensitivity to FLC compared to that of the wild type. The effect of iron depletion on drug sensitivity appeared to be independent of the efflux pump proteins Cdr1p and Cdr2p. We found that iron deprivation led to lowering of membrane ergosterol by 15 to 30%. Subsequently, fluorescence polarization measurements also revealed that iron-restricted Candida cells displayed a 29 to 40% increase in membrane fluidity, resulting in enhanced passive diffusion of the drugs. Northern blot assays revealed that the ERG11 gene was considerably down regulated in iron-deprived cells, which might account for the lowered ergosterol content. Our results show a close relationship between cellular iron and drug susceptibilities of C. albicans. Considering that multidrug resistance is a manifestation of multifactorial phenomena, the influence of cellular iron on the drug susceptibilities of Candida suggests iron as yet another novel determinant of multidrug resistance.
Prasad
Tulika
T
Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Mehrauli Road, New Delhi 110067, India.
Chandra
Aparna
A
Mukhopadhyay
Chinmay K
CK
Prasad
Rajendra
R
D000935:Antifungal Agents / Q000378:metabolism*; D002175:Candida / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism*; D003300:Copper / Q000378:metabolism; D003470:Culture Media; D004058:Diffusion; D015536:Down-Regulation / Q000187:drug effects; D025141:Drug Resistance, Fungal / Q000502:physiology; D004357:Drug Synergism; D004875:Ergosterol / Q000378:metabolism / Q000494:pharmacology; D015725:Fluconazole / Q000494:pharmacology; D016231:Fluorescence Polarization Immunoassay; D005838:Genotype; D006824:Hybridization, Genetic; D007501:Iron / Q000378:metabolism / Q000502:physiology*; D007502:Iron Chelating Agents / Q000494:pharmacology; D008560:Membrane Fluidity / Q000502:physiology*; D008826:Microbial Sensitivity Tests; D012331:RNA, Fungal / Q000096:biosynthesis
D000935:Antifungal Agents; D003470:Culture Media; D007502:Iron Chelating Agents; D012331:RNA, Fungal; D003300:Copper; D015725:Fluconazole; D007501:Iron; D004875:Ergosterol