Antifungal activity of fluconazole in combination with lovastatin and their effects on gene expression in the ergosterol and prenylation pathways in Candida albicans.
The sterol pathway in Candida albicans is the target for several classes of antifungal drugs. Intermediates in the sterol pathway are involved in ergosterol synthesis, prenylation and dolichol synthesis. This study examines gene expression of the sterol pathway in response to lovastatin, an inhibitor of HMG-CoA reductase (Hmg1p), and fluconazole, an inhibitor of 14 alpha-lanosterol demethylase (Erg11p). Minimum inhibitory concentration (MIC) studies indicated that lovastatin acts synergistically with fluconazole in vitro. Semi-quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) results indicated that genes in the early part of the sterol pathway, such as HMG1 and ERG20, did not alter expression in the presence of both lovastatin and fluconazole, whereas genes in the later part of the sterol pathway, such as ERG9 and ERG11, had increased expression in response to these drugs in mid-logarithmic growth. Genes involved in prenylation, such as RAM1 and RAM2, also respond to these drugs in mid-logarithmic growth, although another prenylation gene, CDC43, was not affected. After 24 h of growth, the relative expression of ERG20, ERG9, and ERG11 remained unchanged or increased in the presence of both drugs, while all other genes decreased in expression under all drug treatments.
Song
Jia L
JL
Department of Pathobiology, School of Public Health and Community Medicine, University of Washington, Seattle, Washington, USA.
Lyons
Chris N
CN
Holleman
Scott
S
Oliver
Brian G
BG
White
Theodore C
TC
D001483:Base Sequence; D002176:Candida albicans / Q000187:drug effects / Q000235:genetics* / Q000254:growth & development; D017931:DNA Primers; D004357:Drug Synergism; D004875:Ergosterol / Q000096:biosynthesis / Q000235:genetics*; D015725:Fluconazole / Q000494:pharmacology*; D015966:Gene Expression Regulation, Fungal / Q000187:drug effects*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008148:Lovastatin / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D017368:Protein Prenylation / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D015725:Fluconazole; D008148:Lovastatin; D004875:Ergosterol