Depletion of the squalene synthase (ERG9) gene does not impair growth of Candida glabrata in mice

Citation
H. Nakayama et al., Depletion of the squalene synthase (ERG9) gene does not impair growth of Candida glabrata in mice, ANTIM AG CH, 44(9), 2000, pp. 2411-2418
Citations number
32
Categorie Soggetti
Microbiology
Journal title
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
ISSN journal
00664804 → ACNP
Volume
44
Issue
9
Year of publication
2000
Pages
2411 - 2418
Database
ISI
SICI code
0066-4804(200009)44:9<2411:DOTSS(>2.0.ZU;2-0
Abstract
Squalene synthase (farnesyl-diphosphate farnesyltransferase, EC 2.5.1.21) i s the first committed enzyme of the sterol biosynthesis pathway. Inhibitors of this enzyme have been intensively studied as potential antifungal agent s. To assess the effect of deactivating squalene synthase on the growth of fungi in mice, we isolated the squalene synthase (ERG9) gene from the patho genic fungus Candida glabrata and generated strains in which the CgERG9 gen e was under the control of the tetracycline-regulatable promoter. Depletion of the ERG9 gene by doxycycline (DOX), a derivative of tetracycline, decre ased the cell viability in laboratory media, whereas it did not affect cell growth in mice at all. The growth defect caused by DOX in laboratory media was suppressed by the addition of serum. Analyses of the sterol compositio n of the restored cells in serum-containing media suggest that the defect o f ergosterol biosynthesis can be complemented by the incorporation of exoge nous cholesterol into the cells. Thus, deactivation of squalene synthase di d not affect fungal growth in mice, presumably because the cells were able to incorporate cholesterol from the serum, These results showed that squale ne synthase could not be a suitable target of antifungals for the treatment of C. glabrata infection.