Desketoneoenactin-siderophore conjugates for Candida :: Evidence of iron transport-dependent species selectivity

被引:30
作者
Bernier, G
Girijavallabhan, V
Murray, A
Niyaz, N
Ding, PY
Miller, MJ
Malouin, F
机构
[1] Univ Sherbrooke, Fac Sci, Dept Biol, CEVDM, Sherbrooke, PQ J1K 2R1, Canada
[2] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
关键词
D O I
10.1128/AAC.49.1.241-248.2005
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
We investigated the inhibitory activity of synthetic isocyanurate-based as well as linear mono- and trihy-droxamate siderophore-drug conjugates against Candida spp. The conjugated drug was 13C-desketoneoenactin (DE). The MICs of siderophore-drug conjugates were determined in the absence and presence of 2,2'-dipyridyl to restrict iron availability. The ability of various siderophore types to promote growth in an iron-restricted medium was also assayed. Addition of a siderophore portion to the drug strongly impaired the inhibitory activity of DE. However, the activity of the drug conjugates was increased by up to 16-fold in iron-depleted medium for species having their growth strongly promoted by most hydroxamate-type siderophores (C. albicans, C. stellatoidea, and C. pseudotropicalis). The uptake of 55 Fe from ferrichrome and from two siderophore-drug conjugates was improved when C. albicans cells were grown in a low-iron medium. In the same assay, unlabeled ferrichrome was able to compete with the uptake of 55 Fe from both conjugates, indicating a common mechanism of uptake. A C. albicans strain lacking the siderophore transporter CaSit1/CaArn1 was not able to use ferrichrome or the synthetic ornithine-based trihydroxamate siderophore for growth promotion and was much less susceptible to the sideropbore-drug conjugates than its isogenic parent strain. In summary, the ability of some Candida spp. to use ferrichrome-like siderophores for growth promotion explains the selective activity of hydroxamate-drug conjugates, and this activity seems to be related to the presence, in C. albicans, of the siderophore transporter CaSit1/CaArn1. New conjugate designs are necessary to fully restore or improve the initial DE activity.
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页码:241 / 248
页数:8
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