Desketoneoenactin-siderophore conjugates for Candida: evidence of iron transport-dependent species selectivity.
We investigated the inhibitory activity of synthetic isocyanurate-based as well as linear mono- and trihydroxamate 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 siderophore-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.
Bernier
Geneviève
G
Département de Biologie, Faculté des Sciences, Université de Sherbrooke, 2500 Boul. Université, Sherbrooke, Canada J1K 2R1.
Girijavallabhan
Vinay
V
Murray
Aaron
A
Niyaz
Noormohamed
N
Ding
Pingyu
P
Miller
Marvin J
MJ
Malouin
François
F
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D000935:Antifungal Agents / Q000494:pharmacology; D002175:Candida / Q000145:classification / Q000187:drug effects* / Q000254:growth & development; D002176:Candida albicans / Q000187:drug effects / Q000254:growth & development; D003470:Culture Media; D006877:Hydroxamic Acids / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D017262:Siderophores / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013045:Species Specificity
D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D003470:Culture Media; D006877:Hydroxamic Acids; D017262:Siderophores; C014286:enactin; D007501:Iron