Desketoneoenactin-Siderophore Conjugates for Candida : Evidence of Iron Transport-Dependent Species Selectivity

Abstract

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 siderophoredrug 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.

An encapsulation of iron homeostasis and virulence in Cryptococcus neoformans

“…Drugs that exploit iron uptake mechanism in pathogens also show great promise for therapy. For example, siderophores conjugated to antibiotics and other drugs could exploit uptake systems for entry and this Trojan horse’ approach has been investigated for bacterial, fungal and parasitic diseases [39, 56, 57]. Similarly, toxic analogs of heme, such as non-iron metalloprotoporphyhns depend on heme uptake systems for their inhibitory activity towards bacterial pathogens and show promise against C. neoformans [26, 35, 38].…”

Siderophore-Based Iron Acquisition and Pathogen Control

“…In many cases, the activity of the siderophore-conjugated antibiotics increased compared to those of the nonmodified antibiotics during conditions of iron starvation-mimicking growth conditions in various mammalian body fluids, thus proving the general potential of siderophore-dependent "Trojan horse" antibiotics for therapeutic applications. Not only antibacterial but also antifungal activities were provided by using nucleoside analogues such as 5-flourouridine (218) and neoenactin as well as derivatives such as norneoenactin and desketoneoenactin (18,112). Most of these compounds gave considerable inhibition of C. albicans (MIC Ͻ 1 VOL.…”

Design, Synthesis, and Testing of Non-Nephrotoxic Desazadesferrithiocin Polyether Analogues

“…44 A previous investigation focused on the design of desferrithiocin analogues that balance the lipophilicity/toxicity relationship while iron-clearing efficiency (ICE) is maintained in hopes of eliminating nephrotoxicity. 45 This study led to the less lipophilic, more water-soluble ligand, the polyether (S)-4,5-dihydro-2-[2-hydroxy-4-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (2). 45 A subsequent study assessing the impact of introducing the 3,6,9-trioxadecyloxy group at various positions of the desazadesferrithiocin aromatic ring 46 revealed the 3'-polyether analogue [(S)-4,5-dihydro-2-[2-hydroxy-3-(3,6,9-trioxadecyloxy)phenyl]-4-methyl-4-thiazolecarboxylic acid (3 , Table 1) to also be an orally active iron chelator.…”