In Vitro Activity and In Vivo Efficacy of Icofungipen (PLD-118), a Novel Oral Antifungal Agent, against the Pathogenic Yeast Candida albicans

Abstract

Icofungipen (PLD-118) is the representative of a novel class of antifungals, beta amino acids, active against Candida species. It has been taken through phase II clinical trials. The compound actively accumulates in yeast, competitively inhibiting isoleucyl-tRNA synthetase and consequently disrupting protein biosynthesis. As a result, in vitro activity can be studied only in chemically defined growth media without free amino acids that would compete with the uptake of the compound. The MIC of icofungipen was reproducibly measured in a microdilution assay using yeast nitrogen base medium at pH 6 to 7 after 24 h of incubation at 30 to 37°C using an inoculum of 50 to 100 CFU/well. The MICs for 69 Candida albicans strains ranged from 4 to 32 g/ml. This modest in vitro activity contrasts with the strong in vivo efficacy in C. albicans infection. This was demonstrated in a lethal model of C. albicans infection in mice and rats in which icofungipen showed dose-dependent protection at oral doses of 10 to 20 mg/kg of body weight per day in mice and 2 to 10 mg/kg/day in rats. The in vivo efficacy was also demonstrated against C. albicans isolates with low susceptibility to fluconazole, indicating activity against azole-resistant strains. The efficacy of icofungipen in mice and rats was not influenced by concomitant administration of equimolar amounts of L-isoleucine, which was shown to antagonize its antifungal activity in vitro. Icofungipen shows nearly complete oral bioavailability in a variety of species, and its in vivo efficacy indicates its potential for the oral treatment of yeast infections.

The Double-Length Tyrosyl-tRNA Synthetase from the Eukaryote Leishmania major Forms an Intrinsically Asymmetric Pseudo-Dimer

“…For example, borrelidin is a highly specific anti-ThrRS macrolide produced by Streptomyces that shows anti-malarial activity 37 . Icofungipen is a competitive inhibitor of IleRS that has been shown to be effective against fluconazole-resistant Candida albicans 38 . Ding et al 39 have characterized a compound targeting LeuRS that inhibits growth of bloodstream-form T. brucei but is non-toxic to mammalian cell lines.…”

The antifungal pipeline: a reality check

“…For a variety of reasons, three groups of antifungal compounds — the aminocandins 60,61 , sordarins (which inhibit protein synthesis by stabilizing the ribosome–elongation factor 2 (Ef2) complex) 62 and icofungipen (which is an isoleucyl-tRNA synthesis inhibitor) 63 — have received little recent developmental attention, and a broad-spectrum triazole, albaconazole 64 , is now only studied for its use in treating superficial fungal infections, whereas before it was considered a potential compound for the treatment of systemic fungal diseases 65 . Therefore, these compounds are not emphasized in this Review.…”

Unusual Temperature‐Induced Retention Behavior of Constrained β‐Amino Acid Enantiomers on the Zwitterionic Chiral Stationary Phases ZWIX(+) and ZWIX(–)

“…Icofungipen (PLD‐118; (1 R ,2 S )‐2‐amino‐4‐methylenecyclopentanecarboxylic acid), a β‐amino acid, disturbs the biosynthesis of proteins in Candida albicans. The monoterpene‐based β‐amino acids are excellent building blocks for syntheses of monoterpene‐fused saturated 1,3‐heterocycles, β‐lactam‐based peptidomimetics or β‐peptidic foldamers …”