Antifungal dipeptides incorporating an inhibitor of homoserine dehydrogenase

Abstract

The antifungal activity of 5-hydroxy-4-oxo-L-norvaline (HONV), exhibited under conditions mimicking human serum, may be improved upon incorporation of this amino acid into a dipeptide structure. Several HONV-containing dipeptides inhibited growth of human pathogenic yeasts of the Candida genus in the RPMI-1640 medium, with minimal inhibitory concentration values in the 32 to 64 μg mL −1 range. This activity was not affected by multidrug resistance that is caused by overexpression of genes encoding drug efflux proteins. The mechanism of antifungal action of HONV dipeptides involved uptake by the oligopeptide transport system, subsequent intracellular cleavage by cytosolic peptidases, and inhibition of homoserine dehydrogenase by the released HONV. The relative transport rates determined the anticandidal activity of HONV dipeptides.

Advances in the Synthesis of Enterobactin, Artificial Analogues, and Enterobactin-Derived Antimicrobial Drug Conjugates and Imaging Tools for Infection Diagnosis

“…120 121 122 Sideromycins translocate over the cell envelop barrier the same way as the incorporated siderophore, acting like a Trojan Horse described by Homer in The Odyssey . 70 , 123 124 125 126 127 Prominent examples are the albomycins 18 – 20 (Figure 4 ), 128 129 sideromycins produced by Streptomyces 130 bearing different derivatives of the natural seryl-tRNA synthetase inhibitor SB-217452 ( 21 ) as antimicrobial payload conjugated via an amide linkage to a trishydroxamate, ferrichrome-type siderophore. 131 The albomycins are taken up by the ferrichrome-specific siderophore receptor FhuA 130 132 and their payload gets intracellularly released by cleavage of the amide bond through an endogenous peptidase.…”

Molecular targets for antifungals in amino acid and protein biosynthetic pathways

“…It was also proven that HONV can be useful in systematic murine candidiasis treatment in mice (Yamaguchi et al 1988 ), however, its effectiveness under physiological conditions should be improved. One of the raised approaches was the eight dipeptides containing HONV as the C-terminal amino acid (Skwarecki et al 2018 ). Constructed dipeptides were tested for anticandidal activity in different media.…”

Amino Acid Based Antimicrobial Agents – Synthesis and Properties

“…l ‐Aspartate is a convenient substrate for preparation of δ‐hydroxy‐γ‐oxo‐norvaline. This amino acid, upon reaction with formaldehyde [160] or hexafluoroactetone,[ 161 , 162 ] forms an oxazolidin‐5‐one 196 affording a simultaneous protection of amino and α‐carboxyl functionalities. The free ω‐carboxyl can be then converted into acyl chloride and treated with diazomethane.…”