Abstract
Amphotericin B (AmB) is a very potent antifungal drug with very rare resistance among clinical isolates. Treatment with the AmB formulations available currently is associated with severe side effects. A promising strategy to minimize the toxicity of AmB is reducing its dose by combination therapy with other antifungals, showing synergistic interactions. Therefore, substances that display synergistic interactions with AmB are still being searched for. Screening tests carried out on several dozen of synthetic 1,3,4-thiadiazole derivatives allowed selection of a compound called 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (abbreviated as C1), which shows strong synergistic interaction with AmB and low toxicity towards human cells. The aim of the present study was to investigate the type of in vitro antifungal interactions of the C1 compound with AmB against fungal clinical isolates differing in susceptibility. The results presented in the present paper indicate that the C1 derivative shows strong synergistic interaction with AmB, which allows the use of a dozen to several dozen times lower AmB concentration necessary for 100% inhibition of the growth of pathogenic fungi in vitro. Synergistic interactions were noted for all tested strains, including strains with reduced sensitivity to AmB and azole-resistant isolates. These observations give hope for the possibility of application of the AmB - C1 combinatory therapy in the treatment of fungal infections.
Highlights
With ergosterol contained in the fungal cell membranes, leading to increased permeability to ions and small organic molecules
The plasma Amphotericin B (AmB) concentration in clinical practice should not exceed [1,2] μg/mL; it is ineffective against strains for which the minimal inhibitory concentration (MIC) value is higher than 1 μg/mL, e.g. for Candida strains other than albicans, especially C. glabrata and C. parapsilosis[8]
It was reported that simpotentin, which is a glycolipid composed of a mannosyl group with two medium-chain fatty acids, produced by Simplicillium minatense potentiates AmB activity against C. albicans determined with the in vitro microdilution method[32]
Summary
With ergosterol contained in the fungal cell membranes, leading to increased permeability to ions and small organic molecules. A promising strategy to minimize the toxicity of AmB is to reduce its dose by combination therapy with other antifungals, showing synergistic interactions. Among the studied derivatives of 5-substituted 4-(1,3,4-thiadiazol-2-yl) benzene-1,3-diols, only a compound called 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol (abbreviated as C1) showed strong synergistic interaction with AmB and low toxicity towards human cells This compound has a relatively simple structure (Fig. 1), in which the heterocyclic ring of 1,3,4-thiadiazole is substituted by the benzene-1,3-diol in the 2-position and by the methyl group in the 5-position and is used as a scaffold for the synthesis of more biologically active derivatives possessing antifungal, antitumor, and neuroprotective potential[35,36,37,38,39]. The aim of the present study was to investigate the type of in vitro antifungal interactions of the C1 compound with AmB against clinical isolates of fungal pathogens with different susceptibility to antifungals
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