Synergistic antifungal interactions of amphotericin B with 4-(5-methyl-1,3,4-thiadiazole-2-yl) benzene-1,3-diol

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.