Abstract
Systemic mycoses are one major cause of morbidity/mortality among immunocompromised/debilitated individuals. Studying the mechanism of action is a strategy to develop safer/potent antifungals, warning resistance emergence. The major goal of this study was to elucidate the mechanism of action of three (Z)-5-amino-N’-aryl-1-methyl-1H-imidazole-4-carbohydrazonamides (2h, 2k, 2l) that had previously demonstrated strong antifungal activity against Candida krusei and C. albicans ATCC strains. Activity was confirmed against clinical isolates, susceptible or resistant to fluconazole by broth microdilution assay. Ergosterol content (HPLC-DAD), mitochondrial dehydrogenase activity (MTT), reactive oxygen species (ROS) generation (flow cytometry), germ tube inhibition and drug interaction were evaluated. None of the compounds inhibited ergosterol synthesis. Ascorbic acid reduced the antifungal effect of compounds and significantly decreased ROS production. The metabolic viability of C. krusei was significantly reduced for values of 2MIC. Compounds 2h and 2k caused a significant increase in ROS production for MIC values while for 2l a significant increase was only observed for concentrations above MIC. ROS production seems to be involved in antifungal activity and the higher activity against C. krusei versus C. albicans may be related to their unequal sensitivity to different ROS. No synergism with fluconazole or amphotericin was observed, but the association of 2h with fluconazole might be valuable due to the significant inhibition of the dimorphic transition, a C. albicans virulence mechanism.
Highlights
The search for new antifungal drugs can be based on two different approaches: (i) has stimulated the search for new antifungal agents [3,4]
The search for molecules with antifungal activity correlated with the interference in a speThe search for new antifungal drugs can be based on two different approaches: (i) the cific target on the fungal and/oractivity (ii) thecorrelated search forwith molecules that caninimprove search for molecules with cell antifungal the interference a specificthe activity of an already recognized antifungal agent
Our results suggest that the mechanism underlying the inhibition of C. albicans filamentation by compound 2h was not mediated by the inhibition of the yeast NADH-dehydrogenase since this compound did not interfere with mitochondrial activity, as determined by the mitochondrial dehydrogenase activity (MTT) assay
Summary
Systemic mycoses are one major cause of morbidity and mortality among immunocompromised (HIV infection, neutropenic and transplanted) and debilitated individuals. Systemic mycoses are one major cause of morbidity and mortality among immuno of 13 compromised (HIV infection, neutropenic and transplanted) and debilitated individuals attending health care institutions (e.g., intensive care units) [1,2]. Are increment of fungal andCandida resistance to responsiantifungal ble for the majority of the yeast-like systemic mycosis [1,2]. The search for molecules with antifungal activity correlated with the interference in a speThe search for new antifungal drugs can be based on two different approaches: (i) the cific target on the fungal and/oractivity (ii) thecorrelated search forwith molecules that caninimprove search for molecules with cell antifungal the interference a specificthe activity of an already recognized antifungal agent [5].
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