Abstract
A poorly exploited paradigm in the antimicrobial therapy field is to target virulence traits for drug development. In contrast to target-focused approaches, antivirulence phenotypic screens enable identification of bioactive molecules that induce a desirable biological readout without making a priori assumption about the cellular target. Here, we screened a chemical library of 678 small molecules against the invasive hyphal growth of the human opportunistic yeast Candida albicans. We found that a halogenated salicylanilide (N1-(3,5-dichlorophenyl)-5-chloro-2-hydroxybenzamide) and one of its analogs, Niclosamide, an FDA-approved anthelmintic in humans, exhibited both antifilamentation and antibiofilm activities against C. albicans and the multi-resistant yeast C. auris. The antivirulence activity of halogenated salicylanilides were also expanded to C. albicans resistant strains with different resistance mechanisms. We also found that Niclosamide protected the intestinal epithelial cells against invasion by C. albicans. Transcriptional profiling of C. albicans challenged with Niclosamide exhibited a signature that is characteristic of the mitochondria-to-nucleus retrograde response. Our chemogenomic analysis showed that halogenated salicylanilides compromise the potential-dependant mitochondrial protein translocon machinery. Given the fact that the safety of Niclosamide is well established in humans, this molecule could represent the first clinically approved antivirulence agent against a pathogenic fungus.
Highlights
Candida albicans is an ascomycete fungus that is an important commensal and opportunistic pathogen in humans
We found that N1-(3,5-dichlorophenyl)-5-chloro2-hydroxybenzamide (TCSA: Tri-Chloro-Salicyanilide, for simplified nomenclature), a halogenated salicylanilide, was a potent antifilamentation molecule and inhibited biofilm formation of both C. albicans and the multi-resistant yeast C. auris
Inhibition of filamentation could be associated with the fact that small molecules are very toxic which might systematically alter all developmental process of a fungal cell such as morphogenesis
Summary
Candida albicans is an ascomycete fungus that is an important commensal and opportunistic pathogen in humans. Therapeutic options are limited to treatment with mainly three antifungal classes, namely polyenes, azoles and echinocandins[4] These compounds target the specific fungal biological process of ergosterol metabolism (azoles and polyenes) and cell wall β-1,3-glucan synthesis (echinocandins). There are currently a limited number of novel antifungal molecules on the drug discovery pipelines and most of them target the same cellular processes as azoles and echinocandins[5,6,7]. These molecules will most likely face the same limitations in term of resistance and toxicity. Antivirulence agents might provide an alternative strategy to circumvent antifungal resistance by disarming fungal resistant pathogens from their virulence factors[14]
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