Gemini quaternary ammonium compound PMT12-BF4 inhibits Candida albicans via regulating iron homeostasis

Li-Hang Hsu,Daria Wieczorek,Dobrawa Kwaśniewska,Tang-Long Shen,Shih-Cheng Wang,Ying-Lien Chen

doi:10.1038/s41598-020-59750-5

Li-Hang Hsu, Daria Wieczorek + Show 4 more

Open Access

https://doi.org/10.1038/s41598-020-59750-5

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Abstract

Quaternary ammonium compounds (QACs) are classified as cationic surfactants, and are known for their biocidal activity. However, their modes of action are thus far not completely understood. In this study, we synthesized a gemini QAC, PMT12-BF4 and found that it exerted unsurpassed broad-spectrum antifungal activity against drug susceptible and resistant Candida albicans, and other pathogenic fungi, with a minimal inhibitory concentration (MIC) at 1 or 2 μg/mL. These results indicated that PMT12-BF4 used a mode of action distinct from current antifungal drugs. In addition, fungal pathogens treated with PMT12-BF4 were not able to grow on fresh YPD agar plates, indicating that the effect of PMT12-BF4 was fungicidal, and the minimal fungicidal concentration (MFC) against C. albicans isolates was 1 or 2 μg/mL. The ability of yeast-to-hyphal transition and biofilm formation of C. albicans was disrupted by PMT12-BF4. To investigate the modes of action of PMT12-BF4 in C. albicans, we used an RNA sequencing approach and screened a C. albicans deletion mutant library to identify potential pathways affected by PMT12-BF4. Combining these two approaches with a spotting assay, we showed that the ability of PMT12-BF4 to inhibit C. albicans is potentially linked to iron ion homeostasis.

Highlights

Candida albicans is an opportunistic fungal pathogen causing candidiasis mainly in immunocompromised individuals with candidemia, or superficial infections such as oral thrush and vaginal infections[1]
Simple surfactants whose structures are based on quaternary ammonium compounds (QACs) are usually made of a positive nitrogen atom with four substituents attached to the nitrogen atom, at least one of which is a long alkyl chain
PMT12-BF4 was effective against non-albicans Candida species including C. tropicalis MYA3404 (2 μg/mL) and C. glabrata CBS138 (1 μg/ mL), and other human or plant pathogenic fungi such as Cryptococcus neoformans H99 (1 μg/mL), Aspergillus fumigatus AF293 (2 μg/mL), Fusarium oxysporum FOSC3-a (2 μg/mL), and Fusarium oxysporum f. sp. lycopersici 4287 (2 μg/mL) (Table 2)

Summary

Introduction

Candida albicans is an opportunistic fungal pathogen causing candidiasis mainly in immunocompromised individuals with candidemia, or superficial infections such as oral thrush and vaginal infections[1]. QACs have biocidal activity against Gram-positive and Gram-negative bacteria and against fungal pathogens[6,7]. Polar heads can have a positive charge when synthesized from quaternary ammonium salts, and they can be substituted with alkyl chains called tails. The reason for the increased activity of gemini surfactants is the larger total number of carbon atoms in the hydrophobic chains[9,10]. Their biocidal properties are noteworthy and characterized by a broad spectrum of antimicrobial activity[11,12]. Candida tropicalis MYA3404 Candida glabrata CBS138 Cryptococcus neoformans H99 Malassezia furfur BCRC22950 Aspergillus fumigatus AF293 Fusarium oxysporum FOSC3-a Fusarium oxysporum f. sp. lycopersici 4287

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