The Interkingdom Interaction with Staphylococcus Influences the Antifungal Susceptibility of the Cutaneous Fungus Malassezia

Abstract

Analysis of the microbial community in the human body has revealed that fungi reside with other microbes, such as bacteria, protists, and viruses, within the community. This observation has led to several studies investigating the intra-or inter-kingdom interactions between microbial members influencing skin health and diseases [1][2][3]. For example, Pseudomonas aeruginosa and Aspergillus fumigatus often share the host niche, such as the airways of cystic fibrosis patients, and the interkingdom between the microorganisms is likely to occur within the same ecological site. In this scenario, P. aeruginosa produces metabolites, such as quorum sensing molecules and siderophores, that possess antifungal activity [4]. Furthermore, studies have reported the effect of bacteria on the antifungal susceptibility of pathogenic fungi. The interaction between Staphylococcus epidermidis and Candida albicans, co-colonizers of the skin, has also been investigated, especially in a mixed biofilm format. Fluconazole diffusion was retained, but no difference in susceptibility of C. albicans to the drug was observed in polymicrobial biofilms [5]. A direct influence of secreted enzymes, such as proteinase, from the major skinassociated fungus Malassezia on the biofilm formation of Staphylococcus aureus, a noteworthy skin opportunistic bacterial pathogen, was also demonstrated experimentally [6].Malassezia is a commensal fungus found on the skin surfaces of warm-blooded animals, including humans, and comprised of 18 species [7][8][9]. Several studies based on amplicon sequencing and metagenome analysis demonstrated that Malassezia is the most dominant genus in the human skin. This fungus has been associated with various skin diseases, such as seborrheic dermatitis, dandruff, and atopic dermatitis [10,11]. However, the roles of Malassezia in the skin must still be elucidated. Ketoconazole is an imidazole derivative and the most commonly used azole antifungal drug to treat Malassezia-associated skin diseases [12][13][14]. The mechanism of ketoconazole's action against pathogenic fungi includes inhibiting 14α-lanosterol demethylase, which is encoded by ERG11, and converting lanosterol to ergosterol in the ergosterol biosynthesis pathway for fungal membrane synthesis; this results in the accumulation of toxic sterols causing increased membrane stress and growth arrest [15,16]. Although the effectiveness of ketoconazole is well established, studies have reported that several fungal strains, including Malassezia, that have been isolated from clinical specimens were resistant to the drug [17][18][19]. InThe skin is a dynamic ecosystem on which diverse microbes reside. The interkingdom interaction between microbial species in the skin microbiota is thought to influence the health and disease of the skin although the roles of the intra-and interkingdom interactions remain to be elucidated. In this context, the interactions between Malassezia and Staphylococcus, the most dominant microorganisms in the skin microbiota, have gained attention. This...