Rediscovery of viomellein as an antibacterial compound and identification of its biosynthetic gene cluster in dermatophytes.

Fungi produce a wide variety of compounds, especially those that exhibit biological activity. Such compounds may aid the survival of fungi in the environment or may contribute to host infection for pathogenic species. Regarding dermatophytes, which affect a large number of patients worldwide, studies on metabolites that exhibit biological activity are scarce. In this study, to gain insight into the interaction with skin microbiota at the site of infection, we searched for compounds that exhibit antibacterial activity among the metabolites of Trichophyton rubrum. We rediscovered viomellein, a red pigment, as a potent antibacterial compound and identified its biosynthetic gene (vio) cluster by RNA-sequencing and gene deletion analyses. Sequential reconstruction of the vio cluster genes in Aspergillus oryzae revealed the biosynthetic pathway for viomellein via nor-toralactone, semivioxanthin, and vioxanthin production. The vio gene cluster is widely conserved among dermatophytes and is also present in some Aspergillus and Penicillium species. Consistent with the results, viomellein and its structural analogs, xanthomegnin, and vioxanthin, were shown to be produced by most dermatophyte species. These results suggest that dermatophytes can produce diverse naphthopyranone compounds, some of which have strong growth inhibitory effects against bacteria. This study provides a previously unknown molecular entity for antibiotic production by dermatophytes and provides insight into the interaction between commensal bacteria and dermatophytes.IMPORTANCEDermatophytes are widespread human pathogens in the world, but the mechanisms of infection have been little studied. Although bacterial density at the site of infection is abundant, interaction between dermatophytes and the bacterial community has not yet been studied. Here, to understand the infection ecology of dermatophytes, we searched for antimicrobial substances that would be effective against the dermal bacterial community. We discovered viomellein, which exhibits strong antibacterial activity against gram-positive bacteria such as Staphylococcus aureus, and its biosynthetic genes are shared not only by dermatophytes but also by other fungi. Since many dermatophytes showed the ability to produce viomellein, it is likely that this is the initial infection strategy of dermatophytes, which has been a mystery for long.