Gliotoxin Production and Self-Defense in Filamentous Fungi

Gliotoxin (GT) is a sulfur-containing secondary metabolite that belongs to a class of naturally occurring 2,5-diketopiperazines produced by fungi. Although GT production has been observed only in a few species, GT is the most studied fungal secondary metabolite, and the GT biosynthetic gene cluster (BGC) is broadly present in filamentous fungi. GT has a multitarget mechanism of action: It is fungicidal and bacteriostatic, it induces apoptosis in mammalian cells, and it modulates phagocytosis and neutrophil attraction. GT is important for Aspergillus fumigatus virulence and pathogenesis in humans and in animals and for Trichoderma spp. symbiotic and antagonistic behavior. GT is also toxic for producer and nonproducer organisms. Consequently, very sophisticated mechanisms of GT self-protection have evolved in producers; some of these protective mechanisms are also found in nonproducer organisms. This review discusses the distribution of the GT BGC among filamentous fungi and discusses GT biosynthesis, mechanisms of action and self-defense, and ecological properties.