Penicillium and Talaromyces Species as Rich Sources of Medicinal Natural Products: Past, Present and Future

Filamentous fungi have long served as prolific producers of pharmacologically active natural compounds. Among them, species of Penicillium and Talaromyces occupy a central role in the history of natural product derived medicine. Penicillin, originally discovered from P. notatum in 1928, has transformed medicine and infectious disease through introducing the first widely effective antibacterial agent, inaugurating the antibiotic era. In the 1930s, it was discovered that P. griseofulvum and P. aethiopicum were able to synthesize griseofulvin, a landmark antifungal product. The first statin-like compound, compactin (mevastatin), was discovered in P. citrinum in the 1970s. Mycophenolic acid, first identified in P. brevicompactum, was discovered as a result of a hunt for antibacterial agents for Bacillus anthracis. Subsequently, its derivative, mycophenolate mofetil, was shown to inhibit inosine monophosphate dehydrogenase in lymphocytes; and since then, mycophenolic acid has become a key immunosuppressant for organ transplantation and autoimmune diseases. Historically, Penicillium and Talaromyces were separated primarily based on morphological criteria. In the beginning of this millennium, sequencing of multiple genetic markers revealed that some “Penicillium” species” actually formed a monophyletic group nested within Talaromyces, rather than clustered with the main Penicillium lineage. Both Penicillium and Talaromyces possess genomes rich in biosynthetic gene clusters responsible for producing polyketides, non-ribosomal peptides, terpenoids, and mixed-class metabolites. Most, if not all, of the known medicinal natural compounds produced by the Penicillium and Talaromyces species are synthesized by these biosynthetic gene clusters. Recent rigorous in silico analysis and genomic mining have revealed far more biosynthetic gene clusters than known metabolites.