The evolutionary history and chemical diversity of the echinocandin lipopeptide antifungal metabolites

The echinocandins comprise a major class of antifungal drugs that includes caspofungin, micafungin, and anidulafungin. Through genome sequencing of producing strains in our lab and in those of others, the gene clusters responsible for the major echinocandin-type antifungals have been discovered and mapped. The functions of most catalytic enzymes in the pathway have been elucidated by insertional inactivation or gene expression experiments followed by analysis of altered biosynthetic products. The relationships between gene cluster and chemical structural complexity has provided a framework for testing hypotheses about the evolutionary history of these potent cell-wall-active antifungal lipopeptides. Pathway gene orthologs were identified only among a narrow range of echinocandin-producing fungi of the Eurotiomycetes and Leotiomycetes, but were absent in other Ascomycetes. The most parsimonious explanation for the narrow bimodal Eurotiomycete-Leotiomycete distribution of these metabolites is horizontal gene transfer (HGT). Our results suggest that a HGT event transferred a primordial echinocandin gene cluster between an ancestral Aspergillus species and a Leotiomycete species. Following radiation and descent among a narrow range of Eurotiomycete and Leotiomycete species, pathways either recruited or lost an oxygenase gene for glutamine hydroxylation, a polyketide synthase for autonomous side chain biosynthesis, and an aryl sulfotransferase for homotyrosine sulfation. The echinocandin metabolites illustrate how eukaryote-to-eukaryote HGT may have contributed to diversification of secondary chemistry and evolution of antifungal self-resistance mechanisms during the expansion and radiation of the Ascomycete Fungi. Portions of the results have been recently published in: AEM, 2015, 81(5):1550-1558; NPR, 2014, 31:1348-1375; and BMC Genomics, 2013, 14:339.