Evolution of Chemical Diversity in Echinocandin Lipopeptide Antifungal Metabolites

Abstract

The echinocandins are a class of antifungal drugs that includes caspofungin, micafungin, and anidulafungin. Gene clusters encoding most of the structural complexity of the echinocandins provided a framework for hypotheses about the evolutionary history and chemical logic of echinocandin biosynthesis. Gene orthologs among echinocandin-producing fungi were identified. Pathway genes, including the nonribosomal peptide synthetases (NRPSs), were analyzed phylogenetically to address the hypothesis that these pathways represent descent from a common ancestor. The clusters share cooperative gene contents and linkages among the different strains. Individual pathway genes analyzed in the context of similar genes formed unique echinocandinexclusive phylogenetic lineages. The echinocandin NRPSs, along with the NRPS from the inp gene cluster in Aspergillus nidulans and its orthologs, comprise a novel lineage among fungal NRPSs. NRPS adenylation domains from different species exhibited a one-to-one correspondence between modules and amino acid specificity that is consistent with models of tandem duplication and subfunctionalization. Pathway gene trees and Ascomycota phylogenies are congruent and consistent with the hypothesis that the echinocandin gene clusters have a common origin. The disjunct Eurotiomycete-Leotiomycete distribution appears to be consistent with a scenario of vertical descent accompanied by incomplete lineage sorting and loss of the clusters from most lineages of the Ascomycota. We present evidence for a single evolutionary origin of the echinocandin family of gene clusters and a progression of structural diversification in two fungal classes that diverged approximately 290 to 390 million years ago. Lineagespecific gene cluster evolution driven by selection of new chemotypes contributed to diversification of the molecular functionalities.

Structural diversity in echinocandin biosynthesis: the impact of oxidation steps and approaches toward an evolutionary explanation

“…With this background, the example of pneumocandin biosynthesis in G. lozoyensis (Helotiales), which is by far the best-documented system among the echinocandin producers [2,7,9,[17][18][19][20] is now examined in an effort to ascertain if one of the models can be applied to echinocandin biosynthesis. During pneumocandin fermentation development at Merck & Co. Research Laboratories, over two dozen different pneumocandins were identified [9], with the chemical structures being reported for 16 of these derivatives.…”

“…The history of exploring echinocandin biosynthesis has been featured in previous review articles [1,2,[7][8][9]. In brief, the biosynthetic origin of the non-proteinogenic amino acids and the dimethylmyristate side chain was elucidated in the early 1990s by groups of Tang and Walsh disclosed the genes encoding echinocandin B biosynthesis in the genome of Aspergillus pachycristatus NRRL 11440 (formerly Emericella rugulosa) [13].…”

Aspergillus section Nidulantes (formerly Emericella): Polyphasic taxonomy, chemistry and biology

“…echinulatus ) (Nyfeler & Keller-Schierlein 1974), A. parvathecius, A. navahoensis , A. quadrilineatus , A. rugulosus and A. pachycristatus (= “ Aspergillus nidulans var. roseus ” nomen nudum ) (Boeckner and Kastner, 1981, Klich et al., 2001, de la Cruz et al., 2012, Matsuzawa et al., 2012, Bills et al., 2014, Yue et al., 2015). Aflatoxin production is observed in A. astellatus ( = E. astellata ), A. venezuelensis (= E. venezuelensis ) and A. olivicola (= E. olivicola ) (Frisvad and Samson, 2004, Frisvad et al., 2004, Zalar et al., 2008).…”

Fungal Metabolites for the Control of Biofilm Infections

“…Gene organizations point to aculeacin 74 as having the most ancient biosynthesis pathway, whereas FR190293 81 has the most evolved one. Since no sign of horizontal gene transfer from bacteria could be observed, an origin of echinocandin biosynthesis in the genus Aspergillus can be assumed [120,121].…”