Specialized Metabolites Reveal Evolutionary History and Geographic Dispersion of a Multilateral Symbiosis

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dc.contributor.authorFukuda, Taise T. H.en
dc.contributor.authorHelfrich, Eric J. N.en
dc.contributor.authorMeyers, Emilyen
dc.contributor.authorMelo, Weilan G. P.en
dc.contributor.authorVan Arnam, Ethan B.en
dc.contributor.authorAndes, David R.en
dc.contributor.authorCurrie, Cameron R.en
dc.contributor.authorPupo, Monica T.en
dc.contributor.authorClardy, Jonen
dc.contributor.departmentChemistryen
dc.date.accessioned2021-05-12T12:27:20Zen
dc.date.available2021-05-12T12:27:20Zen
dc.date.issued2021-02-24en
dc.description.abstractFungus-growing ants engage in a multilateral symbiosis: they cultivate a fungal garden as their primary food source and host symbiotic actinobacteria (Pseudonocardia spp.) that provide chemical defenses. The bacterial symbionts produce small specialized metabolites that protect the fungal garden from specific fungal pathogens (Escovopsis spp.), and in return, they are fed by the ant hosts. Multiple studies on the molecules underlying this symbiotic system have led to the discovery of a large number of structurally diverse antifungal molecules, but somewhat surprisingly no shared structural theme emerged from these studies. A large systematic study of Brazilian nests led to the discovery of the widespread production of a potent but overlooked antifungal agent, which we named attinimicin, by nearly two-thirds of all Pseudonocardia strains from multiple sites in Brazil. Here we report the structure of attinimicin, its putative biosynthetic gene cluster, and the evolutionary relationship between attinimicin and two related peptides, oxachelin A and cahuitamycin A. All three nonribosomal peptides are structural isomers with different primary peptide sequences. Attinimicin shows iron-dependent antifungal activity against specific environmental fungal parasites but no activity against the fungal cultivar. Attinimicin showed potent in vivo activity in a mouse Candida albicans infection model comparable to clinically used azole-containing antifungals. In situ detection of attinimicin in both ant nests and on worker ants supports an ecological role for attinimicin in protecting the fungal cultivar from pathogens. The geographic spread of the attinimicin biosynthetic gene cluster in Brazilian Pseudonocardia spp. marks attinimicin as the first specialized metabolite from ant-associated bacteria with broad geographic distribution.en
dc.description.notesThis work was supported by the Sao Paulo Research Foundation (FAPESP) #2015/26349-5 (T.T.H.F.), #2017/17305-0 (T.T.H.F.), #2015/01001-6 (W.G.P.M.) #2013/50954-0 (M.T.P.), and the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brasil (CAPES), Finance Code 001. This work was funded by #U19TW009872 and R01AT009874 (J.C.). We thank Munhyung Bae for the help with the mass spectrometry data and Allison Walker for the help with the bioinformatics. We thank the Information Technology Superintendence at the University of Sa~o Paulo for HPC resources. We thank both the Analytical Chemistry Core (ACC) facility in the Biological Chemistry and Molecular Pharmacology Department within Harvard Medical School for analytical support and the East Quad NMR facility at Harvard Medical School for NMR support. We thank the Duke University School of Medicine for the use of the Sequencing and Genomic Technologies Shared Resource, which provided sequencing service. We thank Zhu Zhuo, Shannan Ho Sui, and the Harvard Chan Bioinformatics Core, for the genome assembly. E.J.N.H. acknowledges funding from a Postdoc Mobility fellowship granted by the Swiss National Science Foundation. M.T.P. also thanks CNPq for research fellowship #303792/2018-3.en
dc.description.sponsorshipSao Paulo Research Foundation (FAPESP)Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP) [2015/26349-5, 2017/17305-0, 2015/01001-6, 2013/50954-0]; Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brasil (CAPES) [001]; Swiss National Science FoundationSwiss National Science Foundation (SNSF)European Commission; CNPqNational Council for Scientific and Technological Development (CNPq) [303792/2018-3]; [U19TW009872]; [R01AT009874]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1021/acscentsci.0c00978en
dc.identifier.eissn2374-7951en
dc.identifier.issn2374-7943en
dc.identifier.issue2en
dc.identifier.pmid33655067en
dc.identifier.urihttp://hdl.handle.net/10919/103249en
dc.identifier.volume7en
dc.language.isoenen
dc.rightsIn Copyright - Non-Commercial Useen
dc.rights.urihttp://rightsstatements.org/vocab/InC-NC/1.0/en
dc.titleSpecialized Metabolites Reveal Evolutionary History and Geographic Dispersion of a Multilateral Symbiosisen
dc.title.serialACS Central Scienceen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
dc.type.dcmitypeStillImageen

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