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

Author(s)

Fukuda, Taise T. H. ^{[1, 2]} ; Helfrich, Eric J. N. ^{[2, 3, 4]} ; Meyers, Emily ^{[2, 5]} ; Melo, Weilan G. P. ^[1] ; Van Arnam, Ethan B. ^{[2, 6, 7]} ; Andes, David R. ^[8] ; Currie, Cameron R. ^[9] ; Pupo, Monica T. ^[1] ; Clardy, Jon ^[2]

Affiliation

^[1] Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil

^[2] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 - USA

^[3] Goethe Univ Frankfurt, Inst Mol Bio Sci, D-60438 Frankfurt - Germany

^[4] LOEWE Ctr Translat Biodivers Genom TBG, D-60325 Frankfurt - Germany

^[5] Virginia Tech, Dept Chem, Blacksburg, VA 24061 - USA

^[6] Pitzer Coll, Keck Sci Dept, Claremont McKenna, Claremont, CA 91711 - USA

^[7] Scripps Coll, Keck Sci Dept, Claremont McKenna, Claremont, CA 91711 - USA

^[8] Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53705 - USA

^[9] Univ Wisconsin, Dept Bacteriol, Madison, WI 53706 - USA

• Document type: Journal article
• Source: ACS CENTRAL SCIENCE; v. 7, n. 2, p. 292-299, FEB 24 2021.
• Web of Science Citations: 1

Abstract

Fungus-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. (AU)

• FAPESP's process: 15/01001-6 - Discovering bacterial symbionts diversity associated with ants in different Brazilian biomes
• Grantee: Weilan Gomes da Paixão Melo
• Support type: Scholarships in Brazil - Post-Doctorate
• FAPESP's process: 13/50954-0 - Novel therapeutic agents from the bacterial symbionts of Brazilian invertebrates
• Grantee: Mônica Tallarico Pupo
• Support type: BIOTA-FAPESP Program - Thematic Grants
• FAPESP's process: 15/26349-5 - Chemical and ecological study of microorganisms associated with the symbiosis Cecropia-Azteca
• Grantee: Taise Tomie Hebihara Fukuda
• Support type: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 17/17305-0 - Understanding the bacterial symbiosis in Cecropia-Azteca system using chemical and genetic tools
• Grantee: Taise Tomie Hebihara Fukuda
• Support type: Scholarships abroad - Research Internship - Doctorate (Direct)