Fukuda, Taise T. H.
Helfrich, Eric J. N.
[2, 3, 4]
Melo, Weilan G. P.
Van Arnam, Ethan B.
[2, 6, 7]
Andes, David R.
Currie, Cameron R.
Pupo, Monica T.
Total Authors: 9
 Univ Sao Paulo, Sch Pharmaceut Sci Ribeirao Preto, BR-14040903 Ribeirao Preto, SP - Brazil
 Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02115 - USA
 Virginia Tech, Dept Chem, Blacksburg, VA 24061 - USA
 Pitzer Coll, Keck Sci Dept, Claremont McKenna, Claremont, CA 91711 - USA
 Scripps Coll, Keck Sci Dept, Claremont McKenna, Claremont, CA 91711 - USA
 Univ Wisconsin, Dept Med, Sch Med & Publ Hlth, Madison, WI 53705 - USA
 Univ Wisconsin, Dept Bacteriol, Madison, WI 53706 - USA
Total Affiliations: 9
ACS CENTRAL SCIENCE;
FEB 24 2021.
Web of Science Citations:
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)