Antileishmanial macrolides from ant-associated Streptomyces sp. ISID311

  • Bioorg Med Chem. 2021 Feb 15:32:116016. doi: 10.1016/j.bmc.2021.116016.
Humberto E Ortega  1 ,  Vitor B Lourenzon  1 ,  Marc G Chevrette  2 ,  Leonardo L G Ferreira  3 ,  René F Ramos Alvarenga  4 ,  Weilan G P Melo  1 ,  Tiago Venâncio  5 ,  Cameron R Currie  6 ,  Adriano D Andricopulo  3 ,  Tim S Bugni  7 ,  Mônica T Pupo  8
Affiliations
  • 1. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil.
  • 2. Wisconsin Institute for Discovery and Department of Plant Pathology, University of Wisconsin-Madison, Madison, WI, United States.
  • 3. Laboratório de Química Medicinal e Computacional, Centro de Pesquisa e Inovação em Biodiversidade e Fármacos, Instituto de Física de São Carlos, Universidade de São Paulo, Av. João Dagnone 1100, São Carlos-SP 13563-120, Brazil.
  • 4. Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, United States.
  • 5. Department of Chemistry, Federal University of São Carlos, 13565-905 São Carlos, Brazil.
  • 6. Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, United States.
  • 7. Pharmaceutical Sciences Division, University of Wisconsin-Madison, Madison, WI, United States. Electronic address: [email protected].
  • 8. Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brazil. Electronic address: [email protected].
PMID: 33493972 DOI: 10.1016/j.bmc.2021.116016
Abstract

Three Antifungal macrolides cyphomycin (1), caniferolide C (2) and GT-35 (3) were isolated from Streptomyces sp. ISID311, a Bacterial symbiont associated with Cyphomyrmex fungus-growing ants. The planar structures of these compounds were established by 1 and 2D NMR data and MS analysis. The relative configurations of 1-3 were established using Kishi's universal NMR database method, NOE/ROE analysis and coupling constants analysis assisted by comparisons with NMR data of related compounds. Detailed bioinformatic analysis of cyphomycin biosynthetic gene cluster confirmed the stereochemical assignments. Compounds 1-3 displayed high antagonism against different strains of Escovopsis sp., pathogen fungi specialized to the fungus-growing ant system. Compounds 1-3 also exhibited potent antiprotozoal activity against intracellular amastigotes of the human parasite Leishmania donovani with IC50 values of 2.32, 0.091 and 0.073 µM, respectively, with high selectivity indexes.

Keywords
Fungus-growing ants; Leishmania donovani; Macrolides; Polyketides; Streptomyces.