Summary auto-generated
This study investigates whether Streptomyces bacteria produce FK506, FK520 (ascomycin), and rapamycin as natural antimicrobial toxins to inhibit competing microorganisms, rather than solely as immunosuppressants. Using growth inhibition assays and genetic approaches, researchers tested three Streptomyces strains against FK506/FK520-sensitive and rapamycin-sensitive yeast (Saccharomyces cerevisiae) and fungal (Cryptococcus neoformans) strains, as well as drug-resistant mutants. Wild-type toxin-producing Streptomyces strains strongly inhibited growth of sensitive cells, while mutant yeast and fungal strains lacking FKBP12 protein or expressing drug-resistant calcineurin or TOR mutations showed resistance. Streptomyces mutants with defective FK506 or rapamycin biosynthetic enzymes produced reduced inhibitory activity. Two-hybrid experiments confirmed that secreted compounds promoted FKBP12/calcineurin and FKBP12/TOR complex formation. These findings support the hypothesis that Streptomyces evolved to synthesize and secrete these compounds as antimicrobial agents against soil competitors, exploiting conserved signaling proteins from unicellular eukaryotes to mammals.
Key findings
- Streptomyces species secrete FK506, FK520, and rapamycin at levels sufficient to inhibit growth of competing Saccharomyces cerevisiae and Cryptococcus neoformans in culture
- Growth inhibition by Streptomyces toxins requires FKBP12 and its targets (calcineurin or TOR kinases), as demonstrated by resistance of mutant microorganisms lacking these proteins
- Streptomyces mutants with disrupted FK506 or rapamycin biosynthetic pathways show dramatically reduced ability to inhibit competitor growth, confirming these compounds are the primary antimicrobial agents
- The secreted toxins promote FKBP12/calcineurin and FKBP12/TOR complex formation in two-hybrid assays, indicating direct interaction with target proteins
- These results support that FK506, FK520, and rapamycin evolved as natural antimicrobial toxins for soil competition, not as immunosuppressants for mammalian T-cell inhibition
This summary was generated automatically from the article PDF and is not part of the original publication. Refer to the PDF for the authoritative text.
Abstract
FK506 and rapamycin are immunosuppressants that inhibit signalling cascades required for T-cell activation, yet both are natural products of Streptomyces that live in the soil. FK506 and rapamycin also have potent antimicrobial activity against yeast and pathogenic fungi, suggesting a natural role in inhibiting growth of competing micro-organisms. The immunosuppressive and antimicrobial activities of FK506 and rapamycin are mediated by binding to the FKBP12 prolyl isomerase and the resulting FKBP12/FK506 and FKBP12/rapamycin complexes inhibit conserved protein targets, either the phosphatase calcineurin or the TOR (target of rapamycin) kinases, respectively. Streptomyces sp., 'Streptomyces hygroscopicus subsp. ascomyceticus' and Streptomyces hygroscopicus, which produce FK506, FK520 (also known as ascomycin, a C21 ethyl derivative of FK506) and rapamycin, respectively, produced toxins that inhibited the growth of competing cells of the yeast Saccharomyces cerevisiae and the pathogenic fungus Cryptococcus neoformans. Yeast and fungal mutants lacking FKBP12 or expressing dominant drug-resistant calcineurin or TOR mutants were resistant to FK506 and rapamycin, and to the toxins produced by Streptomyces. Streptomyces strains with mutations in the FK506 or rapamycin biosynthetic enzymes were impaired in toxin production. Finally, the toxins secreted by 'S. hygroscopicus subsp. ascomyceticus' and S. hygroscopicus promoted formation of FKBP12/calcineurin and FKBP12/TOR complexes in a two-hybrid assay and mutations that rendered calcineurin or TOR drug-resistant prevented interaction. These observations support the hypothesis that Streptomyces evolved to secrete FK506, FK520 and rapamycin as toxins to inhibit the growth of competing yeast and fungi.