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Science ; 366(6465): 606-612, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31672892


Microorganisms living inside plants can promote plant growth and health, but their genomic and functional diversity remain largely elusive. Here, metagenomics and network inference show that fungal infection of plant roots enriched for Chitinophagaceae and Flavobacteriaceae in the root endosphere and for chitinase genes and various unknown biosynthetic gene clusters encoding the production of nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). After strain-level genome reconstruction, a consortium of Chitinophaga and Flavobacterium was designed that consistently suppressed fungal root disease. Site-directed mutagenesis then revealed that a previously unidentified NRPS-PKS gene cluster from Flavobacterium was essential for disease suppression by the endophytic consortium. Our results highlight that endophytic root microbiomes harbor a wealth of as yet unknown functional traits that, in concert, can protect the plant inside out.

J Ind Microbiol Biotechnol ; 46(3-4): 483-492, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30729343


Actinobacteria are a major source of novel bioactive natural products. A challenge in the screening of these microorganisms lies in finding the favorable growth conditions for secondary metabolite production and dereplication of known molecules. Here, we report that Streptomyces sp. MBT27 produces 4-quinazolinone alkaloids in response to elevated levels of glycerol, whereby quinazolinones A (1) and B (2) form a new sub-class of this interesting family of natural products. Global Natural Product Social molecular networking (GNPS) resulted in a quinazolinone-related network that included anthranilic acid (3), anthranilamide (4), 4(3H)-quinazolinone (5), and 2,2-dimethyl-1,2-dihydroquinazolin-4(3H)-one (6). Actinomycins D (7) and X2 (8) were also identified in the extracts of Streptomyces sp. MBT27. The induction of quinazolinone production by glycerol combined with biosynthetic insights provide evidence that glycerol is integrated into the chemical scaffold. The unprecedented 1,4-dioxepane ring, that is spiro-fused into the quinazolinone backbone, is most likely formed by intermolecular etherification of two units of glycerol. Our work underlines the importance of varying the growth conditions for the discovery of novel natural products and for understanding their biosynthesis.

Descoberta de Drogas , Quinazolinonas/química , Streptomyces/química , Produtos Biológicos/química , Fermentação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , ortoaminobenzoatos/química
J Org Chem ; 80(20): 10252-60, 2015 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-26402731


Lasso peptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) that possess a unique "lariat knot" structural motif. Genome mining-targeted discovery of new natural products from microbes obtained from extreme environments has led to the identification of a gene cluster directing the biosynthesis of a new lasso peptide, designated as chaxapeptin 1, in the genome of Streptomyces leeuwenhoekii strain C58 isolated from the Atacama Desert. Subsequently, 1 was isolated and characterized using high-resolution electrospray ionization mass spectrometry and nuclear magnetic resonance methods. The lasso nature of 1 was confirmed by calculating its nuclear Overhauser effect restraint-based solution structure. Chaxapeptin 1 displayed a significant inhibitory activity in a cell invasion assay with human lung cancer cell line A549.

Produtos Biológicos/química , Linhagem Celular/química , Macrolídeos/química , Macrolídeos/farmacologia , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacologia , Peptídeos/química , Peptídeos/síntese química , Ribossomos/química , Streptomyces/química , Sequência de Aminoácidos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/metabolismo , Espectroscopia de Ressonância Magnética , Peptídeos Cíclicos/síntese química
Angew Chem Int Ed Engl ; 54(43): 12697-701, 2015 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-26206556


Pyrrolizidine alkaloids (PAs) are a group of natural products with important biological activities. The discovery and characterization of the multifunctional FAD-dependent enzyme LgnC is now described. The enzyme is shown to convert indolizidine intermediates into pyrrolizidines through an unusual ring expansion/contraction mechanism, and catalyze the biosynthesis of new bacterial PAs, the so-called legonmycins. By genome-driven analysis, heterologous expression, and gene inactivation, the legonmycins were also shown to originate from non-ribosomal peptide synthetases (NRPSs). The biosynthetic origin of bacterial PAs has thus been disclosed for the first time.

Produtos Biológicos/metabolismo , Carbamatos/metabolismo , Oxigenases de Função Mista/metabolismo , Alcaloides de Pirrolizidina/metabolismo , Streptomyces/enzimologia , Produtos Biológicos/química , Carbamatos/química , Genes Bacterianos , Oxigenases de Função Mista/química , Oxigenases de Função Mista/genética , Família Multigênica , Alcaloides de Pirrolizidina/química , Microbiologia do Solo , Streptomyces/química , Streptomyces/genética , Streptomyces/metabolismo