RESUMO
Anaerobic bacteria have only recently been recognized as a source of antibiotics; yet, the metabolic potential of Negativicutes (Gram-negative staining Firmicutes) such as the oak-associated Dendrosporobacter quercicolus has remained unknown. Genome mining of D. quercicolus and phylogenetic analyses revealed a gene cluster for a typeâ II polyketide synthase (PKS) complex that belongs to the most ancestral enzyme systems of this type. Metabolic profiling, NMR analyses, and stable-isotope labeling led to the discovery of a new family of anthraquinone-type polyphenols, the dendrubins, which are diversified by acylation, methylation, and dimerization. Dendrubinâ A and B were identified as strong antibiotics against a range of clinically relevant, human-pathogenic mycobacteria.
Assuntos
Policetídeo Sintases , Quercus , Antibacterianos/química , Antibacterianos/farmacologia , Firmicutes , Humanos , Família Multigênica , Filogenia , Policetídeo Sintases/química , Policetídeo Sintases/genéticaRESUMO
Anaerobic bacteria represent an underexplored source of bioactive natural products with unusual structural features. Here we report the isolation and structure elucidation of an antimycobacterial natural product, clostroindolin, produced by Clostridium beijerinckii. Furthermore, we provide first insights into structure activity relationships, which might guide the development of novel antibiotics against mycobacteria.
Assuntos
Antibacterianos/farmacologia , Clostridium beijerinckii/química , Alcaloides Indólicos/farmacologia , Pironas/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Linhagem Celular Tumoral , Células Endoteliais da Veia Umbilical Humana , Humanos , Alcaloides Indólicos/síntese química , Alcaloides Indólicos/química , Estrutura Molecular , Mycobacteriaceae/efeitos dos fármacos , Pironas/síntese química , Pironas/química , Relação Estrutura-AtividadeRESUMO
S-adenosyl-l-methionine (SAM)-dependent methyltransfer is a common biosynthetic strategy to modify natural products. We investigated the previously uncharacterized Aspergillus fumigatus methyltransferase FtpM, which is encoded next to the bimodular fumaric acid amide synthetase FtpA. Structure elucidation of two new A.â fumigatus natural products, the 1,11-dimethyl esters of fumaryl-l-tyrosine and fumaryl-l-phenylalanine, together with ftpM gene disruption suggested that FtpM catalyzes iterative methylation. Final evidence that a single enzyme repeatedly acts on fumaric acid amides came from an in vitro biochemical investigation with recombinantly produced FtpM. Size-exclusion chromatography indicated that this methyltransferase is active as a dimer. As ftpA and ftpM homologues are found clustered in other fungi, we expect our work will help to identify and annotate natural product biosynthesis genes in various species.