RESUMEN
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.
Asunto(s)
Sintasas Poliquetidas , Quercus , Antibacterianos/química , Antibacterianos/farmacología , Firmicutes , Humanos , Familia de Multigenes , Filogenia , Sintasas Poliquetidas/química , Sintasas Poliquetidas/genéticaRESUMEN
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.
Asunto(s)
Antibacterianos/farmacología , Clostridium beijerinckii/química , Alcaloides Indólicos/farmacología , Pironas/farmacología , Antibacterianos/síntesis química , Antibacterianos/química , Línea Celular Tumoral , Células Endoteliales de la Vena Umbilical Humana , Humanos , Alcaloides Indólicos/síntesis química , Alcaloides Indólicos/química , Estructura Molecular , Mycobacteriaceae/efectos de los fármacos , Pironas/síntesis química , Pironas/química , Relación Estructura-ActividadRESUMEN
Metabolic profiling and genome mining revealed that anaerobic bacteria have the potential to produce acyloin natural products. In addition to sattazolin A and B, three new sattazolin congeners and a novel acyloin named clostrocyloin were isolated from three strains of Clostridium beijerinckii, a bacterium used for industrial solvent production. Bioactivity profiling showed that the sattazolin derivatives possess antimicrobial activities against mycobacteria and pseudomonads with only low cytotoxicity. Clostrocyloin was found to be mainly active against fungi. The thiamine diphosphate (ThDP)-dependent sattazolin-producing synthase was identified in silico and characterized both in vivo and in in vitro enzyme assays. A related acyloin synthase from the clostrocyloin producer was shown to be responsible for the production of the acyloin core of clostrocyloin. The biotransformation experiments provided first insights into the substrate scope of the clostrocyloin synthase and revealed biosynthetic intermediates.
Asunto(s)
Antibacterianos/química , Antibacterianos/farmacología , Antifúngicos/química , Antifúngicos/farmacología , Alcoholes Grasos/química , Alcoholes Grasos/farmacología , Bacterias Anaerobias/química , Vías Biosintéticas , Clostridium/química , Hexanonas/química , Hexanonas/farmacología , Humanos , Indoles/química , Indoles/farmacología , Mycobacterium/efectos de los fármacos , Infecciones por Mycobacterium/tratamiento farmacológico , Micosis/tratamiento farmacológico , Pseudomonas/efectos de los fármacos , Infecciones por Pseudomonas/tratamiento farmacológicoRESUMEN
Around 25% of vegetable food is lost worldwide because of infectious plant diseases, including microbe-induced decay of harvested crops. In wet seasons and under humid storage conditions, potato tubers are readily infected and decomposed by anaerobic bacteria (Clostridium puniceum). We found that these anaerobic plant pathogens harbor a gene locus (type II polyketide synthase) to produce unusual polyketide metabolites (clostrubins) with dual functions. The clostrubins, which act as antibiotics against other microbial plant pathogens, enable the anaerobic bacteria to survive an oxygen-rich plant environment.