| Autor: |
Zhang L; Faculty of Biology, University of Freiburg, Schänzlestrasse 1, 79104 Freiburg, Germany., Esquembre LA; Department of Microbial Bioactive Compounds, Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany., Xia SN; Department of Microbial Bioactive Compounds, Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany., Oesterhelt F; Department of Microbial Bioactive Compounds, Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany., Hughes CC; Department of Microbial Bioactive Compounds, Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany.; Cluster of Excellence EXC 2124: Controlling Microbes to Fight Infection, University of Tübingen, 72076 Tübingen, Germany.; German Center for Infection Research, Partner Site Tübingen, 72076 Tübingen, Germany., Brötz-Oesterhelt H; Department of Microbial Bioactive Compounds, Interfaculty Institute for Microbiology and Infection Medicine, University of Tübingen, 72076 Tübingen, Germany.; Cluster of Excellence EXC 2124: Controlling Microbes to Fight Infection, University of Tübingen, 72076 Tübingen, Germany.; German Center for Infection Research, Partner Site Tübingen, 72076 Tübingen, Germany., Teufel R; Pharmaceutical Biology, Department of Pharmaceutical Sciences, Klingelbergstrasse 50, University of Basel, 4056 Basel, Switzerland. |
| Abstrakt: |
Actinobacteria have traditionally been an important source of bioactive natural products, although many genera remain poorly explored. Here, we report a group of distinctive pyrrole-containing natural products, named synnepyrroles, from Nocardiopsis synnemataformans . Detailed structural characterization by mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy combined with isotope-labeling experiments revealed their molecular structures and biosynthetic precursors acetate, propionate, aspartate, and (for branched analogues) valine. The biosynthetic data points toward an unusual pathway for pyrrole formation via condensation of aspartate with diverse fatty acids that give rise to a unique pyrrole-3,4-dicarboxylate core and variable linear or terminally branched alkyl side chains. In addition, the bioactivity and mode of action of synnepyrrole A were characterized in Bacillus subtilis . Orienting assessment of the phenotype of synnepyrrole A-treated bacteria by high-resolution microscopy suggested the cytoplasmic membrane as the target structure. Further characterization of the membrane effects demonstrated dissipation of the membrane potential and intracellular acidification indicative of protonophore activity. At slightly higher concentrations, synnepyrrole A compromised the barrier function of the cytoplasmic membrane, allowing the passage of otherwise membrane-impermeable dye molecules. |
