Antibacterial pyrrolidinyl and piperidinyl substituted 2,4-diacetylphloroglucinols from Pseudomonas protegens UP46
| Autor: | Anders Broberg, Christina Nord, Joakim Bjerketorp, Bo Öberg, Bengt Guss, Rolf Larsson, Jerry Ståhlberg, Jolanta J. Levenfors |
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| Rok vydání: | 2020 |
| Předmět: |
0301 basic medicine
Magnetic Resonance Spectroscopy Stereochemistry 030106 microbiology Bacillus cereus Microbial Sensitivity Tests Phloroglucinol 01 natural sciences Mass Spectrometry 03 medical and health sciences Minimum inhibitory concentration chemistry.chemical_compound Pseudomonas protegens Alkaloids Biosynthesis Pseudomonas Gram-Negative Bacteria Drug Discovery Humans Chromatography High Pressure Liquid Pharmacology chemistry.chemical_classification Molecular Structure biology 010405 organic chemistry Chemistry Hep G2 Cells biology.organism_classification Anti-Bacterial Agents 0104 chemical sciences Enzyme Antibacterial activity Metabolic Networks and Pathways Bacteria |
| Zdroj: | The Journal of Antibiotics. 73:739-747 |
| ISSN: | 1881-1469 0021-8820 |
| Popis: | In the search for new antibiotic compounds, fractionation of Pseudomonas protegens UP46 culture extracts afforded several known Pseudomonas compounds, including 2,4-diacetylphloroglucinol (DAPG), as well as two new antibacterial alkaloids, 6-(pyrrolidin-2-yl)DAPG (1) and 6-(piperidin-2-yl)DAPG (2). The structures of 1 and 2 were determined by nuclear magnetic resonance spectroscopy and mass spectrometry. Compounds 1 and 2 were found to have antibacterial activity against the Gram-positive bacteria Staphylococcus aureus and Bacillus cereus, with minimal inhibitory concentration (MIC) 2 and 4 μg ml−1, respectively, for 1, and 2 μg ml−1 for both pathogens for 2. The MICs for 1 and 2, against all tested Gram-negative bacteria, were >32 μg ml−1. The half maximal inhibitory concentrations against HepG2 cells for compounds 1 and 2 were 11 and 18 μg ml−1, respectively, which suggested 1 and 2 be too toxic for further evaluation as possible new antibacterial drugs. Stable isotope labelling experiments showed the pyrrolidinyl group of 1 to originate from ornithine and the piperidinyl group of 2 to originate from lysine. The P. protegens acetyl transferase (PpATase) is involved in the biosynthesis of monoacetylphloroglucinol and DAPG. No optical rotation was detected for 1 or 2, and a possible reason for this was investigated by studying if the PpATase may catalyse a stereo-non-specific introduction of the pyrrolidinyl/piperidinyl group in 1 and 2, but unless the PpATase can be subjected to major conformational changes, the enzyme cannot be involved in this reaction. The PpATase is, however, likely to catalyse the formation of 2,4,6-triacetylphloroglucinol from DAPG. |
| Databáze: | OpenAIRE |
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