Genomic mining for antimicrobial lipopeptides and studies on their biosynthesis
Final Report Abstract
The benefits of this partial project are three-fold: a) It revealed the assembly machinery of the two novel promising antibiotics brabantamide and empedopeptin. We encountered several new genes encoding proteins that are capable to perform novel biochemistry. These genes or the resultant proteins can be used in future to find similar antibiotics from genomic data or to get re-engineered in order to generate optimized derivatives. Finally, they can also be further used as bio-bricks in synthetic biology projects. b) Furthermore, with the clarification of the mode of action of the antibiotic brabantamides, we found a novel underexploited target to possibly combat antibiotic resistance. The structure of brabantamide can serve in this context as a pharmacophore for medicinal chemistry projects. c) In addition, eight new promising lipopeptide-based antibiotics were successfully isolated and completely structurally characterized. Some of them show even new cyclization schemes and form new compound families. Surprising was the chemical diversity of the obtained structures considering the number of already known lipopeptides. The correlated gene clusters can be utilized to find similar antibiotics from genomic data and their bioactivities and mode of actions can be investigated in followed-up projects.
Publications
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(2012). Imaging mass spectrometry and genome mining reveal highly antifungal virulence factor of mushroom soft rot pathogen. Angew. Chem. Int. Ed. 51, 13173-13177
Graupner K, Scherlach K, Bretschneider T, Lackner G, Roth M, Gross H, Hertweck C
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(2012). Mass spectral molecular networking of living microbial colonies. PNAS 109, E1743-E1752
Watrous J, Roach P, Alexandrov T, Heath BS, Yang JY, Kersten RD, van der Voort M, Pogliano K, Gross H, Raaijmakers JM, Moore BS, Laskin J, Bandeira N, Dorrestein PC
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(2012). Predicting the structure of cyclic lipopeptides by bioinformatics: Structure revision of arthrofactin. ChemBioChem 13, 2671-2675
Lange A, Sun H, Pilger J, Reinscheid UM, Gross H
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(2012). The lipodepsipeptide empedopeptin inhibits cell wall biosynthesis through Ca2+-dependent complex formation with peptidoglycan precursors. J. Biol. Chem. 287, 20270-20280
Müller A, Münch D, Schmidt Y, Reder-Christ K, Schiffer G, Bendas G, Gross H, Sahl HG, Schneider T, Brötz-Oesterhelt H
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(2014). Biosynthetic origin of the antibiotic cyclo-carbamate brabantamide A (SB-253514) in plant-associated Pseudomonas. ChemBioChem 15, 259-266
Schmidt Y, van der Voort M, Crüsemann M, Piel J, Josten M, Sahl HG, Miess H, Raaijmakers JM, Gross H
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(2014). Cyclic lipopeptides as antibacterial agents - Potent antibiotic activity mediated by intriguing mode of actions. Int. J. Med. Microbiol. 304, 37-43
Schneider T, Müller A, Miess H, Gross H
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(2015). Genome mining and metabolic profiling of the rhizosphere bacterium Pseudomonas sp. SH-C52 for antimicrobial compounds. Frontiers in Microbiol. 6, 693
van der Voort M, Meijer H, Schmidt Y, Watrous J, Dekkers E, Mendes R, Dorrestein PC, Gross H, Raaijmakers JM
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(2015). The novel lipopeptide poaeamide of the endophyte Pseudomonas poae RE*1-1-14 is involved in pathogen suppression and root colonization. Mol. Plant-Microbe Interact. 28 (7), 800-810
Zachow C, Jahanshah G, de Bruijn I, Song C, Ianni F, Pataj Z, Gerhardt H, Pianet I, Lämmerhofer M, Berg G, Gross H, Raaijmakers JM
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(2016). Methods for the comprehensive structural elucidation of constitution and stereochemistry of lipopeptides. J. Chromatogr. A 1428, 280-291
Gerhardt H, Sievers-Engler A, Jahanshah G, Pataj Z Ianni F, Gross H, Lindner W, Lämmerhofer M
