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Multidisciplinary approaches shed light on biosynthesis and unusual structural features of the antimicrobial hybrid NRPS/PKS-synthesized albicidin

Cociancich S., Pesic A., Petras D., Duplan S., Hempel B., Hügelland M., Kemper S., Kerwat D., Kretz J., Mainz A., Marguerettaz M., Noëll J., Pieretti I., Schubert V., Semsary S., Uhlmann S., Vieweg L., Von Eckardstein L., Rott P., Royer M., Süssmuth R.. 2016. In : Towards an integrated view of AMP diversity, functions and applications. Montpellier : s.n., p. 15-15. AMP2016 - Antimicrobial Peptide Symposium. 5, 2016-06-06/2016-06-08, Montpellier (France).

Albicidin is a potent DNA gyrase inhibitor produced by the sugarcane pathogenic bacterium Xanthomonas albilineans. It blocks the d ifferentiation of chloroplasts, resulting in appearance of narrow white stripes on sugarcane leaves that are characteristic of leaf scald d isease. Albicidin targets the bacterial gyrase by a mechanism that is different from the one of any other known DNA gyrases inhibitors [l]. It exhibits antibacterial activity at nanomolar concentrations against Escherichia coli and to a lower extent aga inst numerous human pathogenic bacteria [2]. A decade of intense work was necessary to decipher a lbicid in's biosynthetic pathway and to elucidate its astonishing never-seen-before structure. Albicidin is produced by a hybrid PKS/NRPS system. Such ribosome-independent systems cons ist of modular megasynthetases which operate in an assembly-line fashion to activate, modify and link mostly unusual aminoacid build ing blocks, fina lly resulting in complex bioactive peptide-like molecules. The structure of albicidin, which was predicted by fo rmer in silico sequence a nalyses of its PKS/ NRPS gene cluster [3], was ascertained by means of mass spectrometry and NMR spectroscopy. We demonstrated that a lbicidin exhibits a linear polyaromatic penta-peptidic structure containing the rare aminoacids para-aminobenzoate a nd cyanoalanine [4]. Insights into biosynthesis and structure of natural a nalogues of al bicidin will also be presented [5]. The determination of the structure of albicidin allowed the development of a protocol for the chemical synthesis of this complex molecule [6]. Consequently, new research, such as structureactivity relationship studies, will now be possible.

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