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In recent years, the number of identified non-proteinogenic amino acid-containing secondary metabolites and their biosynthetic gene clusters has greatly expanded in bacteria. A new family of stand-alone adenylation (A) domains involved in the incorporation of ß-amino acids has been previously described. Based on the protein structural analyses of three members of this new family, new ß-amino acid specificity-conferring codes have been proposed. A common specific feature of these stand-alone A domains is that they are co-encoded with a stand-alone acyl carrier protein domain. Based on these specific features, the French partner (BGPI) has identified two new stand-alone A domains expected to be involved in the incorporation of a ß-amino acid. These stand-alone A domains are present in two loci belonging to important pathogenic bacteria. According to their annotation, these loci encode two different new unknown molecules, respectively. Interestingly, by a genetic approach, these loci have both been shown to be required for the bacterial virulence. However, the chemical structure of the secondary metabolites synthesized by these loci remains unknown and the presence of a ß-amino acid has never been yet suspected and explored. This project aims at elucidating the chemical structure of the molecules encoded by these two loci, deciphering their biosynthesis pathways, and refining the functional assignment of their biosynthesis genes. This project will contribute to a better understanding of the incorporation of ß-amino acids by stand-alone A domains in bacteria. Since the targeted microorganisms are important pathogens, this project will essentially contribute to a deeper understanding of their pathogenicity. Consequently, the fight against these pathogens should therefore be facilitated by new data arising from the project. Since genome mining is an important approach to discover new loci encoding new natural products with potentially novel biological activities, this project proposes to mine bacterial genomic sequences available in Genbank for the presence of new loci encoding a stand-alone A domain specific of a ß amino acid. Depending on the biological activity of the characterized ß-amino acid-containing secondary metabolites, this project potentially could lead to industrial applications as antibiotics or plant protection agents. Patents obtained would potentially also contribute to the visibility of the project. The French and German partners BGPI and TU Berlin have developed a long-standing collaboration since 2005, working together on several projects including the structural characterization of the potent antibiotic albicidin.
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