Deciphering and engineering of the molecular diversity of NRPS-derived azacyclic alkaloids in bacteria

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While many biosynthetic pathways in bacteria lead to one or a limited number of products, certain systems produce a diversity of metabolites. The pathways to the bacterial pyrrolizidine alkaloids (PAs) represent striking examples of this phenomenon. A common biosynthetic scheme involving a bimodular nonribosomal peptide synthetase (NRPS) and a monooxygenase, in combination with accessory enzymes and/or spontaneous chemical reactions, leads to diverse azacycles such as pyrrolizidines and cyclocarbamates. In recent work, several of these compounds have been found to attenuate virulence of the producing bacteria during interaction with its host. The molecular mechanisms governing such diversification and underlying their biological activity remain unknown. Given the high interest and broad pharmaceutical potential of azacycle-containing molecules, this project proposes to decipher the molecular basis for the chemical diversity of pyrrolizidine and related alkaloids in bacteria, to elucidate structure-function relationships for key enzymes in the pathways, and to apply the obtained knowledge to generate new-to-nature derivatives with interesting bioactivity, notably as anti-virulence compounds of a major human pathogen, Pseudomonas aeruginosa.