Preparation of Cyclic Prodiginines by Mutasynthesis in Pseudomonas putida KT2440

Prodiginines are a group of naturally occurring pyrrole alkaloids produced by various microorganisms and known for their broad biological activities. The production of nature‐inspired cyclic prodiginines was enabled by combining organic synthesis with a mutasynthesis approach based on the GRAS (generally recognized as safe) certified host strain Pseudomonas putida KT2440. The newly prepared prodiginines exerted antimicrobial effects against relevant alternative biotechnological microbial hosts whereas P. putida itself exhibited remarkable tolerance against all tested prodiginines, thus corroborating the bacterium's exceptional suitability as a mutasynthesis host for the production of these cytotoxic secondary metabolites. Moreover, the produced cyclic prodiginines proved to be autophagy modulators in human breast cancer cells. One promising cyclic prodiginine derivative stood out, being twice as potent as prodigiosin, the most prominent member of the prodiginine family, and its synthetic derivative obatoclax mesylate. Cyclic precursors accepted: New cyclic prodigiosin derivatives were obtained by mutasynthesis in a generally recognized as safe (GRAS) certified strain of P. putida (KT2440) through a combination of organic chemistry and genetic engineering. Bioactivity studies of these prodiginines showed strong antimicrobial activity against biotechnologically relevant microorganisms as well as potent modulation of autophagy in human breast cancer cells.