Discovery and Biosynthesis of Anthrochelin, a Growth‐Promoting Metallophore of the Human Pathogen Luteibacter anthropi

Abstract Various human pathogens have emerged from environmental strains by adapting to higher growth temperatures and the ability to produce virulence factors. A remarkable example of a pathoadapted bacterium is found in the genus Luteibacter , which typically comprises harmless soil microbes, yet Luteibacter anthropi was isolated from the blood of a diseased child. Up until now, nothing has been known about the specialized metabolism of this pathogen. By comparative genome analyses we found that L. anthropi has a markedly higher biosynthetic potential than other bacteria of this genus and uniquely bears an NRPS gene locus tentatively coding for the biosynthesis of a metallophore. By metabolic profiling, stable isotope labeling, and NMR investigation of a gallium complex, we identified a new family of salicylate‐derived nonribosomal peptides named anthrochelins A–D. Surprisingly, anthrochelins feature a C‐terminal homocysteine tag, which might be introduced during peptide termination. Mutational analyses provided insight into the anthrochelin assembly and revealed the unexpected involvement of a cytochrome P450 monooxygenase in oxazole formation. Notably, this heterocycle plays a key role in the binding of metals, especially copper(II). Bioassays showed that anthrochelin significantly promotes the growth of L. anthropi in the presence of low and high copper concentrations, which occur during infections.