Acyl Histidines: New N‐Acyl Amides from Legionella pneumophila

Legionella pneumophila, the causative agent of Legionnaires' disease, is a Gram‐negative gammaproteobacterial pathogen that infects and intracellularly replicates in human macrophages and a variety of protozoa. L. pneumophila encodes an orphan biosynthetic gene cluster (BGC) that contains isocyanide‐associated biosynthetic genes and is upregulated during infection. Because isocyanide‐functionalized metabolites are known to harbor invertebrate innate immunosuppressive activities in bacterial pathogen–insect interactions, we used pathway‐targeted molecular networking and tetrazine‐based chemoseletive ligation chemistry to characterize the metabolites from the orphan pathway in L. pneumophila. We also assessed their intracellular growth contributions in an amoeba and in murine bone‐marrow‐derived macrophages. Unexpectedly, two distinct groups of aromatic amino acid‐derived metabolites were identified from the pathway, including a known tyrosine‐derived isocyanide and a family of new N‐acyl‐l ‐histidine metabolites.