Acyl Histidines: New N-Acyl Amides from Legionella pneumophila

Chembiochem. 2017 Apr 4;18(7):638-646. doi: 10.1002/cbic.201600618. Epub 2017 Mar 6.


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.

Keywords: legionellosis; metabolomics; natural product; pneumonia; secondary metabolism.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acanthamoeba castellanii / microbiology
  • Amides / metabolism*
  • Animals
  • Histidine / analogs & derivatives*
  • Histidine / biosynthesis*
  • Legionella pneumophila / genetics
  • Legionella pneumophila / metabolism*
  • Macrophages / microbiology
  • Mice
  • Molecular Probes / chemistry
  • Multigene Family
  • Pyridines / chemistry


  • 3,6-di-2-pyridyl-1,2,4,5-tetrazine
  • Amides
  • Molecular Probes
  • Pyridines
  • Histidine