Identification of inhibitors of PvdQ, an enzyme involved in the synthesis of the siderophore pyoverdine

ACS Chem Biol. 2014 Jul 18;9(7):1536-44. doi: 10.1021/cb5001586. Epub 2014 May 21.


Pseudomonas aeruginosa produces the peptide siderophore pyoverdine, which is used to acquire essential Fe(3+) ions from the environment. PvdQ, an Ntn hydrolase, is required for the biosynthesis of pyoverdine. PvdQ knockout strains are not infectious in model systems, suggesting that disruption of siderophore production via PvdQ inhibition could be exploited as a target for novel antibacterial agents, by preventing cells from acquiring iron in the low iron environments of most biological settings. We have previously described a high-throughput screen to identify inhibitors of PvdQ that identified inhibitors with IC50 values of ∼100 μM. Here, we describe the discovery of ML318, a biaryl nitrile inhibitor of PvdQ acylase. ML318 inhibits PvdQ in vitro (IC50 = 20 nM) by binding in the acyl-binding site, as confirmed by the X-ray crystal structure of PvdQ bound to ML318. Additionally, the PvdQ inhibitor is active in a whole cell assay, preventing pyoverdine production and limiting the growth of P. aeruginosa under iron-limiting conditions.

Publication types

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

MeSH terms

  • Amidohydrolases / antagonists & inhibitors*
  • Amidohydrolases / chemistry
  • Amidohydrolases / metabolism
  • Anti-Bacterial Agents / chemistry*
  • Anti-Bacterial Agents / pharmacology*
  • Crystallography, X-Ray
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Models, Molecular
  • Oligopeptides / metabolism*
  • Pseudomonas Infections / drug therapy
  • Pseudomonas Infections / enzymology
  • Pseudomonas Infections / microbiology
  • Pseudomonas aeruginosa / enzymology*
  • Pseudomonas aeruginosa / metabolism


  • Anti-Bacterial Agents
  • Enzyme Inhibitors
  • Oligopeptides
  • pyoverdin
  • Amidohydrolases
  • amidase

Associated data

  • PDB/4K2F
  • PDB/4K2G