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Identification of Inhibitors of PvdQ, an Enzyme Involved in the Synthesis of the Siderophore Pyoverdine

Identification of Inhibitors of PvdQ, an Enzyme Involved in the Synthesis of the Siderophore Pyoverdine

Jacqueline M Wurst, Eric J Drake, Jimmy R Theriault, Ivan T Jewett, Lynn VerPlank, Jose R Perez, Sivaraman Dandapani, Michelle Palmer, Samuel M Moskowitz, Stuart L Schreiber, Benito Munoz, Andrew M Gulick

ACS Chem Biol. 2014 Jul 18;9(7):1536-44.

PMID: 24824984

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1610516670	ML318		1610516-67-0	Price

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