posted on 2015-12-17, 03:19authored byJacqueline
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
Pseudomonas aeruginosa produces the peptide siderophore
pyoverdine, which is used to acquire essential Fe3+ 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.