Identification of a small molecule inhibitor of Pseudomonas aeruginosa PvdQ acylase, an enzyme involved in siderophore pyoverdine synthesis

The bacteria Pseudomonas aeruginosa produces a peptide siderophore known as pyoverdine, which has a great affinity for iron and is used to acquire iron from the external environment. Several enzymes such as the PvdQ acylase are required for the biosynthesis of pyoverdine. Deletion of the PvdQ gene disrupts pyoverdine production and hinders P. aeruginosa proliferation. Bacteria defective in pyoverdine synthesis are not infectious implying that disrupting this siderophore production through PvdQ inhibition could be exploited as a putative target for the development of novel antibiotic compounds. This report describes the development of a small molecule inhibitor (ML318, CID 56604881) of PvdQ acylase. ML318 inhibits PvdQ in vitro with an IC50 of 6 nM, has no apparent toxicity in mammalian HeLa cells up to a concentration of 100 μM, and inhibits growth and pyoverdine production in P. aeruginosa exposed to iron-limiting conditions with an IC50 < 50 μM. ML318 can also significantly reduce the intracellular uptake of iron inside the bacteria. This probe is a useful tool for ongoing characterization of pyoverdine’s role in P. aeruginosa biology and could serve as a starting point for the development of a novel antibiotic.