Antibiotic resistance is a growing health concern, and new avenues of antimicrobial drug design
are being actively sought. One suggested pathway to be targeted for inhibitor design is that of iron
scavenging through siderophores. Here we present a high throughput screen to the isochorismatepyruvate
lyase of Pseudomonas aeruginosa, an enzyme required for the production of the
siderophore pyochelin. Compounds identified in the screen are high nanomolar to low micromolar
inhibitors of the enzyme and produce growth inhibition in PAO1 P. aeruginosa in the millimolar
range under iron-limiting conditions. The identified compounds were also tested for enzymatic
inhibition of E. coli chorismate mutase, a protein of similar fold and similar chemistry, and of Y.
enterocolitica salicylate synthase, a protein of differing fold but catalyzing the same lyase
reaction. In both cases, subsets of the inhibitors from the screen were found to be inhibitory to
enzymatic activity (mutase or synthase) in the micromolar range and capable of growth inhibition
in their respective organisms (E. coli or Y. enterocolitica).
Meneely, K. M., Luo, Q., Riley, A. P., Taylor, B., Roy, A., Stein, R. L., … Lamb, A. L. (2014). Expanding the results of a high throughput screen against an isochorismate-pyruvate lyase to enzymes of a similar scaffold or mechanism. Bioorganic & Medicinal Chemistry, 22(21), 5961–5969. http://doi.org/10.1016/j.bmc.2014.09.010