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 isochorismate-pyruvate 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 Escherichia coli chorismate mutase, a protein of similar fold and similar chemistry, and of Yersinia 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).
|Number of pages||9|
|Journal||Bioorganic and Medicinal Chemistry|
|State||Published - Nov 1 2014|
Bibliographical noteFunding Information:
We are grateful to Frank Schoenen, Graham Moran, and Scott Hefty for helpful discussions, and to Chris Gamblin for equipment use. This publication was made possible by funds from Kansas Masonic Cancer Research Institute , from the NIH Grants numbered R01 AI77725 and K02 AI093675 from the National Institute for Allergy and Infectious Disease (A.L.L.), NIH Grant number P20 RR016475 from the INBRE Program of the National Center for Research Resources (Hunt, PI), and by the Graduate Training Program in Dynamic Aspects of Chemical Biology NIH Grant number T32 GM08545 (A.P.R.). The University of Kansas High Throughput Screening Laboratory is funded in part by NIH COBRE Grant 8 P30 GM103495 (Timmermann, PI) and the NCI Cancer Support Grant 5 P30 CA168524 (Jensen, PI).
© 2014 Elsevier Ltd. All rights reserved.
- Chorismate mutase
- Isochorismate-pyruvate lyase
- Salicylate synthase
ASJC Scopus subject areas
- Molecular Medicine
- Molecular Biology
- Pharmaceutical Science
- Drug Discovery
- Clinical Biochemistry
- Organic Chemistry