title: Expanding the results of a high throughput screen against an isochorismate-pyruvate lyase to enzymes of a similar scaffold or mechanism.
abstract: 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).
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave, Lawrence, KS 66045, United States.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Meneely
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave, Lawrence, KS 66045, United States.
authors.forename: Qianyi
authors.initials: Q
authors.lastname: Luo
authors.affiliation: Department of Chemistry, University of Kansas, 1251 Wescoe Hall Dr, Lawrence, KS 66045, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Riley
authors.affiliation: High Throughput Screening Facility, University of Kansas, 2034 Becker Dr, Lawrence, KS 66047, United States.
authors.forename: Byron
authors.initials: B
authors.lastname: Taylor
authors.affiliation: High Throughput Screening Facility, University of Kansas, 2034 Becker Dr, Lawrence, KS 66047, United States.
authors.forename: Anuradha
authors.initials: A
authors.lastname: Roy
authors.affiliation: High Throughput Screening Facility, University of Kansas, 2034 Becker Dr, Lawrence, KS 66047, United States.
authors.forename: Ross L
authors.initials: RL
authors.lastname: Stein
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, 1251 Wescoe Hall Dr, Lawrence, KS 66045, United States.
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.affiliation: Department of Molecular Biosciences, University of Kansas, 1200 Sunnyside Ave, Lawrence, KS 66045, United States. Electronic address: lamb@ku.edu.
authors.forename: Audrey L
authors.initials: AL
authors.lastname: Lamb
mesh_terms: D000900:Anti-Bacterial Agents / Q000737:chemistry* / Q000494:pharmacology*; D001424:Bacterial Infections / Q000188:drug therapy; D002827:Chorismic Acid / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development; D057166:High-Throughput Screening Assays; D006801:Humans; D008958:Models, Molecular; D007652:Oxo-Acid-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011550:Pseudomonas aeruginosa / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D015008:Yersinia enterocolitica / Q000187:drug effects / Q000201:enzymology / Q000254:growth & development
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; C052985:isochorismic acid; D007652:Oxo-Acid-Lyases; C075960:chorismate pyruvate lyase; D002827:Chorismic Acid
keywords: Chorismate mutase; Isochorismate-pyruvate lyase; Salicylate synthase; Siderophore