title: Development, synthesis and structure-activity-relationships of inhibitors of the macrophage infectivity potentiator (Mip) proteins of Legionella pneumophila and Burkholderia pseudomallei.
abstract: The bacteria Burkholderia pseudomallei and Legionella pneumophila cause severe diseases like melioidosis and Legionnaire's disease with high mortality rates despite antibiotic treatment. Due to increasing antibiotic resistances against these and other Gram-negative bacteria, alternative therapeutical strategies are in urgent demand. As a virulence factor, the macrophage infectivity potentiator (Mip) protein constitutes an attractive target. The Mip proteins of B. pseudomallei and L. pneumophila exhibit peptidyl-prolyl cis/trans isomerase (PPIase) activity and belong to the PPIase superfamily. In previous studies, the pipecolic acid moiety proved to be a valuable scaffold for inhibiting this PPIase activity. Thus, a library of pipecolic acid derivatives was established guided by structural information and computational analyses of the binding site and possible binding modes. Stability and toxicity considerations were taken into account in iterative extensions of the library. Synthesis and evaluation of the compounds in PPIase assays resulted in highly active inhibitors. The activities can be interpreted in terms of a common binding mode obtained by docking calculations.
authors: Institute for Pharmacy and Food Chemistry, University of Würzburg, 97074 Würzburg, Germany.
authors: Florian
authors: F
authors: Seufert
authors: Institute for Pharmacy and Food Chemistry, University of Würzburg, 97074 Würzburg, Germany.
authors: Maximilian
authors: M
authors: Kuhn
authors: Institute for Pharmacy and Food Chemistry, University of Würzburg, 97074 Würzburg, Germany.
authors: Michael
authors: M
authors: Hein
authors: Research Center for Enzymology of Proteinfolding, Max-Planck-Institute Halle, 06120 Halle, Germany.
authors: Matthias
authors: M
authors: Weiwad
authors: School of Biosciences, University of Exeter, Exeter, United Kingdom.
authors: Mirella
authors: M
authors: Vivoli
authors: Defence Science and Technology Laboratory, Biomedical Sciences, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
authors: Isobel H
authors: IH
authors: Norville
authors: Defence Science and Technology Laboratory, Biomedical Sciences, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom; Marshall Center for Infectious Disease Research and Training, School of Pathology and Laboratory Medicine, University of Western Australia, Perth, Australia.
authors: Mitali
authors: M
authors: Sarkar-Tyson
authors: Defence Science and Technology Laboratory, Biomedical Sciences, Porton Down, Salisbury, Wiltshire SP4 0JQ, United Kingdom.
authors: Laura E
authors: LE
authors: Marshall
authors: Department of Biopolymers, University of Bayreuth, Universitätsstrasse 30, 95447 Bayreuth, Germany.
authors: Kristian
authors: K
authors: Schweimer
authors: Institute for Molecular Infection Biology, University of Würzburg, 97080 Würzburg, Germany.
authors: Heike
authors: H
authors: Bruhn
authors: Department of Biopolymers, University of Bayreuth, Universitätsstrasse 30, 95447 Bayreuth, Germany.
authors: Paul
authors: P
authors: Rösch
authors: School of Biosciences, University of Exeter, Exeter, United Kingdom.
authors: Nicholas J
authors: NJ
authors: Harmer
authors: Institute for Pharmacy and Food Chemistry, University of Würzburg, 97074 Würzburg, Germany.
authors: Christoph A
authors: CA
authors: Sotriffer
authors: Institute for Pharmacy and Food Chemistry, University of Würzburg, 97074 Würzburg, Germany. Electronic address: ulrike.holzgrabe@uni-wuerzburg.de.
authors: Ulrike
authors: U
authors: Holzgrabe
mesh_terms: D016957:Burkholderia pseudomallei / Q000201:enzymology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D016952:Legionella pneumophila / Q000201:enzymology*; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D019696:Peptidylprolyl Isomerase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D019696:Peptidylprolyl Isomerase
keywords: Burkholderia pseudomallei; Docking analysis; Legionella pneumophila; Macrophage infectivity potentiator protein; Structure–activity-relationships; Synthesis