Novel Cycloheximide Derivatives Targeting the Moonlighting Protein Mip Exhibit Specific Antimicrobial Activity Against Legionella pneumophila.
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AbstractMacrophage infectivity potentiator (Mip) and Mip-like proteins are virulence factors in a wide range of pathogens including Legionella pneumophila. These proteins belong to the FK506 binding protein (FKBP) family of peptidyl-prolyl-cis/trans-isomerases (PPIases). In L. pneumophila, the PPIase activity of Mip is required for invasion of macrophages, transmigration through an in vitro lung-epithelial barrier, and full virulence in the guinea pig infection model. Additionally, Mip is a moonlighting protein that binds to collagen IV in the extracellular matrix. Here, we describe the development and synthesis of cycloheximide derivatives with adamantyl moieties as novel FKBP ligands, and analyze their effect on the viability of L. pneumophila and other bacteria. All compounds efficiently inhibited PPIase activity of the prototypic human FKBP12 as well as Mip with IC50-values as low as 180 nM and 1.7 μM, respectively. Five of these derivatives inhibited the growth of L. pneumophila at concentrations of 30-40 μM, but exhibited no effect on other tested bacterial species indicating a specific spectrum of antibacterial activity. The derivatives carrying a 3,5-dimethyladamantan-1-[yl]acetamide substitution (MT_30.32), and a 3-ethyladamantan-1-[yl]acetamide substitution (MT_30.51) had the strongest effects in PPIase- and liquid growth assays. MT_30.32 and MT_30.51 were also inhibitory in macrophage infection studies without being cytotoxic. Accordingly, by applying a combinatorial approach, we were able to generate novel, hybrid inhibitors consisting of cycloheximide and adamantane, two known FKBP inhibitors that interact with different parts of the PPIase domain, respectively. Interestingly, despite the proven Mip-inhibitory activity, the viability of a Mip-deficient strain was affected to the same degree as its wild type. Hence, we also propose that cycloheximide derivatives with adamantyl moieties are potent PPIase inhibitors with multiple targets in L. pneumophila.
CitationNovel Cycloheximide Derivatives Targeting the Moonlighting Protein Mip Exhibit Specific Antimicrobial Activity Against Legionella pneumophila. 2015, 3:41 Front Bioeng Biotechnol
AffiliationHelmholtz Centre for Infection Research, Inhoffenstraße 7, 38124 Braunschweig, Germany.
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- Collagen binding protein Mip enables Legionella pneumophila to transmigrate through a barrier of NCI-H292 lung epithelial cells and extracellular matrix.
- Authors: Wagner C, Khan AS, Kamphausen T, Schmausser B, Unal C, Lorenz U, Fischer G, Hacker J, Steinert M
- Issue date: 2007 Feb
- Mip protein of Legionella pneumophila exhibits peptidyl-prolyl-cis/trans isomerase (PPlase) activity.
- Authors: Fischer G, Bang H, Ludwig B, Mann K, Hacker J
- Issue date: 1992 May
- Influence of site specifically altered Mip proteins on intracellular survival of Legionella pneumophila in eukaryotic cells.
- Authors: Wintermeyer E, Ludwig B, Steinert M, Schmidt B, Fischer G, Hacker J
- Issue date: 1995 Dec
- Collagen IV-derived peptide binds hydrophobic cavity of Legionella pneumophila Mip and interferes with bacterial epithelial transmigration.
- Authors: Ünal C, Schwedhelm KF, Thiele A, Weiwad M, Schweimer K, Frese F, Fischer G, Hacker J, Faber C, Steinert M
- Issue date: 2011 Oct
- Biochemical and functional analyses of the Mip protein: influence of the N-terminal half and of peptidylprolyl isomerase activity on the virulence of Legionella pneumophila.
- Authors: Köhler R, Fanghänel J, König B, Lüneberg E, Frosch M, Rahfeld JU, Hilgenfeld R, Fischer G, Hacker J, Steinert M
- Issue date: 2003 Aug