Novel cycloheximide derivatives targeting the moonlighting protein Mip exhibit specific antimicrobial activity against Legionella pneumophila

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dc.contributor.authorRasch, Janine
dc.contributor.authorTheuerkorn, Martin
dc.contributor.authorÜnal, Can Murat
dc.contributor.authorHeinsohn, Natascha
dc.contributor.authorTran, Stefan
dc.contributor.authorFischer, Gunter
dc.contributor.authorSteinert, Michael
dc.date.accessioned2021-01-08T21:51:29Z
dc.date.available2021-01-08T21:51:29Z
dc.date.issued2015
dc.departmentTAÜ, Fen Fakültesi, Moleküler Biyoteknoloji Bölümüen_US
dc.descriptionUnal, Can/0000-0003-4710-9567en_US
dc.descriptionWOS:000536548500039en_US
dc.descriptionPubMed: 25870856en_US
dc.description.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 180nM and 1.7 mu M, respectively. Five of these derivatives inhibited the growth of L. pneumophila at concentrations of 30-40 mu M, 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-ethyladamantan1-[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.
dc.description.sponsorshipDeutsche Forschungsgemeinschaft (DFG)German Research Foundation (DFG) [STE 838/8-1]
dc.description.sponsorshipThis work received financial support from the Deutsche Forschungsgemeinschaft (DFG) STE 838/8-1.
dc.identifier.doi10.3389/fbioe.2015.00041
dc.identifier.issn2296-4185
dc.identifier.scopus2-s2.0-84940117734
dc.identifier.scopusqualityQ1
dc.identifier.urihttp://doi.org/10.3389/fbioe.2015.00041
dc.identifier.urihttps://hdl.handle.net/20.500.12846/295
dc.identifier.volume3en_US
dc.identifier.wosWOS:000536548500039
dc.identifier.wosqualityN/A
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.institutionauthorÜnal, Can Murat
dc.language.isoen
dc.publisherFrontiers Media Sa
dc.relation.ispartofFrontiers In Bioengineering And Biotechnology
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanı
dc.rightsinfo:eu-repo/semantics/openAccess
dc.subjectMoonlightingen_US
dc.subjectPpiaseen_US
dc.subjectCycloheximideen_US
dc.subjectAdamantaneen_US
dc.subjectInhibitoren_US
dc.titleNovel cycloheximide derivatives targeting the moonlighting protein Mip exhibit specific antimicrobial activity against Legionella pneumophila
dc.typeArticle

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