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Novel Cycloheximide Derivatives Targeting the Moonlighting Protein Mip Exhibit Specific Antimicrobial Activity

Janine Rasch1, Martin Theuerkorn2, Can Ünal3

  • 1Institut für Mikrobiologie, Technische Universität Braunschweig , Braunschweig , Germany.

Frontiers in Bioengineering and Biotechnology
|April 15, 2015
PubMed

Insights

Novel cycloheximide derivatives with adamantyl groups effectively inhibit peptidyl-prolyl-cis/trans-isomerase (PPIase) activity and L. pneumophila growth. These compounds show specific antibacterial activity and potential as multi-target inhibitors for pathogens.

Area of Science:

  • Microbiology
  • Medicinal Chemistry
  • Biochemistry

Background:

  • Macrophage infectivity potentiator (Mip) is a key virulence factor in Legionella pneumophila, belonging to the FK506 binding protein (FKBP) family.
  • Mip's peptidyl-prolyl-cis/trans-isomerase (PPIase) activity is crucial for L. pneumophila's invasion, transmigration, and overall virulence.
  • Mip also functions as a moonlighting protein, binding to collagen IV in the extracellular matrix.

Purpose of the Study:

  • To develop and synthesize novel cycloheximide derivatives incorporating adamantyl moieties as potential FKBP ligands.
  • To evaluate the inhibitory effects of these novel compounds on PPIase activity and bacterial growth, specifically targeting L. pneumophila.

Main Methods:

  • Synthesis of cycloheximide derivatives with adamantyl substitutions.
  • Assay of inhibitory activity against human FKBP12 and L. pneumophila Mip PPIase.
  • Assessment of compound effects on L. pneumophila and other bacterial growth in liquid cultures.
  • Evaluation of compound cytotoxicity and inhibitory effects in macrophage infection models.

Main Results:

  • Developed cycloheximide-adamantane hybrid compounds that efficiently inhibit FKBP12 and Mip PPIase activity (IC50 values as low as 180 nM and 1.7 μM, respectively).
  • Five derivatives demonstrated specific antibacterial activity against L. pneumophila at 30-40 μM, without affecting other tested bacteria.
  • Compounds MT_30.32 and MT_30.51 showed potent inhibition in PPIase and growth assays, and were non-cytotoxic inhibitors in macrophage infection studies.
  • Interestingly, Mip-deficient L. pneumophila strains were affected similarly to wild-type strains, suggesting Mip is not the sole target.

Conclusions:

  • Cycloheximide derivatives with adamantyl moieties are potent inhibitors of FKBP PPIase activity.
  • These compounds exhibit specific antibacterial activity against L. pneumophila.
  • The findings suggest these novel hybrids may act as multi-target inhibitors, offering a promising avenue for anti-infective drug development.
Keywords:
PPIaseadamantanecycloheximideinhibitormoonlighting

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