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Identification of Small Molecule Inhibitors of Staphylococcus aureus RnpA

Jennifer M Colquhoun1, Lisha Ha2, Andrew Beckley3

  • 1Department of Microbiology and Immunology, University of Rochester School of Medicine, Rochester, NY 14642, USA. jennifer_colquhoun@urmc.rochester.edu.

Antibiotics (Basel, Switzerland)
|May 1, 2019
PubMed

Insights

Researchers identified novel small molecules targeting Staphylococcus aureus RnpA, a dual-function protein essential for bacterial survival. These compounds show potent anti-staphylococcal activity and may lead to new antimicrobial therapies.

Area of Science:

  • Microbiology
  • Drug Discovery
  • Biochemistry

Background:

  • Staphylococcus aureus RnpA is a unique antimicrobial target essential for precursor tRNA processing and mRNA degradation.
  • Developing novel antimicrobials against S. aureus is crucial due to rising resistance.

Purpose of the Study:

  • To screen a large small molecule library for inhibitors of S. aureus RnpA.
  • To identify and optimize novel chemical classes targeting RnpA.
  • To evaluate the anti-staphylococcal activity and therapeutic potential of identified inhibitors.

Main Methods:

  • Utilized a whole cell-based mupirocin synergy assay to screen a 53,000-compound library.
  • Employed medicinal chemistry to establish structure-activity relationships for identified RnpA inhibitors.
  • Assessed in vitro enzyme activity, cellular RnpA inhibition, and in vivo efficacy in a wax worm model.

Main Results:

  • Identified two novel chemical classes of RnpA inhibitors: phenylcarbamoyl cyclic thiophene and piperidinecarboxamide.
  • Compounds demonstrated potent anti-staphylococcal activity, inhibited RnpA's in vitro functions, and had favorable therapeutic indexes.
  • The lead piperidinecarboxamide inhibitor, JC2, showed cellular RnpA mRNA turnover inhibition and in vivo efficacy.

Conclusions:

  • The whole cell screening assay is effective for identifying small molecule RnpA inhibitors from large libraries.
  • The identified chemical classes represent promising progenitors for new RnpA-targeting antimicrobials.
  • Targeting RnpA offers a viable strategy for combating Staphylococcus aureus infections.
Keywords:
RnpAStaphylococcus aureusmRNA degradationmupirocintRNA processing

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