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A Celecoxib Derivative Eradicates Antibiotic-Resistant Staphylococcus aureus and Biofilms by Targeting YidC2

Shiou-Ru Tzeng1, Yi-Wei Huang2, Yao-Qing Zhang1

  • 1Institute of Biochemistry and Molecular Biology, College of Medicine, National Taiwan University, Taipei 10051, Taiwan.

International Journal of Molecular Sciences
|December 10, 2020
PubMed

Insights

Two celecoxib derivatives, Cpd36 and Cpd46, target the YidC2 protein to combat MRSA infections. These compounds effectively eradicate Staphylococcus aureus persisters and biofilms by inhibiting YidC2 function.

Area of Science:

  • Microbiology
  • Drug Discovery
  • Molecular Biology

Background:

  • Methicillin-resistant *Staphylococcus aureus* (MRSA) poses a significant treatment challenge due to antibiotic resistance, persister formation, and biofilms.
  • Existing therapies are limited in effectively eradicating persistent bacterial populations and biofilms.
  • Celecoxib derivatives Cpd36 and Cpd46 have shown potential against staphylococcal infections.

Purpose of the Study:

  • To elucidate the molecular mechanism of action for Cpd36 and Cpd46 against *Staphylococcus aureus*.
  • To investigate the role of the membrane protein translocase YidC2 in mediating bacterial susceptibility and tolerance to these compounds.
  • To evaluate the efficacy of YidC2 inhibitors in eradicating MRSA persisters and biofilms.

Main Methods:

  • Whole-genome resequencing to identify potential drug targets.
  • Bacterial susceptibility testing with YidC2 overexpression strains.
  • Analysis of YidC2-mediated stress tolerance.
  • Assessment of ATP synthase subunit c translocation and bacterial ATP production.
  • Surface plasmon resonance (SPR) assays to study compound-protein interactions.
  • In vitro testing against MRSA persisters and biofilms.

Main Results:

  • Ectopic expression of YidC2 reduced bacterial susceptibility to Cpd36 and Cpd46.
  • Cpd36 and Cpd46 suppressed YidC2-mediated tolerance to environmental stresses.
  • Cpd46 inhibited the translocation of ATP synthase subunit c, reducing bacterial ATP production.
  • Point mutations in the YidC2 substrate-interacting cavity affected Cpd36 binding.
  • Cpd36 and Cpd46 demonstrated efficacy in eradicating MRSA persisters and biofilms.

Conclusions:

  • The membrane protein translocase YidC2 is a key target for Cpd36 and Cpd46.
  • Inhibiting YidC2-mediated membrane protein translocation offers a novel strategy against *Staphylococcus aureus* infections.
  • These findings provide a basis for developing new therapeutics against challenging MRSA infections, including persisters and biofilms.
Keywords:
MRSAsurface plasmon resonancethermal shifttranslocon

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