Pharmacological inhibition of the ClpXP protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell envelope-active antibiotics

Shauna M. McGillivray, Dan N. Tran, Nitya S. Ramadoss, John N. Alumasa, Cheryl Y. Okumura, George Sakoulas, Micah M. Vaughn, Dawn X. Zhang, Kenneth C. Keiler, Victor Nizet

Research output: Contribution to journalArticlepeer-review

29 Scopus citations

Abstract

The ClpXP protease is a critical bacterial intracellular protease that regulates protein turnover in many bacterial species. Here we identified a pharmacological inhibitor of the ClpXP protease, F2, and evaluated its action in Bacillus anthracis and Staphylococcus aureus. We found that F2 exhibited synergistic antimicrobial activity with cathelicidin antimicrobial peptides and antibiotics that target the cell well and/or cell membrane, such as penicillin and daptomycin, in B. anthracis and drug-resistant strains of S. aureus. ClpXP inhibition represents a novel therapeutic strategy to simultaneously sensitize pathogenic bacteria to host defenses and pharmaceutical antibiotics.

Original languageEnglish (US)
Pages (from-to)1854-1861
Number of pages8
JournalAntimicrobial agents and chemotherapy
Volume56
Issue number4
DOIs
StatePublished - Apr 2012

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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