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 journalArticle

24 Citations (Scopus)

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 1 2012

Fingerprint

Bacillus anthracis
Staphylococcus aureus
Peptide Hydrolases
Pharmacology
Daptomycin
Anti-Bacterial Agents
Penicillins
Pharmaceutical Preparations
Cell Membrane
Bacteria
Proteins
cathelicidin antimicrobial peptide
Therapeutics
F2 protease inhibitor

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

Cite this

McGillivray, Shauna M. ; Tran, Dan N. ; Ramadoss, Nitya S. ; Alumasa, John N. ; Okumura, Cheryl Y. ; Sakoulas, George ; Vaughn, Micah M. ; Zhang, Dawn X. ; Keiler, Kenneth C. ; Nizet, Victor. / Pharmacological inhibition of the ClpXP protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell envelope-active antibiotics. In: Antimicrobial agents and chemotherapy. 2012 ; Vol. 56, No. 4. pp. 1854-1861.
@article{f7641813e2444de68f3a7f9634018f01,
title = "Pharmacological inhibition of the ClpXP protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell envelope-active antibiotics",
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.",
author = "McGillivray, {Shauna M.} and Tran, {Dan N.} and Ramadoss, {Nitya S.} and Alumasa, {John N.} and Okumura, {Cheryl Y.} and George Sakoulas and Vaughn, {Micah M.} and Zhang, {Dawn X.} and Keiler, {Kenneth C.} and Victor Nizet",
year = "2012",
month = "4",
day = "1",
doi = "10.1128/AAC.05131-11",
language = "English (US)",
volume = "56",
pages = "1854--1861",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "4",

}

Pharmacological inhibition of the ClpXP protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell envelope-active antibiotics. / McGillivray, Shauna M.; Tran, Dan N.; Ramadoss, Nitya S.; Alumasa, John N.; Okumura, Cheryl Y.; Sakoulas, George; Vaughn, Micah M.; Zhang, Dawn X.; Keiler, Kenneth C.; Nizet, Victor.

In: Antimicrobial agents and chemotherapy, Vol. 56, No. 4, 01.04.2012, p. 1854-1861.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pharmacological inhibition of the ClpXP protease increases bacterial susceptibility to host cathelicidin antimicrobial peptides and cell envelope-active antibiotics

AU - McGillivray, Shauna M.

AU - Tran, Dan N.

AU - Ramadoss, Nitya S.

AU - Alumasa, John N.

AU - Okumura, Cheryl Y.

AU - Sakoulas, George

AU - Vaughn, Micah M.

AU - Zhang, Dawn X.

AU - Keiler, Kenneth C.

AU - Nizet, Victor

PY - 2012/4/1

Y1 - 2012/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84863384066&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84863384066&partnerID=8YFLogxK

U2 - 10.1128/AAC.05131-11

DO - 10.1128/AAC.05131-11

M3 - Article

C2 - 22252821

AN - SCOPUS:84863384066

VL - 56

SP - 1854

EP - 1861

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 4

ER -