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.
authors.affiliation: Department of Biology, Texas Christian University, Fort Worth, Texas, USA. s.mcgillivray@tcu.edu
authors.forename: Shauna M
authors.initials: SM
authors.lastname: McGillivray
authors.forename: Dan N
authors.initials: DN
authors.lastname: Tran
authors.forename: Nitya S
authors.initials: NS
authors.lastname: Ramadoss
authors.forename: John N
authors.initials: JN
authors.lastname: Alumasa
authors.forename: Cheryl Y
authors.initials: CY
authors.lastname: Okumura
authors.forename: George
authors.initials: G
authors.lastname: Sakoulas
authors.forename: Micah M
authors.initials: MM
authors.lastname: Vaughn
authors.forename: Dawn X
authors.initials: DX
authors.lastname: Zhang
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Keiler
authors.forename: Victor
authors.initials: V
authors.lastname: Nizet
mesh_terms: D000595:Amino Acid Sequence; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D023181:Antimicrobial Cationic Peptides / Q000494:pharmacology*; D001408:Bacillus anthracis / Q000187:drug effects / Q000235:genetics; D001419:Bacteria / Q000187:drug effects*; D002462:Cell Membrane / Q000378:metabolism; D024881:Drug Resistance, Bacterial; D004357:Drug Synergism; D049071:Endopeptidase Clp / Q000037:antagonists & inhibitors*; D029968:Escherichia coli Proteins / Q000037:antagonists & inhibitors*; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects; D008969:Molecular Sequence Data; D011480:Protease Inhibitors / Q000494:pharmacology*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development; D013777:Tetrazoles / Q000494:pharmacology; D054804:Cathelicidins
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D029968:Escherichia coli Proteins; C573017:F2 protease inhibitor; D011480:Protease Inhibitors; D013777:Tetrazoles; C483573:ClpXP protease, E coli; D049071:Endopeptidase Clp; D054804:Cathelicidins