title: Bacterial Abscess Formation Is Controlled by the Stringent Stress Response and Can Be Targeted Therapeutically.
abstract: Cutaneous abscess infections are difficult to treat with current therapies and alternatives to conventional antibiotics are needed. Understanding the regulatory mechanisms that govern abscess pathology should reveal therapeutic interventions for these recalcitrant infections. Here we demonstrated that the stringent stress response employed by bacteria to cope and adapt to environmental stressors was essential for the formation of lesions, but not bacterial growth, in a methicillin resistant Staphylococcus aureus (MRSA) cutaneous abscess mouse model. To pharmacologically confirm the role of the stringent response in abscess formation, a cationic peptide that causes rapid degradation of the stringent response mediator, guanosine tetraphosphate (ppGpp), was employed. The therapeutic application of this peptide strongly inhibited lesion formation in mice infected with Gram-positive MRSA and Gram-negative Pseudomonas aeruginosa. Overall, we provide insights into the mechanisms governing abscess formation and a paradigm for treating multidrug resistant cutaneous abscesses.
authors.affiliation: Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Mansour
authors.affiliation: Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Pletzer
authors.affiliation: Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: César
authors.initials: C
authors.lastname: de la Fuente-Núñez
authors.affiliation: Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada.
authors.forename: Paul
authors.initials: P
authors.lastname: Kim
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, United States.
authors.forename: Gordon Y C
authors.initials: GYC
authors.lastname: Cheung
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, United States.
authors.forename: Hwang-Soo
authors.initials: HS
authors.lastname: Joo
authors.affiliation: Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Otto
authors.affiliation: Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada. Electronic address: bob@hancocklab.com.
authors.forename: Robert E W
authors.initials: REW
authors.lastname: Hancock
mesh_terms: D000038:Abscess / Q000188:drug therapy / Q000378:metabolism* / Q000382:microbiology* / Q000473:pathology; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use; D023181:Antimicrobial Cationic Peptides / Q000378:metabolism / Q000494:pharmacology; D001427:Bacterial Toxins / Q000378:metabolism; D018441:Biofilms / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects / Q000235:genetics; D051379:Mice; D008826:Microbial Sensitivity Tests; D013203:Staphylococcal Infections / Q000188:drug therapy / Q000382:microbiology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D013312:Stress, Physiological; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D023181:Antimicrobial Cationic Peptides; D001427:Bacterial Toxins; C025971:staphylococcal delta toxin; D043222:Ubiquitin Thiolesterase; D064570:Ubiquitin-Specific Proteases; C579224:Usp2 protein, mouse
keywords: Cationic peptide; DJK-5; Pseudomonas aeruginosa; Staphylococcus aureus; ppGpp