Bacterial Abscess Formation Is Controlled by the Stringent Stress Response and Can Be Targeted Therapeutically
Sarah C. Mansour,
Daniel Pletzer,
César de la Fuente-Núñez,
Paul Kim,
Gordon Y.C. Cheung,
Hwang-Soo Joo,
Michael Otto,
Robert E.W. Hancock
Affiliations
Sarah C. Mansour
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
Daniel Pletzer
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
César de la Fuente-Núñez
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
Paul Kim
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
Gordon Y.C. Cheung
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, United States
Hwang-Soo Joo
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, United States
Michael Otto
Pathogen Molecular Genetics Section, Laboratory of Bacteriology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20814, United States
Robert E.W. Hancock
Centre for Microbial Diseases and Immunity Research, Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z4, Canada
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.
