A Clinically Selected Staphylococcus aureus clpP Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology

Antimicrobial Agents and Chemotherapy, vol. 67, pp. e0032823

Abstract

Daptomycin is a last-resort antibiotic used for the treatment of infections caused by Gram-positive antibiotic-resistant bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). Treatment failure is commonly linked to accumulation of point mutations; however, the contribution of single mutations to resistance and the mechanisms underlying resistance remain incompletely understood. Here, we show that a single nucleotide polymorphism (SNP) selected during daptomycin therapy inactivates the highly conserved ClpP protease and is causing reduced susceptibility of MRSA to daptomycin, vancomycin, and β-lactam antibiotics as well as decreased expression of virulence factors.

Authors 16

1. Lijuan Xu

   University of Copenhagen

   Affiliation as printed

   Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

2. Camilla Henriksen

   University of Copenhagen

   Affiliation as printed

   Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

3. Viktor Hundtofte Mebus

   University of Copenhagen

   Affiliation as printed

   Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

4. Romain Guérillot

   The University of Melbourne · Peter Doherty Institute

   Affiliation as printed

   Department of Microbiology and Immunology, University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

5. Andreas Petersen

   Statens Serum Institut

   Affiliation as printed

   Statens Serum Institute, Copenhagen, Denmark

6. Nicolas Jacques

   University of Liège · Centre Hospitalier Universitaire de Liège

   Affiliation as printed

   Laboratory of Cardiology, GIGA Institute, University of Liège Hospital, Liège, Belgium

7. Jhih‐Hang Jiang

   The Alfred Hospital · Monash University

   Affiliation as printed

   Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia

   Department of Microbiology, Monash University, Melbourne, Victoria, Australia

   Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia

8. Rico J. E. Derks Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, Netherlands

9. Elena Sánchez‐López Aachen Center for Proteomics and Metabolomics

   Leiden University Medical Center

   Affiliation as printed

   Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, Netherlands

10. Martin A. Giera Aachen Center for Proteomics and Metabolomics

    Leiden University Medical Center

    Affiliation as printed

    Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, Netherlands

11. Kirsten Leeten

    University of Liège · Centre Hospitalier Universitaire de Liège

    Affiliation as printed

    Laboratory of Cardiology, GIGA Institute, University of Liège Hospital, Liège, Belgium

12. Timothy P. Stinear

    The University of Melbourne · Peter Doherty Institute

    Affiliation as printed

    Department of Microbiology and Immunology, University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

13. Cécile Oury

    University of Liège · Centre Hospitalier Universitaire de Liège

    Affiliation as printed

    Laboratory of Cardiology, GIGA Institute, University of Liège Hospital, Liège, Belgium

14. Benjamin P. Howden

    The University of Melbourne · Peter Doherty Institute

    Affiliation as printed

    Department of Microbiology and Immunology, University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia

15. Anton Yariv Peleg

    The Alfred Hospital · Monash University

    Affiliation as printed

    Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia

    Department of Microbiology, Monash University, Melbourne, Victoria, Australia

    Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia

16. Dorte Frees corresponding

    University of Copenhagen

    Affiliation as printed

    Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark