Article (Scientific journals)
A Clinically Selected Staphylococcus aureus clpP Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology.
Xu, Lijuan; Henriksen, Camilla; Mebus, Viktor et al.
2023In Antimicrobial Agents and Chemotherapy, p. 0032823
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Keywords :
ClpP; MRSA; antibiotics; cell wall; daptomycin; vancomycin; Infectious Diseases; Pharmacology (medical); Pharmacology
Abstract :
[en] 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. Super-resolution microscopy demonstrated that inactivation of ClpP reduced binding of daptomycin to the septal site and diminished membrane damage. In both the parental strain and the clpP strain, daptomycin inhibited the inward progression of septum synthesis, eventually leading to lysis and death of the parental strain while surviving clpP cells were able to continue synthesis of the peripheral cell wall in the presence of 10× MIC daptomycin, resulting in a rod-shaped morphology. To our knowledge, this is the first demonstration that synthesis of the outer cell wall continues in the presence of daptomycin. Collectively, our data provide novel insight into the mechanisms behind bacterial killing and resistance to this important antibiotic. Also, the study emphasizes that treatment with last-line antibiotics is selective for mutations that, like the SNP in clpP, favor antibiotic resistance over virulence gene expression.
Disciplines :
Microbiology
Author, co-author :
Xu, Lijuan;  Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Henriksen, Camilla;  Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Mebus, Viktor;  Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
Guérillot, Romain;  Department of Microbiology and Immunology, University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
Petersen, Andreas;  Statens Serum Institute, Copenhagen, Denmark
Jacques, Nicolas ;  Université de Liège - ULiège > GIGA > GIGA Cardiovascular Sciences - Cardiology
Jiang, Jhih-Hang;  Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia ; Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia ; Department of Microbiology, Monash University, Melbourne, Victoria, Australia
Derks, Rico J E;  Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, Netherlands
Sánchez-López, Elena;  Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, Netherlands
Giera, Martin;  Leiden University Medical Center, Center for Proteomics and Metabolomics, Leiden, Netherlands
Leeten, Kirsten  ;  Université de Liège - ULiège > GIGA > GIGA Cardiovascular Sciences - Cardiology
Stinear, Timothy P ;  Department of Microbiology and Immunology, University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
Oury, Cécile  ;  Université de Liège - ULiège > GIGA > GIGA Cardiovascular Sciences - Cardiology
Howden, Benjamin P;  Department of Microbiology and Immunology, University of Melbourne at the Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia
Peleg, Anton Y ;  Department of Infectious Diseases, The Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria, Australia ; Infection and Immunity Program, Monash Biomedicine Discovery Institute, Monash University, Melbourne, Victoria, Australia ; Department of Microbiology, Monash University, Melbourne, Victoria, Australia
Frees, Dorte ;  Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
More authors (6 more) Less
Language :
English
Title :
A Clinically Selected Staphylococcus aureus clpP Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology.
Publication date :
15 May 2023
Journal title :
Antimicrobial Agents and Chemotherapy
ISSN :
0066-4804
eISSN :
1098-6596
Publisher :
American Society for Microbiology, United States
Pages :
e0032823
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
DFF - Danish Council for Independent Research [DK]
CSC - China Scholarship Council [CN]
Available on ORBi :
since 24 May 2023

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