A Clinically Selected Staphylococcus aureus clpP Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology
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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; Guérillot, Romain; Petersen, Andreas; Jacques, Nicolas; Jiang, Jhih Hang; Derks, Rico J.E.; Sánchez-López, Elena; Giera, Martin; Leeten, Kirsten; Stinear, Timothy P.; Oury, Cécile; Howden, Benjamin P.; Peleg, Anton Y.; Frees, Dorte.
In: Antimicrobial Agents and Chemotherapy, Vol. 67, No. 6, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - A Clinically Selected Staphylococcus aureus clpP Mutant Survives Daptomycin Treatment by Reducing Binding of the Antibiotic and Adapting a Rod-Shaped Morphology
AU - Xu, Lijuan
AU - Henriksen, Camilla
AU - Mebus, Viktor
AU - Guérillot, Romain
AU - Petersen, Andreas
AU - Jacques, Nicolas
AU - Jiang, Jhih Hang
AU - Derks, Rico J.E.
AU - Sánchez-López, Elena
AU - Giera, Martin
AU - Leeten, Kirsten
AU - Stinear, Timothy P.
AU - Oury, Cécile
AU - Howden, Benjamin P.
AU - Peleg, Anton Y.
AU - Frees, Dorte
N1 - Publisher Copyright: Copyright © 2023 Xu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
PY - 2023
Y1 - 2023
N2 - 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 b-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.
AB - 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 b-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.
KW - antibiotics
KW - cell wall
KW - ClpP
KW - daptomycin
KW - MRSA
KW - vancomycin
U2 - 10.1128/aac.00328-23
DO - 10.1128/aac.00328-23
M3 - Journal article
C2 - 37184389
AN - SCOPUS:85163738810
VL - 67
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 6
ER -
ID: 362700859