Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system
ABSTRACT The overuse of antibiotics in humans and livestock has driven the emergence and spread of antimicrobial resistance and has therefore prompted research on the discovery of novel antibiotics. Complestatin (Cm) and corbomycin (Cb) are glycopeptide antibiotics with an unprecedented mechanism of...
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2023-10-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.00370-23 |
| _version_ | 1797658182073450496 |
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| author | Carmen Gómez-Arrebola Sara B. Hernandez Elizabeth J. Culp Gerard D. Wright Cristina Solano Felipe Cava Iñigo Lasa |
| author_facet | Carmen Gómez-Arrebola Sara B. Hernandez Elizabeth J. Culp Gerard D. Wright Cristina Solano Felipe Cava Iñigo Lasa |
| author_sort | Carmen Gómez-Arrebola |
| collection | DOAJ |
| description | ABSTRACT The overuse of antibiotics in humans and livestock has driven the emergence and spread of antimicrobial resistance and has therefore prompted research on the discovery of novel antibiotics. Complestatin (Cm) and corbomycin (Cb) are glycopeptide antibiotics with an unprecedented mechanism of action that is active even against methicillin-resistant and daptomycin-resistant Staphylococcus aureus. They bind to peptidoglycan and block the activity of peptidoglycan hydrolases required for remodeling the cell wall during growth. Bacterial signaling through two-component transduction systems (TCSs) has been associated with the development of S. aureus antimicrobial resistance. However, the role of TCSs in S. aureus susceptibility to Cm and Cb has not been previously addressed. In this study, we determined that, among all 16 S. aureus TCSs, VraSR is the only one controlling the susceptibility to Cm and Cb. Deletion of vraSR increased bacterial susceptibility to both antibiotics. Epistasis analysis with members of the vraSR regulon revealed that deletion of spdC, which encodes a membrane protein that scaffolds SagB for cleavage of peptidoglycan strands to achieve physiological length, in the vraSR mutant restored Cm and Cb susceptibility to wild-type levels. Moreover, deletion of either spdC or sagB in the wild-type strain increased resistance to both antibiotics. Further analyses revealed a significant rise in the relative amount of peptidoglycan and its total degree of cross-linkage in ΔspdC and ΔsagB mutants compared to the wild-type strain, suggesting that these changes in the cell wall provide resistance to the damaging effect of Cm and Cb. IMPORTANCE Although Staphylococcus aureus is a common colonizer of the skin and digestive tract of humans and many animals, it is also a versatile pathogen responsible for causing a wide variety and number of infections. Treatment of these infections requires the bacteria to be constantly exposed to antibiotic treatment, which facilitates the selection of antibiotic-resistant strains. The development of new antibiotics is, therefore, urgently needed. In this paper, we investigated the role of the sensory system of S. aureus in susceptibility to two new antibiotics: corbomycin and complestatin. The results shed light on the cell-wall synthesis processes that are affected by the presence of the antibiotic and the sensory system responsible for coordinating their activity. |
| first_indexed | 2024-03-11T17:55:25Z |
| format | Article |
| id | doaj.art-c26da0457511408ab0f2039d94974529 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-03-11T17:55:25Z |
| publishDate | 2023-10-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-c26da0457511408ab0f2039d949745292023-10-17T13:04:36ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972023-10-0111510.1128/spectrum.00370-23Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component systemCarmen Gómez-Arrebola0Sara B. Hernandez1Elizabeth J. Culp2Gerard D. Wright3Cristina Solano4Felipe Cava5Iñigo Lasa6Laboratory of Microbial Pathogenesis, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA , Pamplona, SpainDepartment of Molecular Biology, Laboratory for Molecular Infection Medicine Sweden, Umeå Centre for Microbial Research, Umeå University , Umeå, SwedenDepartment of Biochemistry and Biomedical Sciences, M. G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University , Hamilton, Ontario, CanadaDepartment of Biochemistry and Biomedical Sciences, M. G. DeGroote Institute for Infectious Disease Research, David Braley Centre for Antibiotic Discovery, McMaster University , Hamilton, Ontario, CanadaLaboratory of Microbial Pathogenesis, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA , Pamplona, SpainDepartment of Molecular Biology, Laboratory for Molecular Infection Medicine Sweden, Umeå Centre for Microbial Research, Umeå University , Umeå, SwedenLaboratory of Microbial Pathogenesis, Navarrabiomed, Hospital Universitario de Navarra (HUN), Universidad Pública de Navarra (UPNA), IdiSNA , Pamplona, SpainABSTRACT The overuse of antibiotics in humans and livestock has driven the emergence and spread of antimicrobial resistance and has therefore prompted research on the discovery of novel antibiotics. Complestatin (Cm) and corbomycin (Cb) are glycopeptide antibiotics with an unprecedented mechanism of action that is active even against methicillin-resistant and daptomycin-resistant Staphylococcus aureus. They bind to peptidoglycan and block the activity of peptidoglycan hydrolases required for remodeling the cell wall during growth. Bacterial signaling through two-component transduction systems (TCSs) has been associated with the development of S. aureus antimicrobial resistance. However, the role of TCSs in S. aureus susceptibility to Cm and Cb has not been previously addressed. In this study, we determined that, among all 16 S. aureus TCSs, VraSR is the only one controlling the susceptibility to Cm and Cb. Deletion of vraSR increased bacterial susceptibility to both antibiotics. Epistasis analysis with members of the vraSR regulon revealed that deletion of spdC, which encodes a membrane protein that scaffolds SagB for cleavage of peptidoglycan strands to achieve physiological length, in the vraSR mutant restored Cm and Cb susceptibility to wild-type levels. Moreover, deletion of either spdC or sagB in the wild-type strain increased resistance to both antibiotics. Further analyses revealed a significant rise in the relative amount of peptidoglycan and its total degree of cross-linkage in ΔspdC and ΔsagB mutants compared to the wild-type strain, suggesting that these changes in the cell wall provide resistance to the damaging effect of Cm and Cb. IMPORTANCE Although Staphylococcus aureus is a common colonizer of the skin and digestive tract of humans and many animals, it is also a versatile pathogen responsible for causing a wide variety and number of infections. Treatment of these infections requires the bacteria to be constantly exposed to antibiotic treatment, which facilitates the selection of antibiotic-resistant strains. The development of new antibiotics is, therefore, urgently needed. In this paper, we investigated the role of the sensory system of S. aureus in susceptibility to two new antibiotics: corbomycin and complestatin. The results shed light on the cell-wall synthesis processes that are affected by the presence of the antibiotic and the sensory system responsible for coordinating their activity.https://journals.asm.org/doi/10.1128/spectrum.00370-23Staphylococcus aureustwo-component systemVraSRcomplestatincorbomycinautolysins |
| spellingShingle | Carmen Gómez-Arrebola Sara B. Hernandez Elizabeth J. Culp Gerard D. Wright Cristina Solano Felipe Cava Iñigo Lasa Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system Microbiology Spectrum Staphylococcus aureus two-component system VraSR complestatin corbomycin autolysins |
| title | Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system |
| title_full | Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system |
| title_fullStr | Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system |
| title_full_unstemmed | Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system |
| title_short | Staphylococcus aureus susceptibility to complestatin and corbomycin depends on the VraSR two-component system |
| title_sort | staphylococcus aureus susceptibility to complestatin and corbomycin depends on the vrasr two component system |
| topic | Staphylococcus aureus two-component system VraSR complestatin corbomycin autolysins |
| url | https://journals.asm.org/doi/10.1128/spectrum.00370-23 |
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