Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic β-Lactam and Vancomycin Resistance
ABSTRACT Vancomycin and β-lactams are clinically important antibiotics that inhibit the formation of peptidoglycan cross-links, but their binding targets are different. The binding target of vancomycin is d-alanine-d-alanine (d-Ala-d-Ala), whereas that of β-lactam is penicillin-binding proteins (PBP...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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American Society for Microbiology
2022-08-01
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| Series: | Microbiology Spectrum |
| Subjects: | |
| Online Access: | https://journals.asm.org/doi/10.1128/spectrum.01734-22 |
| _version_ | 1828745964839501824 |
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| author | Si Hyoung Park Umji Choi Su-Hyun Ryu Han Byeol Lee Jin-Won Lee Chang-Ro Lee |
| author_facet | Si Hyoung Park Umji Choi Su-Hyun Ryu Han Byeol Lee Jin-Won Lee Chang-Ro Lee |
| author_sort | Si Hyoung Park |
| collection | DOAJ |
| description | ABSTRACT Vancomycin and β-lactams are clinically important antibiotics that inhibit the formation of peptidoglycan cross-links, but their binding targets are different. The binding target of vancomycin is d-alanine-d-alanine (d-Ala-d-Ala), whereas that of β-lactam is penicillin-binding proteins (PBPs). In this study, we revealed the divergent effects of peptidoglycan (PG) carboxypeptidase DacA on vancomycin and β-lactam resistance in Escherichia coli and Bacillus subtilis. The deletion of DacA induced sensitivity to most β-lactams, whereas it induced strong resistance toward vancomycin. Notably, both phenotypes did not have a strong association with ld-transpeptidases, which are necessary for the formation of PG 3-3 cross-links and covalent bonds between PG and an Lpp outer membrane (OM) lipoprotein. Vancomycin resistance was induced by an increased amount of decoy d-Ala-d-Ala residues within PG, whereas β-lactam sensitivity was associated with physical interactions between DacA and PBPs. The presence of an OM permeability barrier strongly strengthened vancomycin resistance, but it significantly weakened β-lactam sensitivity. Collectively, our results revealed two distinct functions of DacA, which involved inverse modulation of bacterial resistance to clinically important antibiotics, β-lactams and vancomycin, and presented evidence for a link between DacA and PBPs. IMPORTANCE Bacterial PG hydrolases play important roles in various aspects of bacterial physiology, including cytokinesis, PG synthesis, quality control of PG, PG recycling, and stress adaptation. Of all the PG hydrolases, the role of PG carboxypeptidases is poorly understood, especially regarding their impacts on antibiotic resistance. We have revealed two distinct functions of PG carboxypeptidase DacA with respect to antibiotic resistance. The deletion of DacA led to sensitivity to most β-lactams, while it caused strong resistance to vancomycin. Our study provides novel insights into the roles of PG carboxypeptidases in the regulation of antibiotic resistance and a potential clue for the development of a drug to improve the clinical efficacy of β-lactam antibiotics. |
| first_indexed | 2024-04-14T04:13:27Z |
| format | Article |
| id | doaj.art-c81fbf3ec16b419185c2f1532661c818 |
| institution | Directory Open Access Journal |
| issn | 2165-0497 |
| language | English |
| last_indexed | 2024-04-14T04:13:27Z |
| publishDate | 2022-08-01 |
| publisher | American Society for Microbiology |
| record_format | Article |
| series | Microbiology Spectrum |
| spelling | doaj.art-c81fbf3ec16b419185c2f1532661c8182022-12-22T02:13:00ZengAmerican Society for MicrobiologyMicrobiology Spectrum2165-04972022-08-0110410.1128/spectrum.01734-22Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic β-Lactam and Vancomycin ResistanceSi Hyoung Park0Umji Choi1Su-Hyun Ryu2Han Byeol Lee3Jin-Won Lee4Chang-Ro Lee5Department of Biological Sciences, Myongji University, Yongin, Gyeonggido, Republic of KoreaDepartment of Biological Sciences, Myongji University, Yongin, Gyeonggido, Republic of KoreaDepartment of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of KoreaDepartment of Biological Sciences, Myongji University, Yongin, Gyeonggido, Republic of KoreaDepartment of Life Science and Research Institute for Natural Sciences, Hanyang University, Seoul, Republic of KoreaDepartment of Biological Sciences, Myongji University, Yongin, Gyeonggido, Republic of KoreaABSTRACT Vancomycin and β-lactams are clinically important antibiotics that inhibit the formation of peptidoglycan cross-links, but their binding targets are different. The binding target of vancomycin is d-alanine-d-alanine (d-Ala-d-Ala), whereas that of β-lactam is penicillin-binding proteins (PBPs). In this study, we revealed the divergent effects of peptidoglycan (PG) carboxypeptidase DacA on vancomycin and β-lactam resistance in Escherichia coli and Bacillus subtilis. The deletion of DacA induced sensitivity to most β-lactams, whereas it induced strong resistance toward vancomycin. Notably, both phenotypes did not have a strong association with ld-transpeptidases, which are necessary for the formation of PG 3-3 cross-links and covalent bonds between PG and an Lpp outer membrane (OM) lipoprotein. Vancomycin resistance was induced by an increased amount of decoy d-Ala-d-Ala residues within PG, whereas β-lactam sensitivity was associated with physical interactions between DacA and PBPs. The presence of an OM permeability barrier strongly strengthened vancomycin resistance, but it significantly weakened β-lactam sensitivity. Collectively, our results revealed two distinct functions of DacA, which involved inverse modulation of bacterial resistance to clinically important antibiotics, β-lactams and vancomycin, and presented evidence for a link between DacA and PBPs. IMPORTANCE Bacterial PG hydrolases play important roles in various aspects of bacterial physiology, including cytokinesis, PG synthesis, quality control of PG, PG recycling, and stress adaptation. Of all the PG hydrolases, the role of PG carboxypeptidases is poorly understood, especially regarding their impacts on antibiotic resistance. We have revealed two distinct functions of PG carboxypeptidase DacA with respect to antibiotic resistance. The deletion of DacA led to sensitivity to most β-lactams, while it caused strong resistance to vancomycin. Our study provides novel insights into the roles of PG carboxypeptidases in the regulation of antibiotic resistance and a potential clue for the development of a drug to improve the clinical efficacy of β-lactam antibiotics.https://journals.asm.org/doi/10.1128/spectrum.01734-22antibiotic resistancepeptidoglycan hydrolasepeptidoglycan carboxypeptidaseDacAβ-lactamvancomycin |
| spellingShingle | Si Hyoung Park Umji Choi Su-Hyun Ryu Han Byeol Lee Jin-Won Lee Chang-Ro Lee Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic β-Lactam and Vancomycin Resistance Microbiology Spectrum antibiotic resistance peptidoglycan hydrolase peptidoglycan carboxypeptidase DacA β-lactam vancomycin |
| title | Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic β-Lactam and Vancomycin Resistance |
| title_full | Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic β-Lactam and Vancomycin Resistance |
| title_fullStr | Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic β-Lactam and Vancomycin Resistance |
| title_full_unstemmed | Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic β-Lactam and Vancomycin Resistance |
| title_short | Divergent Effects of Peptidoglycan Carboxypeptidase DacA on Intrinsic β-Lactam and Vancomycin Resistance |
| title_sort | divergent effects of peptidoglycan carboxypeptidase daca on intrinsic β lactam and vancomycin resistance |
| topic | antibiotic resistance peptidoglycan hydrolase peptidoglycan carboxypeptidase DacA β-lactam vancomycin |
| url | https://journals.asm.org/doi/10.1128/spectrum.01734-22 |
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