Vancomycin‐intermediate Staphylococcus aureus employs CcpA‐GlmS metabolism regulatory cascade to resist vancomycin
Abstract Vancomycin (VAN)‐intermediate Staphylococcus aureus (VISA) is a critical cause of VAN treatment failure worldwide. Multiple genetic changes are reportedly associated with VISA formation, whereas VISA strains often present common phenotypes, such as reduced autolysis and thickened cell wall....
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| Format: | Article |
| Language: | English |
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Wiley
2024-12-01
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| Series: | MedComm – Future Medicine |
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| Online Access: | https://doi.org/10.1002/mef2.70007 |
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| author | Huagang Peng Yifan Rao Weilong Shang Yi Yang Li Tan Lu Liu Zhen Hu Yuting Wang Xiaonan Huang He Liu Mengyang Li Zuwen Guo Juan Chen Yuhua Yang Jianghong Wu Wenchang Yuan Qiwen Hu Xiancai Rao |
| author_facet | Huagang Peng Yifan Rao Weilong Shang Yi Yang Li Tan Lu Liu Zhen Hu Yuting Wang Xiaonan Huang He Liu Mengyang Li Zuwen Guo Juan Chen Yuhua Yang Jianghong Wu Wenchang Yuan Qiwen Hu Xiancai Rao |
| author_sort | Huagang Peng |
| collection | DOAJ |
| description | Abstract Vancomycin (VAN)‐intermediate Staphylococcus aureus (VISA) is a critical cause of VAN treatment failure worldwide. Multiple genetic changes are reportedly associated with VISA formation, whereas VISA strains often present common phenotypes, such as reduced autolysis and thickened cell wall. However, how mutated genes lead to VISA common phenotypes remains unclear. Here, we show a metabolism regulatory cascade (CcpA‐GlmS), whereby mutated two‐component systems (TCSs) link to the common phenotypes of VISA. We found that ccpA deletion decreased VAN resistance in VISA strains with diverse genetic backgrounds. Metabolic alteration in VISA was associated with ccpA upregulation, which was directly controlled by TCSs WalKR and GraSR. RNA‐sequencing revealed the crucial roles of CcpA in changing the carbon flow and nitrogen flux of VISA to promote VAN resistance. A gate enzyme (GlmS) that drives carbon flow to the cell wall precursor biosynthesis was upregulated in VISA. CcpA directly controlled glmS expression. Blocking CcpA sensitized VISA strains to VAN treatment in vitro and in vivo. Overall, this work uncovers a link between the formation of VISA phenotypes and commonly mutated genes. Inhibition of CcpA‐GlmS cascade is a promising strategy to restore the therapeutic efficiency of VAN against VISA infections. |
| format | Article |
| id | doaj-art-9e04b5bd53334e4298bb1acf320bbb3f |
| institution | OA Journals |
| issn | 2769-6456 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm – Future Medicine |
| spelling | doaj-art-9e04b5bd53334e4298bb1acf320bbb3f2025-08-20T02:38:59ZengWileyMedComm – Future Medicine2769-64562024-12-0134n/an/a10.1002/mef2.70007Vancomycin‐intermediate Staphylococcus aureus employs CcpA‐GlmS metabolism regulatory cascade to resist vancomycinHuagang Peng0Yifan Rao1Weilong Shang2Yi Yang3Li Tan4Lu Liu5Zhen Hu6Yuting Wang7Xiaonan Huang8He Liu9Mengyang Li10Zuwen Guo11Juan Chen12Yuhua Yang13Jianghong Wu14Wenchang Yuan15Qiwen Hu16Xiancai Rao17Department of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Emergency Medicine, Xinqiao Hospital Army Medical University Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, School of Medicine Chongqing University Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Pharmacy, Xinqiao Hospital Army Medical University Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaKingMed School of Laboratory Medicine Guangzhou Medical University Guangzhou ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaDepartment of Microbiology, College of Basic Medical Sciences, Army Medical University Key Laboratory of Microbial Engineering under the Educational Committee in Chongqing Chongqing ChinaAbstract Vancomycin (VAN)‐intermediate Staphylococcus aureus (VISA) is a critical cause of VAN treatment failure worldwide. Multiple genetic changes are reportedly associated with VISA formation, whereas VISA strains often present common phenotypes, such as reduced autolysis and thickened cell wall. However, how mutated genes lead to VISA common phenotypes remains unclear. Here, we show a metabolism regulatory cascade (CcpA‐GlmS), whereby mutated two‐component systems (TCSs) link to the common phenotypes of VISA. We found that ccpA deletion decreased VAN resistance in VISA strains with diverse genetic backgrounds. Metabolic alteration in VISA was associated with ccpA upregulation, which was directly controlled by TCSs WalKR and GraSR. RNA‐sequencing revealed the crucial roles of CcpA in changing the carbon flow and nitrogen flux of VISA to promote VAN resistance. A gate enzyme (GlmS) that drives carbon flow to the cell wall precursor biosynthesis was upregulated in VISA. CcpA directly controlled glmS expression. Blocking CcpA sensitized VISA strains to VAN treatment in vitro and in vivo. Overall, this work uncovers a link between the formation of VISA phenotypes and commonly mutated genes. Inhibition of CcpA‐GlmS cascade is a promising strategy to restore the therapeutic efficiency of VAN against VISA infections.https://doi.org/10.1002/mef2.70007catabolite control protein Ametabolic changesStaphylococcus aureustwo‐component systemvancomycin resistance |
| spellingShingle | Huagang Peng Yifan Rao Weilong Shang Yi Yang Li Tan Lu Liu Zhen Hu Yuting Wang Xiaonan Huang He Liu Mengyang Li Zuwen Guo Juan Chen Yuhua Yang Jianghong Wu Wenchang Yuan Qiwen Hu Xiancai Rao Vancomycin‐intermediate Staphylococcus aureus employs CcpA‐GlmS metabolism regulatory cascade to resist vancomycin MedComm – Future Medicine catabolite control protein A metabolic changes Staphylococcus aureus two‐component system vancomycin resistance |
| title | Vancomycin‐intermediate Staphylococcus aureus employs CcpA‐GlmS metabolism regulatory cascade to resist vancomycin |
| title_full | Vancomycin‐intermediate Staphylococcus aureus employs CcpA‐GlmS metabolism regulatory cascade to resist vancomycin |
| title_fullStr | Vancomycin‐intermediate Staphylococcus aureus employs CcpA‐GlmS metabolism regulatory cascade to resist vancomycin |
| title_full_unstemmed | Vancomycin‐intermediate Staphylococcus aureus employs CcpA‐GlmS metabolism regulatory cascade to resist vancomycin |
| title_short | Vancomycin‐intermediate Staphylococcus aureus employs CcpA‐GlmS metabolism regulatory cascade to resist vancomycin |
| title_sort | vancomycin intermediate staphylococcus aureus employs ccpa glms metabolism regulatory cascade to resist vancomycin |
| topic | catabolite control protein A metabolic changes Staphylococcus aureus two‐component system vancomycin resistance |
| url | https://doi.org/10.1002/mef2.70007 |
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