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| Structural analysis of the CARB beta-lactamase from Vibrio parahaemolyticus facilitates application of the beta-lactam/beta-lactamase inhibitor therapy | |
| Li, Peihai1,2,3; Liu, Changshui1,2; Li, Baojie4; Ma, Qingjun1,2,5 | |
| 2020-04-01 | |
| 发表期刊 | BIOCHIMIE
 |
| ISSN | 0300-9084 |
| 卷号 | 171页码:213-222 |
| 通讯作者 | Ma, Qingjun(qma@qdio.ac.cn) |
| 摘要 | beta-Lactams are the most widely used antibiotics in treating bacterial infections. However, they are rarely applied in infections caused by Vibrio parahaemolyticus, as the bacterium is intrinsically resistant to penicillins by expressing beta-lactamase. Here we report structural characterization of the CARB beta-lactamase from V. parahaemolyticus (CARB-20). CARB-20 is a class A beta-lactamase, belonging to subclass A1 (containing 70STFKAL75, 130SDNTAANL137, 164RXEXXLN170, 231VGDKTG236, etc.), group LSBL2 (with the disulfide bridge C77-C123, motif 231IADRSGAG238 and R244). CARB-20 adopts a typical subclass A1 beta-lactamase fold consisting of two domains. Its active site is constituted by four conserved motifs, similar to that of known subclass A1 beta-lactamases. Analysis of the active site structure reveals its substrate preference for penicillin, ampicillin and carbenicillin but not for latterly developed cephalosporins. Meanwhile, beta-lactamase inhibitors such as clavulanate and sulbactam can well fit into the active site, supporting beta-lactams combined with beta-lactamase inhibitors as a potential approach for treating infection of V. parahaemolyticus. The residues around the active site show certain variations, which can be useful for specific inhibitor design. In the directed evolution experiment, CARB-20 exhibited plasticity in developing significant resistance to inhibitors by accumulated residue substitutions. Therefore, careful monitoring of enzyme mutations is necessary for successfully applying beta-lactam/beta-lactamase inhibitor combination therapy. Taken together, our results open up an avenue of inhibitor design targeting vibrio beta-lactamases, facilitating the application of beta-lactams in treating vibrio infections. (C) 2020 Elsevier B.V. and Societe Francaise de Biochimie et Biologie Moleculaire (SFBBM). All rights reserved. |
| 关键词 | Vibrio parahaemolyticus CARB beta-lactamase CARB-17 family Directed evolution Inhibitor resistance |
| DOI | 10.1016/j.biochi.2020.03.011 |
| 收录类别 | SCI |
| 语种 | 英语 |
| 资助项目 | 100-talents Project of Chinese Academy of Sciences[Y62429101L] ; [18-1-2-12-zhc] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| WOS类目 | Biochemistry & Molecular Biology |
| WOS记录号 | WOS:000525866900024 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://ir.qdio.ac.cn/handle/337002/167137 |
| 专题 | 实验海洋生物学重点实验室 |
| 通讯作者 | Ma, Qingjun |
| 作者单位 | 1.Chinese Acad Sci, Inst Oceanol, Key Lab Expt Marine Biol, Qingdao, Peoples R China 2.Qingdao Natl Lab Marine Sci & Technol, Lab Marine Biol & Biotechnol, Qingdao, Peoples R China 3.Qilu Univ Technol, Key Lab Drug Screening Technol, Biol Inst, Shandong Acad Sci, Jinan, Shandong, Peoples R China 4.Lunan Pharmaceut Grp, Linyi, Shandong, Peoples R China 5.Chinese Acad Sci, Ctr Ocean Megasci, Qingdao, Peoples R China |
| 第一作者单位 | 中国科学院海洋研究所 |
| 通讯作者单位 | 中国科学院海洋研究所; 中国科学院海洋大科学研究中心 |
| 推荐引用方式 GB/T 7714 | Li, Peihai,Liu, Changshui,Li, Baojie,et al. Structural analysis of the CARB beta-lactamase from Vibrio parahaemolyticus facilitates application of the beta-lactam/beta-lactamase inhibitor therapy[J]. BIOCHIMIE,2020,171:213-222. |
| APA | Li, Peihai,Liu, Changshui,Li, Baojie,&Ma, Qingjun.(2020).Structural analysis of the CARB beta-lactamase from Vibrio parahaemolyticus facilitates application of the beta-lactam/beta-lactamase inhibitor therapy.BIOCHIMIE,171,213-222. |
| MLA | Li, Peihai,et al."Structural analysis of the CARB beta-lactamase from Vibrio parahaemolyticus facilitates application of the beta-lactam/beta-lactamase inhibitor therapy".BIOCHIMIE 171(2020):213-222. |
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| Structural analysis （2557KB） | 期刊论文 | 出版稿 | 限制开放 | CC BY-NC-SA | 浏览 | |
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