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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
Source PublicationBIOCHIMIE
ISSN0300-9084
Volume171Pages:213-222
Corresponding AuthorMa, Qingjun(qma@qdio.ac.cn)
Abstractbeta-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.
KeywordVibrio parahaemolyticus CARB beta-lactamase CARB-17 family Directed evolution Inhibitor resistance
DOI10.1016/j.biochi.2020.03.011
Indexed BySCI
Language英语
Funding Project100-talents Project of Chinese Academy of Sciences[Y62429101L] ; [18-1-2-12-zhc]
WOS Research AreaBiochemistry & Molecular Biology
WOS SubjectBiochemistry & Molecular Biology
WOS IDWOS:000525866900024
PublisherELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
Citation statistics
Cited Times:2[WOS]   [WOS Record]     [Related Records in WOS]
Document Type期刊论文
Identifierhttp://ir.qdio.ac.cn/handle/337002/167137
Collection实验海洋生物学重点实验室
Corresponding AuthorMa, Qingjun
Affiliation1.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
First Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences
Corresponding Author AffilicationInstitute of Oceanology, Chinese Academy of Sciences;  Center for Ocean Mega-Science, Chinese Academy of Sciences
Recommended Citation
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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