Please use this identifier to cite or link to this item:
http://hdl.handle.net/10397/79808
DC Field | Value | Language |
---|---|---|
dc.contributor | Department of Applied Biology and Chemical Technology | en_US |
dc.contributor | Chinese Mainland Affairs Office | en_US |
dc.creator | Pan, XH | en_US |
dc.creator | He, YJ | en_US |
dc.creator | Chen, TF | en_US |
dc.creator | Chan, KF | en_US |
dc.creator | Zhao, YX | en_US |
dc.date.accessioned | 2018-12-21T07:13:27Z | - |
dc.date.available | 2018-12-21T07:13:27Z | - |
dc.identifier.issn | 0066-4804 | en_US |
dc.identifier.uri | http://hdl.handle.net/10397/79808 | - |
dc.language.iso | en | en_US |
dc.publisher | American Society for Microbiology | en_US |
dc.rights | © 2017 American Society for Microbiology. All Rights Reserved. | en_US |
dc.subject | Beta-lactamase inhibitor | en_US |
dc.subject | Carbapenem-like | en_US |
dc.subject | Class C beta-lactamase | en_US |
dc.title | Modified penicillin molecule with carbapenem- like stereochemistry specifically inhibits class C beta-lactamases | en_US |
dc.type | Journal/Magazine Article | en_US |
dc.identifier.volume | 61 | en_US |
dc.identifier.issue | 12 | en_US |
dc.identifier.doi | 10.1128/AAC.01288-17 | en_US |
dcterms.abstract | Bacterial beta-actamases readily inactivate most penicillins and cephalosporins by hydrolyzing and "opening" their signature beta-lactam ring. In contrast, carbapenems resist hydrolysis by many serine-based class A, C, and D beta-lactamases due to their unique stereochemical features. To improve the resistance profile of penicillins, we synthesized a modified penicillin molecule, MPC-1, by "grafting" carbapenem-like stereochemistry onto the penicillin core. Chemical modifications include the trans conformation of hydrogen atoms at C-5 and C-6 instead of cis, and a 6-alpha hydroxyethyl moiety to replace the original 6-beta aminoacyl group. MPC-1 selectively inhibits class C beta-lactamases, such as P99, by forming a nonhydrolyzable acyl adduct, and its inhibitory potency is similar to 2 to 5 times higher than that for clinically used beta-lactamase inhibitors clavulanate and sulbactam. The crystal structure of MPC-1 forming the acyl adduct with P99 reveals a novel binding mode for MPC-1 that resembles carbapenem bound in the active site of class A beta-lactamases. Furthermore, in this novel binding mode, the carboxyl group of MPC-1 blocks the deacylation reaction by occluding the critical catalytic water molecule and renders the acyl adduct nonhydrolyzable. Our results suggest that by incorporating carbapenem-like stereochemistry, the current collection of over 100 penicillins and cephalosporins can be modified into candidate compounds for development of novel beta-lactamase inhibitors. | en_US |
dcterms.accessRights | open access | en_US |
dcterms.bibliographicCitation | Antimicrobial agents and chemotherapy, Dec. 2017, v. 61, no. 12, e01288-17 | en_US |
dcterms.isPartOf | Antimicrobial agents and chemotherapy | en_US |
dcterms.issued | 2017-12 | - |
dc.identifier.isi | WOS:000416578900036 | - |
dc.identifier.pmid | 28971874 | - |
dc.identifier.eissn | 1098-6596 | en_US |
dc.identifier.artn | e01288-17 | en_US |
dc.identifier.rosgroupid | 2017006645 | - |
dc.description.ros | 2017-2018 > Academic research: refereed > Publication in refereed journal | en_US |
dc.description.validate | 201812 bcrc | en_US |
dc.description.oa | Version of Record | en_US |
dc.identifier.FolderNumber | RGC-B1-109, ABCT-0597 | - |
dc.description.fundingSource | RGC | en_US |
dc.description.fundingSource | Others | en_US |
dc.description.fundingText | Health and Medical Research Fund; Shenzhen Basic Research Program of China; the Research Committee of the Hong Kong Polytechnic University | en_US |
dc.description.pubStatus | Published | en_US |
dc.identifier.OPUS | 6800050 | - |
Appears in Collections: | Journal/Magazine Article |
Files in This Item:
File | Description | Size | Format | |
---|---|---|---|---|
AAC.01288-17.pdf | 2.37 MB | Adobe PDF | View/Open |
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