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Multiscale simulations of clavulanate inhibition identify the reactive complex in class A β-lactamases and predict efficiency of inhibition

Research output: Contribution to journalArticle

Original languageEnglish
Number of pages4
JournalBiochemistry
Early online date29 May 2018
DOIs
DateAccepted/In press - 26 Apr 2018
DateE-pub ahead of print (current) - 29 May 2018

Abstract

Clavulanate is used as an effective drug in combina-tion with β-lactam antibiotics to treat infections of some antibiotic resistant bacteria. Here, we per-form combined quantum mechanics / molecular mechanics simulations of several covalent com-plexes of clavulanate with class A β-lactamases KPC-2 and TEM-1. Simulations of the deacylation reactions identify the decarboxylated trans-enamine complex as responsible for inhibition. Further, the simulations correctly discriminate between enzymes that are effectively inhibited (TEM-1) from those that are not (KPC-2) providing a 'computational assay' for clinically relevant inhibition.

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  • Full-text PDF (accepted author manuscript)

    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via ACS at https://pubs.acs.org/action/doSearch?text1=Multiscale+simulations+of+clavulanate+inhibition&quickLinkYear=&quickLinkVolume=&field1=Title&type=within&publication=40025959. Please refer to any applicable terms of use of the publisher.

    Accepted author manuscript, 7 MB, PDF-document

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