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dc.contributor.authorAlexander, J.A.N.
dc.contributor.authorRadaeva, M.
dc.contributor.authorKing, D.T.
dc.contributor.authorChambers, H.F.
dc.contributor.authorCherkasov, A.
dc.contributor.authorChatterjee, S.S.
dc.contributor.authorStrynadka, N.C.J.
dc.date.accessioned2020-08-21T15:58:12Z
dc.date.available2020-08-21T15:58:12Z
dc.date.issued2020
dc.identifier.urihttps://www.scopus.com/inward/record.uri?eid=2-s2.0-85089301142&doi=10.1074%2fjbc.RA120.013029&partnerID=40&md5=c57e091f749375c297546d8b429831c5
dc.identifier.urihttp://hdl.handle.net/10713/13572
dc.description.abstractMethicillin-resistant Staphylococcus aureus (MRSA) infections cause significant mortality and morbidity globally. MRSA resistance to β-lactam antibiotics is mediated by two divergons that control levels of a β-lactamase, PC1, and a penicillin-binding protein poorly acylated by β-lactam antibiotics, PBP2a. Expression of genes encoding these proteins is controlled by two integral membrane proteins, BlaR1 and MecR1, which both have an extracellular β-lactam-binding sensor domain. Here, we solved the X-ray crystallographic structures of the BlaR1 and MecR1 sensor domains in complex with avibactam, a diazabicyclooctane β-lactamase inhibitor at 1.6-2.0 Å resolution. Additionally, we show that S. aureus SF8300, a clinically relevant strain from the USA300 clone of MRSA, responds to avibactam by up-regulating the expression of the blaZ and pbp2a antibiotic-resistance genes, encoding PC1 and PBP2a, respectively. The BlaR1-avibactam structure of the carbamoyl-enzyme intermediate revealed that avibactam is bound to the active-site serine in two orientations ∼180° to each other. Although a physiological role of the observed alternative pose remains to be validated, our structural results hint at the presence of a secondary sulfate-binding pocket that could be exploited in the design of future inhibitors of BlaR1/MecR1 sensor domains or the structurally similar class D β-lactamases. The MecR1-avibactam structure adopted a singular avibactam orientation similar to one of the two states observed in the BlaR1-avibactam structure. Given avibactam up-regulates expression of blaZ and pbp2a antibiotic resistance genes, we suggest further consideration and research is needed to explore what effects administering β-lactam-avibactam combinations have on treating MRSA infections. Copyright 2020 Alexander et al.en_US
dc.description.urihttps://doi.org/10.1074/jbc.RA120.013029en_US
dc.language.isoen_USen_US
dc.publisherAmerican Society for Biochemistry and Molecular Biology Inc.en_US
dc.relation.ispartofThe Journal of biological chemistry
dc.subjectantibiotic resistanceen_US
dc.subjectantibioticsen_US
dc.subjectavibactamen_US
dc.subjectBlaR1en_US
dc.subjectcrystal structureen_US
dc.subjectdiazabicyclooctaneen_US
dc.subjectdrug actionen_US
dc.subjectgene expressionen_US
dc.subjectinfectious diseaseen_US
dc.subjectMecR1en_US
dc.subjectmethicillin-resistant Staphylococcus aureus (MRSA)en_US
dc.subjectmolecular dockingen_US
dc.subjectsensor domainen_US
dc.subjectStaphylococcus aureus (S. aureus)en_US
dc.subjectX-ray crystallographyen_US
dc.subject?-lactamen_US
dc.subject?-lactam antibioticsen_US
dc.subject?-lactamaseen_US
dc.titleStructural analysis of avibactam-mediated activation of the bla and mec divergons in methicillin-resistant Staphylococcus aureusen_US
dc.typeArticleen_US
dc.identifier.doi10.1074/jbc.RA120.013029
dc.identifier.pmid32518158


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