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    Structural analysis of avibactam-mediated activation of the bla and mec divergons in methicillin-resistant Staphylococcus aureus

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    Author
    Alexander, J.A.N.
    Radaeva, M.
    King, D.T.
    Chambers, H.F.
    Cherkasov, A.
    Chatterjee, S.S.
    Strynadka, N.C.J.
    Date
    2020
    Journal
    The Journal of biological chemistry
    Publisher
    American Society for Biochemistry and Molecular Biology Inc.
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1074/jbc.RA120.013029
    Abstract
    Methicillin-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.
    Keyword
    antibiotic resistance
    antibiotics
    avibactam
    BlaR1
    crystal structure
    diazabicyclooctane
    drug action
    gene expression
    infectious disease
    MecR1
    methicillin-resistant Staphylococcus aureus (MRSA)
    molecular docking
    sensor domain
    Staphylococcus aureus (S. aureus)
    X-ray crystallography
    ?-lactam
    ?-lactam antibiotics
    ?-lactamase
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    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85089301142&doi=10.1074%2fjbc.RA120.013029&partnerID=40&md5=c57e091f749375c297546d8b429831c5; http://hdl.handle.net/10713/13572
    ae974a485f413a2113503eed53cd6c53
    10.1074/jbc.RA120.013029
    Scopus Count
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    UMB Open Access Articles 2020

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