Structural analysis of avibactam-mediated activation of the bla and mec divergons in methicillin-resistant Staphylococcus aureus
Author
Alexander, J.A.N.Radaeva, M.
King, D.T.
Chambers, H.F.
Cherkasov, A.
Chatterjee, S.S.
Strynadka, N.C.J.
Date
2020Journal
The Journal of biological chemistryPublisher
American Society for Biochemistry and Molecular Biology Inc.Type
Article
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Show full item recordAbstract
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 resistanceantibiotics
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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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/10713/13572ae974a485f413a2113503eed53cd6c53
10.1074/jbc.RA120.013029
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