Structural analysis of avibactam-mediated activation of the bla and mec divergons in methicillin-resistant Staphylococcus aureus
JournalThe Journal of biological chemistry
PublisherAmerican Society for Biochemistry and Molecular Biology Inc.
MetadataShow full item record
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.
methicillin-resistant Staphylococcus aureus (MRSA)
Staphylococcus aureus (S. aureus)
Identifier to cite or link to this itemhttps://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
- Crystal structures of the Apo and penicillin-acylated forms of the BlaR1 beta-lactam sensor of Staphylococcus aureus.
- Authors: Wilke MS, Hills TL, Zhang HZ, Chambers HF, Strynadka NC
- Issue date: 2004 Nov 5
- Unbound and acylated structures of the MecR1 extracellular antibiotic-sensor domain provide insights into the signal-transduction system that triggers methicillin resistance.
- Authors: Marrero A, Mallorquí-Fernández G, Guevara T, García-Castellanos R, Gomis-Rüth FX
- Issue date: 2006 Aug 18
- X-ray crystal structure of the acylated beta-lactam sensor domain of BlaR1 from Staphylococcus aureus and the mechanism of receptor activation for signal transduction.
- Authors: Birck C, Cha JY, Cross J, Schulze-Briese C, Meroueh SO, Schlegel HB, Mobashery S, Samama JP
- Issue date: 2004 Nov 3
- Activation of BlaR1 protein of methicillin-resistant Staphylococcus aureus, its proteolytic processing, and recovery from induction of resistance.
- Authors: Llarrull LI, Toth M, Champion MM, Mobashery S
- Issue date: 2011 Nov 4
- Genomic identification of cryptic susceptibility to penicillins and β-lactamase inhibitors in methicillin-resistant Staphylococcus aureus.
- Authors: Harrison EM, Ba X, Coll F, Blane B, Restif O, Carvell H, Köser CU, Jamrozy D, Reuter S, Lovering A, Gleadall N, Bellis KL, Uhlemann AC, Lowy FD, Massey RC, Grilo IR, Sobral R, Larsen J, Rhod Larsen A, Vingsbo Lundberg C, Parkhill J, Paterson GK, Holden MTG, Peacock SJ, Holmes MA
- Issue date: 2019 Oct