6O9S

Crystal structure of Staphylococcus aureus MecR1 antibiotic-sensor domain in complex with avibactam

Summary for 6O9S

• Entry DOI: 10.2210/pdb6o9s/pdb
• Descriptor: Methicillin resistance mecR1 protein, (2S,5R)-1-formyl-5-[(sulfooxy)amino]piperidine-2-carboxamide, SULFATE ION, ... (4 entities in total)
• Functional Keywords: beta-lactam antibiotic sensor domain, antibiotic complex, signaling protein
• Biological source: Staphylococcus aureus
• Total number of polymer chains: 1
• Total formula weight: 30591.77

Authors

Alexander, J.A.N.,Strynadka, N.C.J. (deposition date: 2019-03-14, release date: 2020-06-10, Last modification date: 2024-11-20)

Primary citation

Alexander, J.A.N.,Radaeva, M.,King, D.T.,Chambers, H.F.,Cherkasov, A.,Chatterjee, S.S.,Strynadka, N.C.J.
Structural analysis of avibactam-mediated activation of the bla and mec divergons in methicillin-resistant Staphylococcus aureus .
J.Biol.Chem., 295:10870-10884, 2020

PubMed Abstract: Methicillin-resistant (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 SF8300, a clinically relevant strain from the USA300 clone of MRSA, responds to avibactam by up-regulating the expression of the and 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 and 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.

PubMed: 32518158
DOI: 10.1074/jbc.RA120.013029

Experimental method

X-RAY DIFFRACTION (1.59 Å)