6Q9N

Crystal structure of PBP2a from MRSA in complex with piperacillin and quinazolinone

Summary for 6Q9N

• Entry DOI: 10.2210/pdb6q9n/pdb
• Descriptor: Penicillin binding protein 2 prime, 3-[2-[(~{E})-2-(4-ethynylphenyl)ethenyl]-4-oxidanylidene-quinazolin-3-yl]benzoic acid, Piperacillin (Open Form), ... (7 entities in total)
• Functional Keywords: penicillin binding protein, hydrolase
• Biological source: Staphylococcus aureus (strain Mu50 / ATCC 700699)
• Total number of polymer chains: 2
• Total formula weight: 148327.98

Authors

Martinez-Caballero, S.,Batuecas, M.T.,Hermoso, J.A. (deposition date: 2018-12-18, release date: 2019-11-27, Last modification date: 2024-10-16)

Primary citation

Janardhanan, J.,Bouley, R.,Martinez-Caballero, S.,Peng, Z.,Batuecas-Mordillo, M.,Meisel, J.E.,Ding, D.,Schroeder, V.A.,Wolter, W.R.,Mahasenan, K.V.,Hermoso, J.A.,Mobashery, S.,Chang, M.
The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus.
Antimicrob.Agents Chemother., 63:-, 2019

PubMed Abstract: The quinazolinones are a new class of antibacterials with efficacy against methicillin-resistant (MRSA). The quinazolinones target cell wall biosynthesis and have a unique mechanism of action by binding to the allosteric site of penicillin-binding protein 2a (PBP 2a). We investigated the potential for synergism of a lead quinazolinone with several antibiotics of different classes using checkerboard and time-kill assays. The quinazolinone synergized with β-lactam antibiotics. The combination of the quinazolinone with commercial piperacillin-tazobactam showed bactericidal synergy at sub-MICs of all three drugs. We demonstrated the efficacy of the triple-drug combination in a mouse MRSA neutropenic thigh infection model. The proposed mechanism for the synergistic activity in MRSA involves inhibition of the β-lactamase by tazobactam, which protects piperacillin from hydrolysis, which can then inhibit its target, PBP 2. Furthermore, the quinazolinone binds to the allosteric site of PBP 2a, triggering the allosteric response. This leads to the opening of the active site, which, in turn, binds another molecule of piperacillin. In other words, PBP 2a, which is not normally inhibited by piperacillin, becomes vulnerable to inhibition in the presence of the quinazolinone. The collective effect is the impairment of cell wall biosynthesis, with bactericidal consequence. Two crystal structures for complexes of the antibiotics with PBP 2a provide support for the proposed mechanism of action.

PubMed: 30858202
DOI: 10.1128/AAC.02637-18

Experimental method

X-RAY DIFFRACTION (2.5 Å)