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Editor's Pick Mechanisms of Action: Physiological Effects

The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus

Jeshina Janardhanan, Renee Bouley, Siseth Martínez-Caballero, Zhihong Peng, Mayte Batuecas-Mordillo, Jayda E. Meisel, Derong Ding, Valerie A. Schroeder, William R. Wolter, Kiran V. Mahasenan, Juan A. Hermoso, Shahriar Mobashery, Mayland Chang
Jeshina Janardhanan
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
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Renee Bouley
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
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Siseth Martínez-Caballero
bDepartment of Crystallography and Structural Biology, Instituto de Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, Madrid, Spain
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Zhihong Peng
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
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Mayte Batuecas-Mordillo
bDepartment of Crystallography and Structural Biology, Instituto de Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, Madrid, Spain
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Jayda E. Meisel
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
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Derong Ding
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
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Valerie A. Schroeder
cFreimann Life Science Center, University of Notre Dame, Notre Dame, Indiana, USA
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William R. Wolter
cFreimann Life Science Center, University of Notre Dame, Notre Dame, Indiana, USA
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Kiran V. Mahasenan
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
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Juan A. Hermoso
bDepartment of Crystallography and Structural Biology, Instituto de Química-Física Rocasolano, Consejo Superior de Investigaciones Científicas, Madrid, Spain
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Shahriar Mobashery
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
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Mayland Chang
aDepartment of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana, USA
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DOI: 10.1128/AAC.02637-18
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ABSTRACT

The quinazolinones are a new class of antibacterials with in vivo efficacy against methicillin-resistant Staphylococcus aureus (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.

FOOTNOTES

    • Received 18 December 2018.
    • Returned for modification 7 January 2019.
    • Accepted 5 March 2019.
    • Accepted manuscript posted online 11 March 2019.
  • Supplemental material for this article may be found at https://doi.org/10.1128/AAC.02637-18.

  • Copyright © 2019 American Society for Microbiology.

All Rights Reserved.

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The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus
Jeshina Janardhanan, Renee Bouley, Siseth Martínez-Caballero, Zhihong Peng, Mayte Batuecas-Mordillo, Jayda E. Meisel, Derong Ding, Valerie A. Schroeder, William R. Wolter, Kiran V. Mahasenan, Juan A. Hermoso, Shahriar Mobashery, Mayland Chang
Antimicrobial Agents and Chemotherapy Apr 2019, 63 (5) e02637-18; DOI: 10.1128/AAC.02637-18

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The Quinazolinone Allosteric Inhibitor of PBP 2a Synergizes with Piperacillin and Tazobactam against Methicillin-Resistant Staphylococcus aureus
Jeshina Janardhanan, Renee Bouley, Siseth Martínez-Caballero, Zhihong Peng, Mayte Batuecas-Mordillo, Jayda E. Meisel, Derong Ding, Valerie A. Schroeder, William R. Wolter, Kiran V. Mahasenan, Juan A. Hermoso, Shahriar Mobashery, Mayland Chang
Antimicrobial Agents and Chemotherapy Apr 2019, 63 (5) e02637-18; DOI: 10.1128/AAC.02637-18
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KEYWORDS

MRSA
allosterism
piperacillin
quinazolinone
synergy
tazobactam

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