Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital- and community-acquired infections. MRSA has been identified as a serious threat to public health by the Centers for Disease Control and Prevention. Many antibiotics on the market are no longer effective in treating MRSA infections, which results in >11,000 deaths a year in the United States alone. The currently approved antibiotics for treating MRSA infections are vancomycin, linezolid, ceftaroline, and daptomycin, of which only linezolid can be dosed orally. In addition, resistance has been documented for all four of these approved drugs. This underscores the importance to develop new, orally available antibiotics that can effectively treat these bacterial infections. We have discovered a new class of antibacterial agents, the quinazolinones, which are effective in a mouse model of MRSA infection and characterized their mechanism of action. The lead quinazolinone is water soluble, has good oral bioavailability, low clearance, and is not toxic; however it has a modest volume of distribution. The quinazolinone binds to the allosteric site of penicillin-binding protein (PBP) 2a, an enzyme involved in cell-wall synthesis, and triggers opening of the active site. This proposal aims to perform lead optimization of the quinazolinone class, to investigate the synergy between the quinazolinones and other antibiotics, and to further investigate the mechanism of action of the quinazolinones. This proposal is an interdisciplinary project that involves organic synthesis, biochemistry, microbiology, structural biology, pharmacology, and animal models of infection. These studies will expand our knowledge in designing effective anti-MRSA compounds and understanding this new class of antibacterials.

Public Health Relevance

This project aims to develop a new antibacterial agent effective against methicillin-resistant Staphylococcus aureus (MRSA), a pathogen that is resistant to many of the currently available antibiotics. This pathogen has been identified by the Centers for Disease Control and Prevention as a serious threat to public health in the United States, which needs prompt action to keep MRSA infections in check. MRSA infections are frequently acquired in the hospital-setting; however the recent increase in community-acquired infections and the emergence of highly virulent strains emphasizes the urgent need for new treatment options for this pathogen.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Predoctoral Individual National Research Service Award (F31)
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Special Emphasis Panel (ZRG1-F04A-W (20))
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Xu, Zuoyu
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University of Notre Dame
Schools of Arts and Sciences
Notre Dame
United States
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Mahasenan, Kiran V; Molina, Rafael; Bouley, Renee et al. (2017) Conformational Dynamics in Penicillin-Binding Protein 2a of Methicillin-Resistant Staphylococcus aureus, Allosteric Communication Network and Enablement of Catalysis. J Am Chem Soc 139:2102-2110
Bouley, Renee; Ding, Derong; Peng, Zhihong et al. (2016) Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials. J Med Chem 59:5011-21
Bouley, Renee; Kumarasiri, Malika; Peng, Zhihong et al. (2015) Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one. J Am Chem Soc 137:1738-41
Gonzales, Patrick R; Pesesky, Mitchell W; Bouley, Renee et al. (2015) Synergistic, collaterally sensitive ?-lactam combinations suppress resistance in MRSA. Nat Chem Biol 11:855-61
Wang, Huan; Lee, Mijoon; Peng, Zhihong et al. (2015) Synthesis and evaluation of 1,2,4-triazolo[1,5-a]pyrimidines as antibacterial agents against Enterococcus faecium. J Med Chem 58:4194-203