Staphylococcus aureus is a common bacterium found in moist areas of the human body and skin. Approximately 29% of the US population is colonized in the nose with S. aureus, of which 1.5% is methicillin- resistant S. aureus (MRSA). Annually, 278,000 people in the US are hospitalized with MRSA infections, resulting in 19,000 deaths. Spread of MRSA is also found in community-acquired infections, with over 6 million outpatient visits every year in the US caused by MRSA. Over the years, -lactams were antibiotics of choice in treatment of S. aureus infections. However, these agents faced obsolescence with the emergence of MRSA. We have discovered the quinazolinone class of antibacterial agents, which exhibit activity against MRSA, including hard-to-treat vancomycin- and linezolid-resistant MRSA strains. The lead quinazolinone shows efficacy in animal models of infection and has oral bioavailability in mice. The quinazolinones have antibacterial activity o their own, but they also synergize with -lactam antibiotics. We have shown that the quinazolinones bind to the allosteric site in penicillin-binding protein 2a (PBP2a), an unprecedented mode of action for any antibacterial. The binding to the allosteric site triggers opening of the active site, a unique mechanism that can also be exploited to inactivate PBP2a by co-administration with -lactam antibiotics, thus resurrecting obsolete -lactam antibiotics i treatment of MRSA.
Three Specific Aims are proposed for lead optimization of the quinazolinone class of antibiotics. These studies include additional mechanism of action experiments, pharmacodynamics, investigation of emergence of resistance, and evaluation of combinations of the quinazolinones with other antibiotics. These studies will chart the preclinical development of these novel antibiotics, which hold promise in treatment of infections by Gram-positive bacteria, including MRSA.

Public Health Relevance

Infections caused by drug-resistant Staphylococcus aureus are difficult to treat and result in 19,000 deaths in the US every year. Previously, -lactam antibiotics like penicillin were the drugs of choice in treatment of these infections. However, wit the emergence of drug-resistant bacteria, these antibiotics are not used. New antibiotics are needed to fight these infections, especially drugs that can be given orally. Our group has discovered a new class of antibiotics referred to as the quinazolinones that show activity against hard-to-treat drug-resistant bacteria. Furthermore, the quinazolinones trigger inactivation of a critical bacterial protein when given in combination with -lactam antibiotics, thereby allowing these obsolete -lactam antibiotics to be used against drug-resistant bacteria. Our goal is to develop the quinazolinone antibiotics for the treatment of drug- resistant bacterial infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI116548-01
Application #
8856982
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Xu, Zuoyu
Project Start
2015-03-20
Project End
2020-02-29
Budget Start
2015-03-20
Budget End
2016-02-29
Support Year
1
Fiscal Year
2015
Total Cost
$633,873
Indirect Cost
$214,320
Name
University of Notre Dame
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556
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