A New Class of Quinazolinone Antibiotics

Technology Summary
Staphylococcus aureus ( S aureus) is a leading source of serious bacterial infections in humans. A growing nmber of S. aureus strains are showing increasing resistance to current antibiotics and Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for 126,000 hospitalizations and 19,000 deaths in the US each year.  Therefore, the development of new antibiotics for treatment of MRSA infections is essential, especially the development of orally-available antibiotics.

University of Notre Dame researchers have discovered a new orally active class of quinazolinone antibiotics that shows effective excellent activity against S. aureus strains, both methicillin-sensitive and methicillin-resistant strains, both in vitro and in vivo. The antibiotics bind to PBP2a and PBP1 as targets. The quinazolinone class synergizes with β-lactam antibiotics. The combination with piperacillin and tazobactam kills MRSA. For the synergistic activity, the quinazolinones have a unique mechanism of action, binding to the allosteric site of PBP2a and opening the active site of PBP2a where the β-lactam antibiotic piperacillin can now bind for covalent inhibition.

Market Advantages

Circumvent known MRSA resistance mechanisms
Display in vitro efficacy
Display in vivo efficacy in mouse- models of infection
Synergistic with β-lactam antibiotics

Intellectual Property

US Patent 9,776,975
(Quinazolinone Antibiotics)

Technology Readiness Status
TRL 4 - Lab Validation

 

Publications

Discovery of Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl) quinazolin-4(3H)-one.  doi:10.1021/jacs.5b00056

The Quinazolinone Allosteric Inhibitor of PBP2a Synergizes with Piperacillin and Tazobactam against Methicillin-resistant
S. aureus. Antimicrob. Agents Chemother. 2019, 63, e02637-18.

Structure-Activity Relationship for the 4(3H)-Quinazolinone Antibacterials. J. Med. Chem. 2016, 59, 5011-5021.