Methicillin-resistant Staphylococcus aureus (MRSA) has become a major threat worldwide due to its resistance to a wide range of antibiotics. MRSA encodes a unique penicillin-binding protein (PBP), termed PBP2a, which exhibits a low affinity to traditional �-lactam antibiotics. This low affinity is attributed structurally to the presence of a loop that creates a closed active-site conformation. Allosteric activation of PBP2a is required in order to induce an open state, which is catalytically functional. PBP2a is a target for MRSA antibacterial discovery. In silico docking and scoring of a 1.2-million compound library using the structure of PBP2a led to the discovery of a novel non-covalent inhibitor containing a quinazolinone core with promising antibacterial activity. Subsequent medicinal chemistry explorations of the structural space led to a quinazolinone with efficacy in a mouse model of infection. The elucidation of the structure of a complex of PBP2a with this quinazolinone showed binding to the allosteric site, as well as profound protein conformational changes at the active site. These conformational changes lead to enlargement of the active site and access to the site by the antibiotic. Further exploration of the antibacterial mechanism of action has been investigated through the use of macromolecular synthesis assays, which show inhibition of peptidogylcan biosynthesis by a quinazolinone. Enzyme activity assays have also shown that this quinazolinone inhibits PBP2a and PBP1, an essentail monofunctional transpeptidase. The current lead quinazolinone demonstrates excellent solubility and good pharmacokinetics in mice. Further investigations of the quinazolinone structural template have been explored in an attempt to discover an analog which balances potent in vitro activity with good pharmacokinetics and water solubility. Overall this class of antibiotics shows promise in utilizing PBPs as important biological targets in antibacterial drug development.

Discovery of quinazolinones as an antibiotic class active against methicillin-resistant <i>Staphylococcus aureus</i>

248th National Meeting (2014)

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Discovery of quinazolinones as an antibiotic class active against methicillin-resistant Staphylococcus aureus