Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of hospital-acquired infections and is the cause of approximately 11,000 deaths a year in the United States alone. This organism displays broad resistance to the β-lactam class of antibiotics by expressing an additional penicillin-binding binding protein (PBP), called PBP2a, which displays low affinity to the β-lactams. This protein is able to evade inhibition by the β-lactams through a closed active site that is regulated allosterically. The quinazolinones were discovered through in silico screening of a 1.2 million compound library against the PBP2a active site. The quinazolinones affect peptidoglycan synthesis through inhibition of PBP2a and PBP1 of S. aureus. Elucidation of the structure of PBP2a in complex with the lead quinazolinone showed binding to the allosteric site, which produced conformational changes at the active site. An initial lead quinazolinone was identified that demonstrated excellent solubility and good pharmacokinetics in mice. This compound was the result of over 60 structural variations of the initial hit compound, which allowed us to deduce a structure-activity relationship for the quinazolinones. Ten compounds were selected based on antibacterial activity to be tested for in vivo efficacy, pharmacokinetics, and in vitro cytotoxicity. Three compounds from this library, all containing carboxylic acid functionalities, demonstrated good in vivo efficacy as well as pharmacokinetics. From these variations a new lead compound was identified that shows a higher volume of distribution, more potent in vitro antibacterial activity, and efficacy in vivo.

Discovery of new quinazolinone antibiotics for the treatment of methicillin-resistant Staphylococcus aureus

254th National Meeting (2017)

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