The ability to resist the effect of a wide range of antibiotics makes methicillin-resistant Staphylococcus aureus (MRSA) a leading global human pathogen. A key determinant of resistance to -lactam antibiotics in this organism is penicillin-binding protein 2a (PBP2a), an enzyme that catalyzes the crosslinking reaction between two adjacent peptide stems during the peptidoglycan biosynthesis. In the face of the clinical challenge posed by resistant bacteria, the present needs for novel classes of antibiotics are genuine. In silico docking and screening, followed by chemical synthesis of a library of quinazolinones, led to the discovery of (E)-3-(3-carboxyphenyl)-2- (4-cyanostyryl)quinazolin-4(3H)-one as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional and structural assays showing binding of new antibiotic to PBP2a. We document that the antibiotic also inhibits PBP1 of S. aureus, indicating a broad targeting of structurally similar PBPs by this antibiotic. This class of antibiotics holds promise in fighting MRSA infections.

Reference:
Bouley, R.; Kumarasiri, M.; Peng, Z.; Otero, L.; Song, W.; Suckow, M.; Schroeder, V.; Wolter, W.; Lastochkin, E.; Antunes, N.; Pi, H.; Vakulenko, S.; Hermoso, J.; Chang, M.; Mobashery, S. Discovery of Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one, J. Am. Chem. Soc. 2015, 137, 1738-1741.