Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3 H)-one

© 2015 American Chemical Society. 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 (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. 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.Peer Reviewe

Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one

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 (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. 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.Fil: Bouley, Renee. University Of Notre Dame-indiana; Estados UnidosFil: Kumarasiri, Malika. University Of Notre Dame-indiana; Estados UnidosFil: Peng, Zhihong. University Of Notre Dame-indiana; Estados UnidosFil: Otero, Lisandro Horacio. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; España. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Pque. Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; ArgentinaFil: Song, Wei. University Of Notre Dame-indiana; Estados UnidosFil: Suckow, Mark A.. University Of Notre Dame-indiana; Estados UnidosFil: Schroeder, Valerie A.. University Of Notre Dame-indiana; Estados UnidosFil: Wolter, William R.. University Of Notre Dame-indiana; Estados UnidosFil: Lastochkin, Elena. University Of Notre Dame-indiana; Estados UnidosFil: Antunes, Nuno T.. University Of Notre Dame-indiana; Estados UnidosFil: Pi, Hualiang. University Of Notre Dame-indiana; Estados UnidosFil: Vakulenko, Sergei. University Of Notre Dame-indiana; Estados UnidosFil: Hermoso, Juan Antonio. Consejo Superior de Investigaciones Cientificas. Instituto de Quimica Fisica; EspañaFil: Chang, Mayland. University Of Notre Dame-indiana; Estados UnidosFil: Mobashery, Shahriar. University Of Notre Dame-indiana; Estados Unido