Discovery of Antibiotic (E)-3-(3-Carboxyphenyl)-2-(4- cyanostyryl)quinazolin-4(3H)-one

BOULEY, RENEE; KUMARASIRI, MALIKA; PENG, ZHIHONG; OTERO, LISANDRO HORACIO; SONG, WEI; SUCKOW, MARK; SCHROEDER, VALERIE A. ; WOLTER, WILLIAM R. ; LASTOCHKIN, ELENA; ANTUNES, NUNO; PI, HUALIANG ; VAKULENKO, SERGEI ; HERMOSO, JUAN ANTONIO; CHANG, MAYLAND; MOBASHERY, SHAHRIAR

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY

AMER CHEMICAL SOC

Lugar: Washington; Año: 2015 vol. 137 p. 1738 - 1741

0002-7863

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.