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

• Published in: Journal of the American Chemical Society 2015-02, Vol.137 (5), p.1738-1741
• Main Authors: Bouley, Renee, Kumarasiri, Malika, Peng, Zhihong, Otero, Lisandro H, Song, Wei, Suckow, Mark A, Schroeder, Valerie A, Wolter, William R, Lastochkin, Elena, Antunes, Nuno T, Pi, Hualiang, Vakulenko, Sergei, Hermoso, Juan A, Chang, Mayland, Mobashery, Shahriar
• Format: Article
• Language: English
• Subjects: Anti-Bacterial Agents - pharmacokinetics; Anti-Bacterial Agents - pharmacology; Bacterial Proteins - chemistry; Bacterial Proteins - metabolism; Biological Availability; Drug Discovery; Microbial Sensitivity Tests; Models, Molecular; Penicillin-Binding Proteins; Protein Conformation; Quinazolinones - pharmacokinetics; Quinazolinones - pharmacology; Staphylococcus - drug effects
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.5b00056

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.