Discovery of Antibiotic ( <i>E</i> )-3-(3-Carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3 <i>H</i> )-one

Renee A. Bouley(University of Notre Dame), Malika Kumarasiri(University of Notre Dame), Zhihong Peng(University of Notre Dame), Lisandro H. Otero(Instituto de Química Física Blas Cabrera), Wei Song(University of Notre Dame), Mark A. Suckow(University of Notre Dame), Valerie A. Schroeder(University of Notre Dame), William R. Wolter(University of Notre Dame), Elena Lastochkin(University of Notre Dame), Nuno T. Antunes(University of Notre Dame), Hualiang Pi(University of Notre Dame), Sergei B. Vakulenko(University of Notre Dame), J.A. Hermoso(Consejo Superior de Investigaciones Científicas), Mayland Chang(University of Notre Dame), Shahriar Mobashery(University of Notre Dame)
Journal of the American Chemical Society
January 28, 2015
10.1021/jacs.5b00056
Cited by 147Open Access
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Abstract

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.

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