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

Renee Bouley, Malika Kumarasiri, Zhihong Peng, Lisandro H. Otero, Wei Song, Mark A. Suckow, Valerie A. Schroeder, William R. Wolter, Elena Lastochkin, Nuno T. Antunes, Hualiang Pi, Sergei Vakulenko, Juan A. Hermoso, Mayland Chang, Shahriar Mobashery

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68 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1738-1741
Number of pages4
JournalJournal of the American Chemical Society
Volume137
Issue number5
DOIs
StatePublished - Feb 11 2015

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