title: Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one.
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.
authors: Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.
authors: Renee
authors: R
authors: Bouley
authors: Malika
authors: M
authors: Kumarasiri
authors: Zhihong
authors: Z
authors: Peng
authors: Lisandro H
authors: LH
authors: Otero
authors: Wei
authors: W
authors: Song
authors: Mark A
authors: MA
authors: Suckow
authors: Valerie A
authors: VA
authors: Schroeder
authors: William R
authors: WR
authors: Wolter
authors: Elena
authors: E
authors: Lastochkin
authors: Nuno T
authors: NT
authors: Antunes
authors: Hualiang
authors: H
authors: Pi
authors: Sergei
authors: S
authors: Vakulenko
authors: Juan A
authors: JA
authors: Hermoso
authors: Mayland
authors: M
authors: Chang
authors: Shahriar
authors: S
authors: Mobashery
mesh_terms: D000900:Anti-Bacterial Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000737:chemistry / Q000378:metabolism; D001682:Biological Availability; D055808:Drug Discovery; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D046915:Penicillin-Binding Proteins; D011487:Protein Conformation; D052999:Quinazolinones / Q000493:pharmacokinetics / Q000494:pharmacology*; D013210:Staphylococcus / Q000187:drug effects
chemical_list: C000605389:(E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one; D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D046915:Penicillin-Binding Proteins; D052999:Quinazolinones; C487789:mecA protein, Staphylococcus aureus; C061339:4-hydroxyquinazoline
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