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J Am Chem Soc. 2015 Feb 11;137(5):1738-41. doi: 10.1021/jacs.5b00056. Epub 2015 Feb 2.

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

Author information

1
Department of Chemistry and Biochemistry, University of Notre Dame , Notre Dame, Indiana 46556, United States.

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.

PMID:
25629446
PMCID:
PMC4607046
DOI:
10.1021/jacs.5b00056
[Indexed for MEDLINE]
Free PMC Article

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