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

doi:10.1021/jacs.5b00056

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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128 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 language	English
Pages (from-to)	1738-1741
Number of pages	4
Journal	Journal of the American Chemical Society
Volume	137
Issue number	5
DOIs	https://doi.org/10.1021/jacs.5b00056
State	Published - Feb 11 2015

Bibliographical note

Publisher Copyright:
© 2015 American Chemical Society.

ASJC Scopus subject areas

Catalysis
General Chemistry
Biochemistry
Colloid and Surface Chemistry

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Bouley, R., Kumarasiri, M., Peng, Z., Otero, L. H., Song, W., Suckow, M. A., Schroeder, V. A., Wolter, W. R., Lastochkin, E., Antunes, N. T., Pi, H., Vakulenko, S., Hermoso, J. A., Chang, M., & Mobashery, S. (2015). Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3 H)-one. Journal of the American Chemical Society, 137(5), 1738-1741. https://doi.org/10.1021/jacs.5b00056

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title = "Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3 H)-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.",

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

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doi = "10.1021/jacs.5b00056",

language = "English",

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Bouley, R, Kumarasiri, M, Peng, Z, Otero, LH, Song, W, Suckow, MA, Schroeder, VA, Wolter, WR, Lastochkin, E, Antunes, NT, Pi, H, Vakulenko, S, Hermoso, JA, Chang, M & Mobashery, S 2015, 'Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3 H)-one', Journal of the American Chemical Society, vol. 137, no. 5, pp. 1738-1741. https://doi.org/10.1021/jacs.5b00056

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AU - Bouley, Renee

AU - Kumarasiri, Malika

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AU - Otero, Lisandro H.

AU - Song, Wei

AU - Suckow, Mark A.

AU - Schroeder, Valerie A.

AU - Wolter, William R.

AU - Lastochkin, Elena

AU - Antunes, Nuno T.

AU - Pi, Hualiang

AU - Vakulenko, Sergei

AU - Hermoso, Juan A.

AU - Chang, Mayland

AU - Mobashery, Shahriar

PY - 2015/2/11

Y1 - 2015/2/11

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

Abstract

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ASJC Scopus subject areas

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