GlmU is a bifunctional enzyme with acetyltransferase and uridyltransferase activities, and is essential for the biosynthesis of the bacterial cell wall. Inhibition results in a loss of cell viability. GlmU is therefore considered a potential target for novel antibacterial agents. A HTS (high-throughput screen) identified a series of aminoquinazolines with submicromolar potency against the uridyltransferase reaction. Biochemical and biophysical characterization showed competition with UTP binding. We determined the crystal structure of a representative aminoquinazoline bound to the Haemophilus influenzae isoenzyme at a resolution of 2.0 Å. The inhibitor occupies part of the UTP site, skirts the outer perimeter of the GlcNAc1-P (N-acetylglucosamine-1-phosphate) pocket and anchors a hydrophobic moiety into a lipophilic pocket. Our SAR (structure–activity relationship) analysis shows that all of these interactions are essential for inhibitory activity in this series. The crystal structure suggests that the compound would block binding of UTP and lock GlmU in an apo-enzyme-like conformation, thus interfering with its enzymatic activity. Our lead generation effort provides ample scope for further optimization of these compounds for antibacterial drug discovery.
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September 2012
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Research Article|
August 28 2012
An aminoquinazoline inhibitor of the essential bacterial cell wall synthetic enzyme GlmU has a unique non-protein-kinase-like binding mode
Nicholas A. Larsen;
Nicholas A. Larsen
*Discovery Sciences Unit, AstraZeneca R&D Boston, Waltham, MA 02451, U.S.A.
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Tory J. Nash;
Tory J. Nash
†Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, U.S.A.
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Marshall Morningstar;
Marshall Morningstar
†Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, U.S.A.
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Adam B. Shapiro;
Adam B. Shapiro
†Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, U.S.A.
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Camil Joubran;
Camil Joubran
†Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, U.S.A.
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Carolyn J. Blackett;
Carolyn J. Blackett
‡Discovery Sciences Unit, AstraZeneca UK, Alderley Park, Macclesfield, Chesire SK10 4TG, U.K.
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Arthur D. Patten;
Arthur D. Patten
†Infection Innovative Medicines Unit, AstraZeneca R&D Boston, Waltham, MA 02451, U.S.A.
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P. Ann Boriack-Sjodin;
P. Ann Boriack-Sjodin
*Discovery Sciences Unit, AstraZeneca R&D Boston, Waltham, MA 02451, U.S.A.
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Peter Doig
Peter Doig
1
*Discovery Sciences Unit, AstraZeneca R&D Boston, Waltham, MA 02451, U.S.A.
1To whom correspondence should be addressed (email peter.doig@astrazeneca.com).
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Publisher: Portland Press Ltd
Received:
April 12 2012
Revision Received:
June 13 2012
Accepted:
June 22 2012
Accepted Manuscript online:
June 22 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 446 (3): 405–413.
Article history
Received:
April 12 2012
Revision Received:
June 13 2012
Accepted:
June 22 2012
Accepted Manuscript online:
June 22 2012
Citation
Nicholas A. Larsen, Tory J. Nash, Marshall Morningstar, Adam B. Shapiro, Camil Joubran, Carolyn J. Blackett, Arthur D. Patten, P. Ann Boriack-Sjodin, Peter Doig; An aminoquinazoline inhibitor of the essential bacterial cell wall synthetic enzyme GlmU has a unique non-protein-kinase-like binding mode. Biochem J 15 September 2012; 446 (3): 405–413. doi: https://doi.org/10.1042/BJ20120596
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