ArticleThe Journal of biological chemistry2011
In vitro validation of acetyltransferase activity of GlmU as an antibacterial target in Haemophilus influenzae.
Article in The Journal of biological chemistry, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 41 citations in OpenAlex.
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- Biosynthesis of uridine diphosphate N-Acetylglucosamine: An underexploited pathway in the search for novel antibiotics?IUBMB life · 2022Review
- Computer-Based Identification of Potential Druggable Targets in Multidrug-ResistantMicroorganisms · 2022Article
- Discovery of Harmaline as a Potent Inhibitor of Sphingosine Kinase-1: A Chemopreventive Role in Lung Cancer.ACS omega · 2020Article
- Enhancement of Production of D-Glucosamine in Escherichia coli by Blocking Three Pathways Involved in the Consumption of GlcN and GlcNAc.Molecular biotechnology · 2020Article
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- Iron Regulation inFrontiers in microbiology · 2018Article
- Structure elucidation and in silico docking studies of a novel furopyrimidine antibiotics synthesized by endolithic bacterium Actinomadura sp. AL2.World journal of microbiology & biotechnology · 2017Article
- Mutant Alleles of lptD Increase the Permeability of Pseudomonas aeruginosa and Define Determinants of Intrinsic Resistance to Antibiotics.Antimicrobial agents and chemotherapy · 2016Article
- Depletion of M. tuberculosis GlmU from Infected Murine Lungs Effects the Clearance of the Pathogen.PLoS pathogens · 2015Article
- ESKAPEing the labyrinth of antibacterial discovery.Nature reviews. Drug discovery · 2015Review
- The role of a novel auxiliary pocket in bacterial phenylalanyl-tRNA synthetase druggability.The Journal of biological chemistry · 2014Article
- Substrate-bound crystal structures reveal features unique to Mycobacterium tuberculosis N-acetyl-glucosamine 1-phosphate uridyltransferase and a catalytic mechanism for acetyl transfer.The Journal of biological chemistry · 2012Article
- Novel rapidly diversifiable antimicrobial RNA polymerase switch region inhibitors with confirmed mode of action in Haemophilus influenzae.Journal of bacteriology · 2012Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
10 authors at 2 institutions in 3 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GlmU is a bifunctional enzyme that is essential for bacterial growth, converting D-glucosamine 1-phosphate into UDP-GlcNAc via acetylation and subsequent uridyl transfer. A biochemical screen of AstraZeneca's compound library using GlmU of Escherichia coli identified novel sulfonamide inhibitors of the acetyltransferase reaction. Steady-state kinetics, ligand-observe NMR, isothermal titration calorimetry, and x-ray crystallography showed that the inhibitors were competitive with acetyl-CoA substrate. Iterative chemistry efforts improved biochemical potency against gram-negative isozymes 300-fold and afforded antimicrobial activity against a strain of Haemophilus influenzae lacking its major efflux pump. Inhibition of precursor incorporation into bacterial macromolecules was consistent with the antimicrobial activity being caused by disruption of peptidoglycan and fatty acid biosyntheses. Isolation and characterization of two different resistant mutant strains identified the GlmU acetyltransferase domain as the molecular target. These data, along with x-ray co-crystal structures, confirmed the binding mode of the inhibitors and explained their relative lack of potency against gram-positive GlmU isozymes. This is the first example of antimicrobial compounds mediating their growth inhibitory effects specifically via GlmU.
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