Targeting Bacillosamine Biosynthesis in Bacterial Pathogens: Development of Inhibitors to a Bacterial Amino-Sugar Acetyltransferase from Campylobacter jejuni

De Schutter, Joris W.; Morrison, James P.; Morrison, Michael J.; Ciulli, Alessio; Imperiali, Barbara

doi:10.1021/acs.jmedchem.6b01869

Title: Targeting Bacillosamine Biosynthesis in Bacterial Pathogens: Development of Inhibitors to a Bacterial Amino-Sugar Acetyltransferase from Campylobacter jejuni

Journal Article · 21 February 2017 · Journal of Medicinal Chemistry

DOI: https://doi.org/10.1021/acs.jmedchem.6b01869 · OSTI ID:1357622

De Schutter, Joris W. ^[1]; Morrison, James P. ^[1]; Morrison, Michael J. ^[1];

^[2];

^[3]

Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Dept. of Chemistry
Univ. of Dundee (Scotland). Division of Biological Chemistry and Drug Discovery, School of Life Sciences
Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States). Dept. of Chemistry, and Dept. of Biology

The glycoproteins of selected microbial pathogens often include highly modified carbohydrates such as 2,4-diacetamidobacillosamine (diNAcBac). These glycoconjugates are involved in host–cell interactions and may be associated with the virulence of medically significant Gram-negative bacteria. In light of genetic studies demonstrating the attenuated virulence of bacterial strains in which modified carbohydrate biosynthesis enzymes have been knocked out, we are developing small molecule inhibitors of selected enzymes as tools to evaluate whether such compounds modulate virulence. We performed fragment-based and high-throughput screens against an amino-sugar acetyltransferase enzyme, PglD, involved in biosynthesis of UDP-diNAcBac in Campylobacter jejuni. Herein we report optimization of the hits into potent small molecule inhibitors (IC₅₀ < 300 nM). Biophysical characterization shows that the best inhibitors are competitive with acetyl coenzyme A and an X-ray cocrystal structure reveals that binding is biased toward occupation of the adenine subpocket of the AcCoA binding site by an aromatic ring.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (US)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1357622

Journal Information:: Journal of Medicinal Chemistry, Journal Name: Journal of Medicinal Chemistry Journal Issue: 5 Vol. 60; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Title: Targeting Bacillosamine Biosynthesis in Bacterial Pathogens: Development of Inhibitors to a Bacterial Amino-Sugar Acetyltransferase from Campylobacter jejuni

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