Targeting Bacillosamine Biosynthesis in Bacterial Pathogens: Development of Inhibitors to a Bacterial Amino-Sugar Acetyltransferase from Campylobacter jejuni.
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.
Department of Chemistry, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Joris W
JW
De Schutter
Department of Chemistry, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
James P
JP
Morrison
Department of Chemistry, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Michael J
MJ
Morrison
Division of Biological Chemistry and Drug Discovery, School of Life Sciences, University of Dundee , DD1 5EH Dundee, Scotland.
Alessio
0000-0002-8654-1670
A
Ciulli
Department of Chemistry, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.|Department of Biology, Massachusetts Institute of Technology , 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, United States.
Barbara
0000-0002-5749-7869
B
Imperiali
D000123:Acetyltransferases / Q000037:antagonists & inhibitors*; D000606:Amino Sugars / Q000494:pharmacology*; D016123:Campylobacter jejuni / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D006595:Hexosamines / Q000037:antagonists & inhibitors* / Q000096:biosynthesis
D000606:Amino Sugars; D006595:Hexosamines; C013920:4-deoxyneosamine C; D000123:Acetyltransferases