Targeting Bacillosamine
Biosynthesis in Bacterial
Pathogens: Development of Inhibitors to a Bacterial Amino-Sugar Acetyltransferase
from Campylobacter jejuni
posted on 2017-02-09, 00:00authored byJoris
W. De Schutter, James P. Morrison, Michael J. Morrison, Alessio Ciulli, Barbara Imperiali
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.