3 research outputs found
Structural and Functional Basis for Targeting <i>Campylobacter jejuni</i> Agmatine Deiminase To Overcome Antibiotic Resistance
<i>Campylobacter jejuni</i> is the most common bacterial
cause of gastroenteritis and a major contributor to infant mortality
in the developing world. The increasing incidence of antibiotic-resistant <i>C. jejuni</i> only adds to the urgency to develop effective
therapies. Because of the essential role that polyamines play, particularly
in protection from oxidative stress, enzymes involved in the biosynthesis
of these metabolites are emerging as promising antibiotic targets.
The recent description of an alternative pathway for polyamine synthesis,
distinct from that in human cells, in <i>C. jejuni</i> suggests
this pathway could be a target for novel therapies. To that end, we
determined X-ray crystal structures of <i>C. jejuni</i> agmatine
deiminase (CjADI) and demonstrated that loss of CjADI function contributes
to antibiotic sensitivity, likely because of polyamine starvation.
The structures provide details of key molecular features of the active
site of this protein. Comparison of the unliganded structure (2.1
Å resolution) to that of the CjADI–agmatine complex (2.5
Ă…) reveals significant structural rearrangements that occur upon
substrate binding. The shift of two helical regions of the protein
and a large conformational change in a loop near the active site generate
a narrow binding pocket around the bound substrate. This change optimally
positions the substrate for catalysis. In addition, kinetic analysis
of this enzyme demonstrates that CjADI is an iminohydrolase that effectively
deiminates agmatine. Our data suggest that <i>C. jejuni</i> agmatine deiminase is a potentially important target for combatting
antibiotic resistance, and these results provide a valuable framework
for guiding future drug development