Capsule anchoring in Bacillus anthracis occurs by a transpeptidation reaction that is inhibited by capsidin.
Bacillus anthracis, the causative agent of anthrax, is a dangerous biological weapon, as spores derived from drug-resistant strains cause infections for which antibiotic therapy is no longer effective. We sought to develop an anti-infective therapy for anthrax and targeted CapD, an enzyme that cleaves poly-gamma-D-glutamate capsule and generates amide bonds with peptidoglycan cross-bridges to deposit capsular material into the envelope of B. anthracis. In agreement with the model that capsule confers protection from phagocytic clearance, B. anthracis capD variants failed to deposit capsule into the envelope and displayed defects in anthrax pathogenesis. By screening chemical libraries, we identified the CapD inhibitor capsidin, 4-[(4-bromophenyl)thio]-3-(diacetylamino)benzoic acid), which covalently modifies the active-site threonine of the transpeptidase. Capsidin treatment blocked capsular assembly by B. anthracis and enabled phagocytic killing of non-encapsulated vegetative forms.
Richter
Stefan
S
Department of Microbiology, University of Chicago, Chicago, IL 60637, USA.
Anderson
Valerie J
VJ
Garufi
Gabriella
G
Lu
Lianghua
L
Budzik
Jonathan M
JM
Joachimiak
Andrzej
A
He
Chuan
C
Schneewind
Olaf
O
Missiakas
Dominique
D
D062365:Aminobenzoates / Q000494:pharmacology*; D000818:Animals; D000881:Anthrax / Q000382:microbiology*; D000900:Anti-Bacterial Agents / Q000494:pharmacology; D001408:Bacillus anthracis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D016667:Bacterial Capsules / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D006168:Guinea Pigs; D010457:Peptidoglycan / Q000378:metabolism*; D010458:Peptidyl Transferases / Q000235:genetics / Q000378:metabolism*; D011099:Polyglutamic Acid / Q000031:analogs & derivatives / Q000378:metabolism; D013440:Sulfides / Q000494:pharmacology*; D014774:Virulence
C538725:4-((4-bromophenyl)thio)-3-(diacetylamino)benzoic acid; D062365:Aminobenzoates; D000900:Anti-Bacterial Agents; D010457:Peptidoglycan; D013440:Sulfides; C511775:poly(gamma-glutamic acid); D011099:Polyglutamic Acid; D010458:Peptidyl Transferases