A Small-Molecule Screening Platform for the Discovery of Inhibitors of Undecaprenyl Diphosphate Synthase.
The bacterial cell wall has long been a celebrated target for antibacterial drug discovery due to its critical nature in bacteria and absence in mammalian systems. At the heart of the cell wall biosynthetic pathway lies undecaprenyl phosphate (Und-P), the lipid-linked carrier upon which the bacterial cell wall is built. This study exploits recent insights into the link between late-stage wall teichoic acid inhibition and Und-P production, in Gram-positive organisms, to develop a cell-based small-molecule screening platform that enriches for inhibitors of undecaprenyl diphosphate synthase (UppS). Screening a chemical collection of 142,000 small molecules resulted in the identification of 6 new inhibitors of UppS. To date, inhibitors of UppS have generally shown off-target effects on membrane potential due to their physical-chemical characteristics. We demonstrate that MAC-0547630, one of the six inhibitors identified, exhibits selective, nanomolar inhibition against UppS without off-target effects on membrane potential. Such characteristics make it a unique chemical probe for exploring the inhibition of UppS in bacterial cell systems.
Department of Biochemistry and Biomedical Sciences and ‡Michael G. DeGroote Institute of Infectious Disease Research, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Tomasz L
TL
Czarny
Department of Biochemistry and Biomedical Sciences and ‡Michael G. DeGroote Institute of Infectious Disease Research, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Eric D
ED
Brown
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics / Q000254:growth & development; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects / Q000201:enzymology / Q000235:genetics; D004353:Drug Evaluation, Preclinical; D008826:Microbial Sensitivity Tests; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D054852:Small Molecule Libraries; D019883:Alkyl and Aryl Transferases; C023266:undecaprenyl pyrophosphate synthetase
UppS; antagonism; antibiotic drug discovery; cell wall; targocil; wall teichoic acid