1. Academic Validation
  2. A Small-Molecule Screening Platform for the Discovery of Inhibitors of Undecaprenyl Diphosphate Synthase

A Small-Molecule Screening Platform for the Discovery of Inhibitors of Undecaprenyl Diphosphate Synthase

  • ACS Infect Dis. 2016 Jul 8;2(7):489-99. doi: 10.1021/acsinfecdis.6b00044.
Tomasz L Czarny 1 Eric D Brown 1
Affiliations

Affiliation

  • 1 Department of Biochemistry and Biomedical Sciences and ‡Michael G. DeGroote Institute of Infectious Disease Research, McMaster University , Hamilton, Ontario L8N 3Z5, Canada.
Abstract

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.

Keywords

UppS; antagonism; antibiotic drug discovery; cell wall; targocil; wall teichoic acid.

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