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A synthetic lethal approach for compound and target identification in Staphylococcus aureus
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A synthetic lethal approach for compound and target identification in Staphylococcus aureus
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Journal Article
A synthetic lethal approach for compound and target identification in Staphylococcus aureus
2016
Overview
A series of synthetic lethal strategies identifies a small-molecule inhibitor of
Staphylococcus aureus
DltB, links teichoic acid
D
-alanylation to virulence and identifies synergistic antibiotic drug combinations.
The majority of bacterial proteins are dispensable for growth in the laboratory but nevertheless have important physiological roles. There are no systematic approaches to identify cell-permeable small-molecule inhibitors of these proteins. We demonstrate a strategy to identify such inhibitors that exploits synthetic lethal relationships both for small-molecule discovery and for target identification. Applying this strategy in
Staphylococcus aureus
, we have identified a compound that inhibits DltB, a component of the teichoic acid
D
-alanylation machinery that has been implicated in virulence. This
D
-alanylation inhibitor sensitizes
S. aureus
to aminoglycosides and cationic peptides and is lethal in combination with a wall teichoic acid inhibitor. We conclude that DltB is a druggable target in the
D
-alanylation pathway. More broadly, the work described demonstrates a systematic method to identify biologically active inhibitors of major bacterial processes that can be adapted to numerous organisms.
Publisher
Nature Publishing Group US,Nature Publishing Group
Subject
/ Aminoglycosides - pharmacology
/ Anti-Bacterial Agents - chemistry
/ Anti-Bacterial Agents - pharmacology
/ Antimicrobial Cationic Peptides - pharmacology
/ Bacterial Proteins - antagonists & inhibitors
/ Bacterial Proteins - genetics
/ Bacterial Proteins - metabolism
/ Drug Evaluation, Preclinical - methods
/ High-Throughput Screening Assays - methods
/ Membrane Transport Proteins - genetics
/ Membrane Transport Proteins - metabolism
/ Mutation
/ Peptides
/ Small Molecule Libraries - pharmacology
/ Staphylococcus aureus - drug effects
/ Staphylococcus aureus - genetics
/ Staphylococcus aureus - metabolism
