Format

Send to

Choose Destination
Chem Biol. 2013 Feb 21;20(2):272-84. doi: 10.1016/j.chembiol.2012.11.013.

Discovery of wall teichoic acid inhibitors as potential anti-MRSA β-lactam combination agents.

Author information

1
Infectious Disease Biology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.

Abstract

Innovative strategies are needed to combat drug resistance associated with methicillin-resistant Staphylococcus aureus (MRSA). Here, we investigate the potential of wall teichoic acid (WTA) biosynthesis inhibitors as combination agents to restore β-lactam efficacy against MRSA. Performing a whole-cell pathway-based screen, we identified a series of WTA inhibitors (WTAIs) targeting the WTA transporter protein, TarG. Whole-genome sequencing of WTAI-resistant isolates across two methicillin-resistant Staphylococci spp. revealed TarG as their common target, as well as a broad assortment of drug-resistant bypass mutants mapping to earlier steps of WTA biosynthesis. Extensive in vitro microbiological analysis and animal infection studies provide strong genetic and pharmacological evidence of the potential effectiveness of WTAIs as anti-MRSA β-lactam combination agents. This work also highlights the emerging role of whole-genome sequencing in antibiotic mode-of-action and resistance studies.

PMID:
23438756
PMCID:
PMC3762323
DOI:
10.1016/j.chembiol.2012.11.013
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Elsevier Science Icon for PubMed Central
Loading ...
Support Center