Discovery of Wall Teichoic Acid Inhibitors As Potential Anti-MRSA β-lactam Combination Agents

Overview

Journal Chem Biol

Publisher Elsevier

Specialties Biochemistry
Biology
Chemistry

Date 2013 Feb 27

PMID 23438756

Citations 66

Authors

Hao Wang

Charles J Gill

Sang H Lee

Paul Mann

Paul Zuck

Timothy C Meredith

Nicholas Murgolo

Xinwei She

Susan Kales

Lianzhu Liang

Jenny Liu

Jin Wu

John Santa Maria

Jing Su

Jianping Pan

Judy Hailey

Debra McGuinness

Christopher M Tan

Amy Flattery

Suzanne Walker

Todd Black

Terry Roemer

Affiliations

Soon will be listed here.

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.

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