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

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 WalkerTodd Black, Terry Roemer

Research output: Contribution to journalArticle

87 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)272-284
Number of pages13
JournalChemistry and Biology
Volume20
Issue number2
DOIs
StatePublished - Feb 21 2013

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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    Wang, H., Gill, C. J., Lee, S. H., Mann, P., Zuck, P., Meredith, T. C., Murgolo, N., She, X., Kales, S., Liang, L., Liu, J., Wu, J., Santa Maria, J., Su, J., Pan, J., Hailey, J., McGuinness, D., Tan, C. M., Flattery, A., ... Roemer, T. (2013). Discovery of wall teichoic acid inhibitors as potential anti-MRSA β-lactam combination agents. Chemistry and Biology, 20(2), 272-284. https://doi.org/10.1016/j.chembiol.2012.11.013