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 Walker; Todd Black; Terry Roemer

doi:10.1016/j.chembiol.2012.11.013

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

Biochemistry & Molecular Biology

Research output: Contribution to journal › Article › peer-review

121 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 language	English (US)
Pages (from-to)	272-284
Number of pages	13
Journal	Chemistry and Biology
Volume	20
Issue number	2
DOIs	https://doi.org/10.1016/j.chembiol.2012.11.013
State	Published - 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

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title = "Discovery of wall teichoic acid inhibitors as potential anti-MRSA β-lactam combination agents",

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.",

author = "Hao Wang and Gill, {Charles J.} and Lee, {Sang H.} and Paul Mann and Paul Zuck and Meredith, {Timothy C.} and Nicholas Murgolo and Xinwei She and Susan Kales and Lianzhu Liang and Jenny Liu and Jin Wu and {Santa Maria}, John and Jing Su and Jianping Pan and Judy Hailey and Debra McGuinness and Tan, {Christopher M.} and Amy Flattery and Suzanne Walker and Todd Black and Terry Roemer",

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doi = "10.1016/j.chembiol.2012.11.013",

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Wang, H, Gill, CJ, Lee, SH, Mann, P, Zuck, P, Meredith, TC, Murgolo, N, She, X, Kales, S, Liang, L, Liu, J, Wu, J, Santa Maria, J, Su, J, Pan, J, Hailey, J, McGuinness, D, Tan, CM, Flattery, A, Walker, S, Black, T & Roemer, T 2013, 'Discovery of wall teichoic acid inhibitors as potential anti-MRSA β-lactam combination agents', Chemistry and Biology, vol. 20, no. 2, pp. 272-284. https://doi.org/10.1016/j.chembiol.2012.11.013

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AU - Meredith, Timothy C.

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AU - She, Xinwei

AU - Kales, Susan

AU - Liang, Lianzhu

AU - Liu, Jenny

AU - Wu, Jin

AU - Santa Maria, John

AU - Su, Jing

AU - Pan, Jianping

AU - Hailey, Judy

AU - McGuinness, Debra

AU - Tan, Christopher M.

AU - Flattery, Amy

AU - Walker, Suzanne

AU - Black, Todd

AU - Roemer, Terry

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

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