Details

Autor(en) / Beteiligte

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

Titel

Discovery of Novel Wall Teichoic Acid Inhibitors as Effective anti-MRSA β-lactam Combination Agents

Ist Teil von

• Chemistry & biology, 2013-02, Vol.20 (2), p.272-284

Erscheinungsjahr

2013

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• 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.