Discovery of Wall Teichoic Acid Inhibitors as Potential Anti-MRSA beta-Lactam Combination Agents

作者：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^*

来源：Chemistry & Biology, 2013, 20(2): 272-284.

DOI：10.1016/j.chembiol.2012.11.013

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 beta-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 beta-lactam combination agents. This work also highlights the emerging role of whole-genome sequencing in antibiotic mode-of-action and resistance studies.

• 出版日期2013-2-21