Author/Authors :
Hao Wang، نويسنده , , Charles J. Gill، نويسنده , , Sang H. Lee، نويسنده , , Paul Mann، نويسنده , , Paul Zuck، نويسنده , , Timothy C. Meredith، نويسنده , , Nicholas Murgolo، نويسنده , , Xinwei She، نويسنده , , Susan Kales، نويسنده , , Lianzhu Liang، نويسنده , , Jenny Liu، نويسنده , , Jin Wu، نويسنده , , John Santa Maria، نويسنده , , Jing Su، نويسنده , , IEEE
Jianping Pan، نويسنده , , Judy Hailey، نويسنده , , Debra Mcguinness، نويسنده , , Christopher M. Tan، نويسنده , , Amy، نويسنده ,
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.
