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.
authors: Infectious Disease Biology, Merck Research Laboratories, Kenilworth, NJ 07033, USA.
authors: Hao
authors: H
authors: Wang
authors: Charles J
authors: CJ
authors: Gill
authors: Sang H
authors: SH
authors: Lee
authors: Paul
authors: P
authors: Mann
authors: Paul
authors: P
authors: Zuck
authors: Timothy C
authors: TC
authors: Meredith
authors: Nicholas
authors: N
authors: Murgolo
authors: Xinwei
authors: X
authors: She
authors: Susan
authors: S
authors: Kales
authors: Lianzhu
authors: L
authors: Liang
authors: Jenny
authors: J
authors: Liu
authors: Jin
authors: J
authors: Wu
authors: John
authors: J
authors: Santa Maria
authors: Jing
authors: J
authors: Su
authors: Jianping
authors: J
authors: Pan
authors: Judy
authors: J
authors: Hailey
authors: Debra
authors: D
authors: Mcguinness
authors: Christopher M
authors: CM
authors: Tan
authors: Amy
authors: A
authors: Flattery
authors: Suzanne
authors: S
authors: Walker
authors: Todd
authors: T
authors: Black
authors: Terry
authors: T
authors: Roemer
mesh_terms: D019943:Amino Acid Substitution; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D002473:Cell Wall / Q000187:drug effects*; D004353:Drug Evaluation, Preclinical; D024881:Drug Resistance, Bacterial; D016680:Genome, Bacterial; D055624:Methicillin-Resistant Staphylococcus aureus / Q000187:drug effects* / Q000235:genetics; D008826:Microbial Sensitivity Tests; D009994:Osmolar Concentration; D010641:Phenotype; D017422:Sequence Analysis, DNA; D013682:Teichoic Acids / Q000096:biosynthesis* / Q000737:chemistry; D013696:Temperature; D047090:beta-Lactams / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D013682:Teichoic Acids; D047090:beta-Lactams