Arylthiazole antibiotics targeting intracellular methicillin-resistant Staphylococcus aureus (MRSA) that interfere with bacterial cell wall synthesis

Eur J Med Chem. 2017 Oct 20;139:665-673. doi: 10.1016/j.ejmech.2017.08.039. Epub 2017 Aug 18.


The promising antibacterial potency of arylthiazole antibiotics is offset by their limited activity against intracellular bacteria (namely methicillin-resistant Staphylococcus aureus (MRSA)), similar to many clinically-approved antibiotics. The failure to target these hidden pathogens is due to the compounds' lack of proper characteristics to accumulate intracellularly. Fine tuning of the size and polar-surface-area of the linking heteroaromatic ring provided a new series of 5-thiazolylarylthiazoles with balanced properties that allow them to sufficiently cross and accumulate inside macrophages infected with MRSA. The most promising compound 4i exhibited rapid bactericidal activity, good metabolic stability and produced over 80% reduction of intracellular MRSA in infected macrophages.

Keywords: Antibiotic drug resistance; Caenorhabditis elegans; Intracellular infection; MRSA; Methicillin-resistant Staphylococcus aureus; Pharmacokinetics.

MeSH terms

  • Animals
  • Anti-Bacterial Agents / chemical synthesis
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Bacillus subtilis / cytology
  • Bacillus subtilis / drug effects
  • Bacillus subtilis / metabolism
  • Cell Line
  • Cell Wall / drug effects*
  • Cell Wall / metabolism
  • Dose-Response Relationship, Drug
  • Macrophages / drug effects*
  • Macrophages / microbiology
  • Methicillin-Resistant Staphylococcus aureus / cytology
  • Methicillin-Resistant Staphylococcus aureus / drug effects*
  • Methicillin-Resistant Staphylococcus aureus / metabolism
  • Mice
  • Molecular Structure
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis
  • Thiazoles / chemistry
  • Thiazoles / pharmacology*


  • Anti-Bacterial Agents
  • Thiazoles