Substituted Salicylanilides as Inhibitors of Two-Component Regulatory Systems in Bacteria

J Med Chem. 1998 Jul 30;41(16):2939-45. doi: 10.1021/jm9803572.

Abstract

A new class of inhibitors of the two-component regulatory systems (TCS) of bacteria was discovered based on the salicylanilide screening hits, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR study versus a model TCS, KinA/Spo0F, demonstrated the importance of electron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, derivatives 8 and 16, containing the 2, 3-dihydroxybenzanilide structural motif, were potent inhibitors of the autophosphorylation of the KinA kinase, with IC50s of 2.8 and 6. 3 &microM, respectively. Compound 8 also inhibited the TCS mediating vancomycin resistance (VanS/VanR) in a genetically engineered Enterococcus faecalis cell line at concentrations subinhibitory for growth. Closantel (1), tetrachlorosalicylanilide (9), and several related derivatives (2, 7, 10, 11, 20) had antibacterial activity against the drug-resistant organisms, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faecium (VREF).

MeSH terms

  • Anti-Bacterial Agents / chemical synthesis*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology
  • Bacillus subtilis / enzymology
  • Bacillus subtilis / metabolism
  • Bacillus subtilis / physiology
  • Bacterial Proteins / antagonists & inhibitors*
  • Drug Evaluation, Preclinical
  • Drug Resistance, Microbial
  • Enterococcus faecium / drug effects
  • Enterococcus faecium / enzymology
  • Enterococcus faecium / genetics
  • Enterococcus faecium / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology
  • Gram-Positive Bacteria / drug effects*
  • Gram-Positive Bacteria / enzymology
  • Gram-Positive Bacteria / physiology
  • Luciferases / genetics
  • Luciferases / metabolism
  • Methicillin Resistance
  • Microbial Sensitivity Tests
  • Phosphorylation
  • Protein Kinase Inhibitors*
  • Protein Kinases / genetics
  • Salicylanilides / chemical synthesis*
  • Salicylanilides / chemistry
  • Salicylanilides / pharmacology
  • Spores, Bacterial / drug effects
  • Staphylococcus aureus / drug effects
  • Structure-Activity Relationship
  • Transcription Factors / antagonists & inhibitors
  • Transcription Factors / genetics
  • Vancomycin / pharmacology

Substances

  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Enzyme Inhibitors
  • Protein Kinase Inhibitors
  • Salicylanilides
  • Spo0F protein, Bacillus subtilis
  • Transcription Factors
  • kinA protein, Bacillus subtilis
  • VanR protein, bacteria
  • VanS protein, Enterococcus
  • Vancomycin
  • Luciferases
  • Protein Kinases
  • closantel
  • 3,3',4',5-tetrachlorosalicylanilide