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 µM, 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
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Anti-Bacterial Agents / chemical synthesis*
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology
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Bacillus subtilis / enzymology
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Bacillus subtilis / metabolism
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Bacillus subtilis / physiology
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Bacterial Proteins / antagonists & inhibitors*
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Drug Evaluation, Preclinical
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Drug Resistance, Microbial
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Enterococcus faecium / drug effects
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Enterococcus faecium / enzymology
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Enterococcus faecium / genetics
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Enterococcus faecium / metabolism
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Gram-Positive Bacteria / drug effects*
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Gram-Positive Bacteria / enzymology
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Gram-Positive Bacteria / physiology
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Luciferases / genetics
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Luciferases / metabolism
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Methicillin Resistance
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Microbial Sensitivity Tests
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Phosphorylation
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Protein Kinase Inhibitors*
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Protein Kinases / genetics
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Salicylanilides / chemical synthesis*
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Salicylanilides / chemistry
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Salicylanilides / pharmacology
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Spores, Bacterial / drug effects
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Staphylococcus aureus / drug effects
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Structure-Activity Relationship
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / genetics
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Vancomycin / pharmacology
Substances
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Anti-Bacterial Agents
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Bacterial Proteins
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Enzyme Inhibitors
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Protein Kinase Inhibitors
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Salicylanilides
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Spo0F protein, Bacillus subtilis
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Transcription Factors
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kinA protein, Bacillus subtilis
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VanR protein, bacteria
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VanS protein, Enterococcus
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Vancomycin
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Luciferases
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Protein Kinases
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closantel
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3,3',4',5-tetrachlorosalicylanilide