Substituted salicylanilides as inhibitors of two-component regulatory systems in bacteria.
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).
Macielag
M J
MJ
The R.W. Johnson Pharmaceutical Research Institute, 1000 Route 202, Raritan, New Jersey 08869, USA.
Demers
J P
JP
Fraga-Spano
S A
SA
Hlasta
D J
DJ
Johnson
S G
SG
Kanojia
R M
RM
Russell
R K
RK
Sui
Z
Z
Weidner-Wells
M A
MA
Werblood
H
H
Foleno
B D
BD
Goldschmidt
R M
RM
Loeloff
M J
MJ
Webb
G C
GC
Barrett
J F
JF
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001412:Bacillus subtilis / Q000201:enzymology / Q000378:metabolism / Q000502:physiology; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D004353:Drug Evaluation, Preclinical; D004352:Drug Resistance, Microbial; D016984:Enterococcus faecium / Q000187:drug effects / Q000201:enzymology / Q000235:genetics / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006094:Gram-Positive Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000502:physiology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D016106:Methicillin Resistance; D008826:Microbial Sensitivity Tests; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000235:genetics; D012458:Salicylanilides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013171:Spores, Bacterial / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics; D014640:Vancomycin / Q000494:pharmacology
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D012458:Salicylanilides; C080951:Spo0F protein, Bacillus subtilis; D014157:Transcription Factors; C075521:kinA protein, Bacillus subtilis; C073902:VanR protein, bacteria; C073901:VanS protein, Enterococcus; D014640:Vancomycin; D008156:Luciferases; D011494:Protein Kinases; C023342:closantel; C003390:3,3',4',5-tetrachlorosalicylanilide