RESUMO
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).
Assuntos
Antibacterianos/síntese química , Proteínas de Bactérias/antagonistas & inibidores , Inibidores Enzimáticos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Inibidores de Proteínas Quinases , Salicilanilidas/síntese química , Antibacterianos/química , Antibacterianos/farmacologia , Bacillus subtilis/enzimologia , Bacillus subtilis/metabolismo , Bacillus subtilis/fisiologia , Avaliação Pré-Clínica de Medicamentos , Resistência Microbiana a Medicamentos , Enterococcus faecium/efeitos dos fármacos , Enterococcus faecium/enzimologia , Enterococcus faecium/genética , Enterococcus faecium/metabolismo , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Bactérias Gram-Positivas/enzimologia , Bactérias Gram-Positivas/fisiologia , Luciferases/genética , Luciferases/metabolismo , Resistência a Meticilina , Testes de Sensibilidade Microbiana , Fosforilação , Proteínas Quinases/genética , Salicilanilidas/química , Salicilanilidas/farmacologia , Esporos Bacterianos/efeitos dos fármacos , Staphylococcus aureus/efeitos dos fármacos , Relação Estrutura-Atividade , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/genética , Vancomicina/farmacologiaRESUMO
A series of diaryltriazole analogs was discovered to inhibit bacterial two-component regulatory systems in our primary assays, KinA/Spo0F and NRII/NRI. They also showed inhibitory activity in whole cell mechanism-based assays, and they possessed potent activities against several strains of Gram-positive pathogenic bacteria in the standard MIC broth assay.
