SUBSTITUTED SALICYLANILIDES AS INHIBITORS OF 2-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 hit s, closantel (1) and tetrachlorosalicylanilide (9). A systematic SAR s tudy versus a model TCS, KinA/SpoOF, demonstrated the importance of el ectron-attracting substituents in the salicyloyl ring and hydrophobic groups in the anilide moiety for optimal activity. In addition, deriva tives 8 and 16, containing the 2,3-dihydroxy-benzanilide structural mo tif, were potent inhibitors of the autophosphorylation of the KinA kin ase, with IC(50)s of 2.8 and 6.3 mu M, respectively. Compound 8 also i nhibited the TCS mediating vancomycin resistance (VanS/VanR) in a gene tically engineered Enterococcus faecalis cell line at concentrations s ubinhibitory 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 S taphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus faec ium (VREF).