RESUMEN

MurF catalyzes the last cytoplasmic step of bacterial cell wall synthesis and is essential for bacterial survival. Our previous studies used a pharmacophore model of a MurF inhibitor to identify additional inhibitors with improved properties. We now present the characterization of two such inhibitors, the diarylquinolines DQ1 and DQ2. DQ1 inhibited Escherichia coli MurF (50% inhibitory concentration, 24 microM) and had modest activity (MICs, 8 to 16 microg/ml) against lipopolysaccharide (LPS)-defective E. coli and wild-type E. coli rendered permeable with polymyxin B nonapeptide. DQ2 additionally displayed activity against gram-positive bacteria (MICs, 8 to 16 microg/ml), including methicillin (meticillin)-susceptible and -resistant Staphylococcus aureus isolates and vancomycin-susceptible and -resistant Enterococcus faecalis and Enterococcus faecium isolates. Treatment of LPS-defective E. coli cells with >or=2x MIC of DQ1 resulted in a 75-fold-greater accumulation of the MurF substrate compared to the control, a 70% decline in the amount of the MurF product, and eventual cell lysis, consistent with the inhibition of MurF within bacteria. DQ2 treatment of S. aureus resulted in similar effects on the MurF substrate and product quantities. At lower levels of DQ1 (

Asunto(s)

Antibacterianos/farmacología , Bacterias/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Péptido Sintasas/antagonistas & inhibidores , Quinolinas/farmacología , Antibacterianos/química , Enterococcus faecalis/efectos de los fármacos , Enterococcus faecium/efectos de los fármacos , Inhibidores Enzimáticos/química , Escherichia coli/efectos de los fármacos , Pruebas de Sensibilidad Microbiana , Estructura Molecular , Péptido Sintasas/genética , Péptido Sintasas/fisiología , Quinolinas/química , Staphylococcus aureus/efectos de los fármacos