Antibacterial Drug Leads:DNA and Enzyme Multitargeting.

Wereport the results of an investigation of the activity of aseries of amidine and bisamidine compounds against Staphylococcus aureusand Escherichiacoli. The most active compounds bound to an AT-richDNA dodecamer (CGCGAATTCGCG)2and using DSC were foundto increase the melting transition by up to 24 °C. Several compoundsalso inhibited undecaprenyl diphosphate synthase (UPPS) with IC50values of 100–500 nM, and we found good correlations(R2= 0.89, S. aureus; R2= 0.79, E. coli) between experimental and predicted cell growth inhibition by usingDNA ΔTmand UPPS IC50experimental results together with one computed descriptor. We alsosolved the structures of three bisamidines binding to DNA as wellas three UPPS structures. Overall, the results are of general interestin the context of the development of resistance-resistant antibioticsthat involve multitargeting. [ABSTRACT FROM AUTHOR]