
Antibacterial Drug Leads: DNA and Enzyme Multitargeting
Author(s) -
Wei Zhu,
Yang Wang,
Kai Li,
Jian Gao,
Chih-Hsien Huang,
ChunChi Chen,
Tzu Ping Ko,
Yonghui Zhang,
ReyTing Guo,
Eric Oldfield
Publication year - 2015
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/jm501449u
Subject(s) - chemistry , escherichia coli , dna , context (archaeology) , enzyme , biochemistry , staphylococcus aureus , amidine , stereochemistry , bacteria , gene , biology , genetics , paleontology
We report the results of an investigation of the activity of a series of amidine and bisamidine compounds against Staphylococcus aureus and Escherichia coli. The most active compounds bound to an AT-rich DNA dodecamer (CGCGAATTCGCG)2 and using DSC were found to increase the melting transition by up to 24 °C. Several compounds also inhibited undecaprenyl diphosphate synthase (UPPS) with IC50 values of 100-500 nM, and we found good correlations (R(2) = 0.89, S. aureus; R(2) = 0.79, E. coli) between experimental and predicted cell growth inhibition by using DNA ΔTm and UPPS IC50 experimental results together with one computed descriptor. We also solved the structures of three bisamidines binding to DNA as well as three UPPS structures. Overall, the results are of general interest in the context of the development of resistance-resistant antibiotics that involve multitargeting.