Antibacterial drug leads: DNA and enzyme multitargeting

Wei Zhu, Yang Wang, Kai Li, Jian Gao, Chun Hsiang Huang, Chun Chi Chen, Tzu Ping Ko, Yonghui Zhang, Rey Ting Guo, Eric Oldfield

Research output: Contribution to journalArticlepeer-review


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 (R2 = 0.89, S. aureus; R2 = 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.

Original languageEnglish (US)
Pages (from-to)1215-1227
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number3
StatePublished - Feb 12 2015

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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