Abstract
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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Alkyl and Aryl Transferases / antagonists & inhibitors*
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Alkyl and Aryl Transferases / metabolism
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Amidines / chemical synthesis
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Amidines / chemistry
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Amidines / pharmacology*
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Anti-Bacterial Agents / chemical synthesis
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Anti-Bacterial Agents / chemistry
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Anti-Bacterial Agents / pharmacology*
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Cell Proliferation / drug effects
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DNA, Bacterial / chemistry
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DNA, Bacterial / drug effects*
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Dose-Response Relationship, Drug
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Escherichia coli / cytology
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Escherichia coli / drug effects*
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Escherichia coli / enzymology*
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Microbial Sensitivity Tests
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Molecular Structure
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Staphylococcus aureus / cytology
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Staphylococcus aureus / drug effects*
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Staphylococcus aureus / enzymology
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Structure-Activity Relationship
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Temperature
Substances
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Amidines
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Anti-Bacterial Agents
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DNA, Bacterial
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Alkyl and Aryl Transferases
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undecaprenyl pyrophosphate synthetase
Associated data
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PDB/3WYI
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PDB/3WYJ
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PDB/4U82
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PDB/4U8A
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PDB/4U8B
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PDB/4U8C