title: Antibacterial drug leads: DNA and enzyme multitargeting.
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.
authors.affiliation: Department of Chemistry, University of Illinois at Urbana-Champaign , 600 South Mathews Avenue, Urbana, Illinois 61801, United States.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Li
authors.forename: Jian
authors.initials: J
authors.lastname: Gao
authors.forename: Chun-Hsiang
authors.initials: CH
authors.lastname: Huang
authors.forename: Chun-Chi
authors.initials: CC
authors.lastname: Chen
authors.forename: Tzu-Ping
authors.initials: TP
authors.lastname: Ko
authors.forename: Yonghui
authors.initials: Y
authors.lastname: Zhang
authors.forename: Rey-Ting
authors.initials: RT
authors.lastname: Guo
authors.forename: Eric
authors.initials: E
authors.lastname: Oldfield
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000578:Amidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004269:DNA, Bacterial / Q000737:chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004926:Escherichia coli / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology*; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D013211:Staphylococcus aureus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D013696:Temperature
chemical_list: D000578:Amidines; D000900:Anti-Bacterial Agents; D004269:DNA, Bacterial; D019883:Alkyl and Aryl Transferases; C023266:undecaprenyl pyrophosphate synthetase