Antibacterial Drug Leads: DNA and Enzyme Multitargeting

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

doi:10.1021/jm501449u

Title: Antibacterial Drug Leads: DNA and Enzyme Multitargeting

Journal Article · Fri Jan 09 00:00:00 EST 2015 · Journal of Medicinal Chemistry

DOI:https://doi.org/10.1021/jm501449u· OSTI ID:1172407

Zhu, Wei ^[1]; Wang, Yang ^[1]; Li, Kai ^[1]; Gao, Jian ^[2]; Huang, Chun-Hsiang ^[2]; Chen, Chun-Chi ^[2]; Ko, Tzu-Ping ^[3]; Zhang, Yonghui ^[1]; Guo, Rey-Ting ^[2]; Oldfield, Eric ^[1]

Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Chemistry
Chinese Academy of Sciences (CAS), Tianjin (China). Inst. of Industrial Biotechnology, Industrial Enzymes National Engineering Lab.
Academia Sinica, Taipei (Taiwan). Inst. of Biological Chemistry

Here, 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 ΔT_m and UPPS IC₅₀ experimental results together with one computed descriptor. Finally, 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.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES); National Institutes of Health (NIH); National Basic Research Program of China; National Natural Science Foundation of China (NSFC)

Grant/Contract Number:: AC02-06CH11357; 085P1000817; 2011CB710800; 2011CBA00805; 31200053; 31300615

OSTI ID:: 1172407

Journal Information:: Journal of Medicinal Chemistry, Vol. 58, Issue 3; ISSN 0022-2623

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Cited by: 38 works

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Pentamidine sensitizes Gram-negative pathogens to antibiotics and overcomes acquired colistin resistance Stokes, Jonathan M.; MacNair, Craig R.; Ilyas, Bushra Nature Microbiology, Vol. 2, Issue 5 https://doi.org/10.1038/nmicrobiol.2017.28	journal	March 2017
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