skip to main content
OSTI.GOV title logo U.S. Department of Energy
Office of Scientific and Technical Information

Title: Antibacterial Drug Leads: DNA and Enzyme Multitargeting

Abstract

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 IC 50 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 ΔT m and UPPS IC 50 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.

Authors:
 [1];  [1];  [1];  [2];  [2];  [2];  [3];  [1];  [2];  [1]
  1. Univ. of Illinois, Urbana-Champaign, IL (United States). Dept. of Chemistry
  2. Chinese Academy of Sciences (CAS), Tianjin (China). Inst. of Industrial Biotechnology, Industrial Enzymes National Engineering Lab.
  3. Academia Sinica, Taipei (Taiwan). Inst. of Biological Chemistry
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Institutes of Health (NIH); National Basic Research Program of China; National Natural Science Foundation of China (NNSFC)
OSTI Identifier:
1172407
Grant/Contract Number:
AC02-06CH11357; 085P1000817; 2011CB710800; 2011CBA00805; 31200053; 31300615
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Medicinal Chemistry
Additional Journal Information:
Journal Volume: 58; Journal Issue: 3; Journal ID: ISSN 0022-2623
Publisher:
American Chemical Society (ACS)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; Drug discovery; Protein structure; DNA minor groove binder; Undecaprenyl diphosphate synthase*

Citation Formats

Zhu, Wei, Wang, Yang, Li, Kai, Gao, Jian, Huang, Chun-Hsiang, Chen, Chun-Chi, Ko, Tzu-Ping, Zhang, Yonghui, Guo, Rey-Ting, and Oldfield, Eric. Antibacterial Drug Leads: DNA and Enzyme Multitargeting. United States: N. p., 2015. Web. doi:10.1021/jm501449u.
Zhu, Wei, Wang, Yang, Li, Kai, Gao, Jian, Huang, Chun-Hsiang, Chen, Chun-Chi, Ko, Tzu-Ping, Zhang, Yonghui, Guo, Rey-Ting, & Oldfield, Eric. Antibacterial Drug Leads: DNA and Enzyme Multitargeting. United States. doi:10.1021/jm501449u.
Zhu, Wei, Wang, Yang, Li, Kai, Gao, Jian, Huang, Chun-Hsiang, Chen, Chun-Chi, Ko, Tzu-Ping, Zhang, Yonghui, Guo, Rey-Ting, and Oldfield, Eric. Fri . "Antibacterial Drug Leads: DNA and Enzyme Multitargeting". United States. doi:10.1021/jm501449u. https://www.osti.gov/servlets/purl/1172407.
@article{osti_1172407,
title = {Antibacterial Drug Leads: DNA and Enzyme Multitargeting},
author = {Zhu, Wei and Wang, Yang and Li, Kai and Gao, Jian and Huang, Chun-Hsiang and Chen, Chun-Chi and Ko, Tzu-Ping and Zhang, Yonghui and Guo, Rey-Ting and Oldfield, Eric},
abstractNote = {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 ΔTm 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.},
doi = {10.1021/jm501449u},
journal = {Journal of Medicinal Chemistry},
number = 3,
volume = 58,
place = {United States},
year = {Fri Jan 09 00:00:00 EST 2015},
month = {Fri Jan 09 00:00:00 EST 2015}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record

Citation Metrics:
Cited by: 18 works
Citation information provided by
Web of Science

Save / Share: