Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 14, Issue 14, Pages 4731-4739Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2006.03.028
Keywords
cyclicpeptides; macrocycles; antibiotics; Holliday junction; antibiotic resistance; peptides
Funding
- Biotechnology and Biological Sciences Research Council [BB/C514523/1] Funding Source: researchfish
- Biotechnology and Biological Sciences Research Council [BB/C514523/1] Funding Source: Medline
- NIAID NIH HHS [AI058241-01] Funding Source: Medline
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Holliday junctions (HJs) are formed as transient DNA intermediates during site-specific and homologous recombination. Both of these genetic exchange pathways are critical for normal DNA metabolism and repair. Trapping HJs leads to bacterial cell death by preventing proper segregation of the resulting interlinked chromosomes. Macrocyclic peptides designed to target this intermediate were synthesized with the goal of identifying compounds with specificity for this unique molecular target. We discovered ten macrocycles, both hexameric and octameric peptides, capable of trapping HJs in vitro. Those macrocycles containing tyrosine residues proved most effective. These data demonstrate that C-2 symmetrical macrocycles offer excellent synthetic targets for the development of novel antibiotic agents. Furthermore, the active compounds identified provide valuable tools for probing different pathways of recombinational exchange. (c) 2006 Elsevier Ltd. All rights reserved.
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