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Novel antibiotics: C-2 symmetrical macrocycles inhibiting Holliday junction DNA binding by E. coli RuvC

Research output: Contribution to journalJournal article

Published
  • Po-Shen Pan
  • Fiona Curtis
  • Chris Carroll
  • Irene Medina
  • Lisa Liotta
  • Gary Sharples
  • Shelli McAlpine
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<mark>Journal publication date</mark>15/07/2006
<mark>Journal</mark>Bioorganic and Medicinal Chemistry
Issue number14
Volume14
Number of pages9
Pages (from-to)4731-4739
Publication statusPublished
Original languageEnglish

Abstract

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.