Novel antibiotics: C-2 symmetrical macrocycles inhibiting Holliday junction DNA binding by E. coli RuvC.
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.
Department of Chemistry and Biochemisty, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182-1030, USA.
Po-Shen
PS
Pan
Fiona A
FA
Curtis
Chris L
CL
Carroll
Irene
I
Medina
Lisa A
LA
Liotta
Gary J
GJ
Sharples
Shelli R
SR
McAlpine
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045566:DNA, Cruciform / Q000187:drug effects* / Q000378:metabolism*; D004706:Endodeoxyribonucleases / Q000378:metabolism*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D029968:Escherichia coli Proteins / Q000378:metabolism*; D066298:In Vitro Techniques; D046911:Macromolecular Substances; D008958:Models, Molecular; D015394:Molecular Structure; D009690:Nucleic Acid Conformation; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011487:Protein Conformation; D013212:Staphylococcus epidermidis / Q000187:drug effects
D000900:Anti-Bacterial Agents; D045566:DNA, Cruciform; D029968:Escherichia coli Proteins; D046911:Macromolecular Substances; D009842:Oligopeptides; D010456:Peptides, Cyclic; C069806:ruvC protein, E coli; D004706:Endodeoxyribonucleases