Synthesis of full length and truncated microcin B17 analogues as DNA gyrase poisons.
Microcin B17 (MccB17) is a post-translationally modified peptide containing thiazole and oxazole heterocycles that interrupt the peptide backbone. MccB17 is capable of poisoning DNA gyrase through stabilization of the gyrase-DNA cleavage complex and has therefore attracted significant attention. Using a combination of Fmoc-strategy solid-phase peptide synthesis and solution-phase fragment assembly we have prepared a library of full-length and truncated MccB17 analogues to investigate key structural requirements for gyrase-poisoning activity. Synthetic peptides lacking the glycine-rich N-terminal portion of the full-length sequence showed strong stabilization of the gyrase-DNA cleavage complex with increased potency relative to the full-length sequences. This truncation, however, led to a decrease in antibacterial activity of these analogues relative to their full-length counterparts indicating a potential role of the N-terminal region of the natural product for cellular uptake.
School of Chemistry, The University of Sydney, NSW 2006, Australia. richard.payne@sydney.edu.au.
Robert E
RE
Thompson
Frédéric
F
Collin
Anthony
A
Maxwell
Katrina A
KA
Jolliffe
Richard J
RJ
Payne
D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D001430:Bacteriocins / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D053837:DNA Cleavage / Q000187:drug effects; D027081:DNA Gyrase / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004926:Escherichia coli / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008968:Molecular Conformation; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001430:Bacteriocins; D004791:Enzyme Inhibitors; C020411:microcin; D027081:DNA Gyrase