In vivo processing and antibiotic activity of microcin B17 analogs with varying ring content and altered bisheterocyclic sites

Ranabir Sinha Roy, Neil L. Kelleher, Jill C. Milne, Christopher T. Walsh*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

52 Scopus citations

Abstract

Background: The Escherichia coli peptide antibiotic microcin B17 (MccB17) contains four oxazole and four thiazole rings, and inhibits DNA gyrase. The role of individual and tandem pairs of heterocycles in bioactivity has not been determined previously. Results: The two tandem 4,2-bisheterocycles in MccB17 were varied by expression of MccB17 or mutants containing altered sequences at Gly39-Ser40-Cys41 or Gly54-Cys55-Ser56. A mixture of five-nine-ring MccB17 isoforms were separated and quantitated for antibiotic potency. Mutagenesis of the thiazole-oxazole pair significantly affected antibiotic activity compared with the upstream oxazole-thiazole, which might stabilize partially cyclized intermediates against proteolysis. Conclusions: Enzymatic heterocyclization in native MccB17 occurs distributively. Antibiotic activity correlates with the number of rings and is differentially sensitive to both the location and the identity of the 4,2-tandem heterocycle pairs in MccB17. Such tandem heterocycles might be useful pharmacophores in combinatorial libraries.

Original languageEnglish (US)
Pages (from-to)305-318
Number of pages14
JournalChemistry and Biology
Volume6
Issue number5
DOIs
StatePublished - May 1999

Keywords

  • Antibiotic
  • Gyrase
  • Heterocycles
  • Microcin B17
  • Mutagenesis

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

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