New Pacidamycin Antibiotics Through Precursor-Directed Biosynthesis

Sabine Gruschow, Emma J. Rackham, Benjamin Elkins, Philip L. A. Newilll, Lionel M. Hill, Rebecca J. M. Goss*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Citations (Scopus)

Abstract

Pacidamycins, mureidomycins and napsamycins are structurally related uridyl peptide antibiotics that inhibit translocase I, an as yet clinically unexploited target. This potentially important bioactivity coupled to the biosynthetically intriguing structure of pacidamycin make this natural product a fascinating subject for study. A precursor-directed biosynthesis approach was employed in order to access new pacidamycin derivatives. Strikingly, the biosynthetic machinery exhibited highly relaxed substrate specificity with the majority of the tryptophan analogues that were ad-ministered; this resulted in the production of new pacidamycin derivatives. Remarkably, 2-methyl-, 7-methyl-, 7-chloro- and 7-bromotryptophans produced their corresponding pacidamycin analogues in larger amounts than the natural pacidamycin. Low levels or no incorporation was observed for tryptophans substituted at positions 4, 5 and 6. The ability to generate bromo- and chloropacidamycins opens up the possibility of further functionalising these compounds through chemical cross-coupling in order to access a much larger family of derivatives.

Original languageEnglish
Pages (from-to)355-360
Number of pages6
JournalChemBioChem
Volume10
Issue number2
DOIs
Publication statusPublished - 26 Jan 2009

Keywords

  • antibiotics
  • translocase I
  • SERIES
  • ANALOGS
  • PEPTIDYLNUCLEOSIDE ANTIBIOTICS
  • MUREIDOMYCINS-A-D
  • pacidamycins
  • uridyl peptide antibiotic
  • SPHEROPLAST FORMING ACTIVITY
  • TRANSLOCASE
  • STRUCTURAL ELUCIDATION
  • PSEUDOMONAS-AERUGINOSA ACTIVITY
  • COUPLING REACTIONS
  • Pseudomonas aeruginosa
  • biosynthesis
  • FERMENTATION

Fingerprint

Dive into the research topics of 'New Pacidamycin Antibiotics Through Precursor-Directed Biosynthesis'. Together they form a unique fingerprint.

Cite this