N-(3-oxohexanoyl)-L-homoserine lactone regulates carbapenem antibiotic production in Erwinia carotovora

Biochem J. 1992 Dec 15;288 ( Pt 3)(Pt 3):997-1004. doi: 10.1042/bj2880997.

Abstract

Erwinia carotovora A.T.C.C. 39048 produces the antibiotic 1-carbapen-2-em-3-carboxylic acid. A number of mutants with a carbapenem-non-producing phenotype were selected as part of an investigation into the molecular and genetic basis of carbapenem biosynthesis. Cross-feeding studies revealed that the mutants fell into two discrete groups. Group 1 mutants were found to secrete a diffusible low-molecular-mass compound which restored carbapenem production in group 2 mutants. This compound was isolated from the spent culture supernatant of a group 1 mutant using solvent extraction, hydrophobic-interaction chromatography and silica-gel chromatography, and finally purified by reverse-phase semipreparative h.p.l.c. M.s. and n.m.r. spectroscopy revealed that the compound was N-(3-oxohexanoyl)homoserine lactone. Both D- and L-isomers were synthesized, and subsequent analysis by c.d. established that the natural product has the L-configuration. Although carbapenem production was restored by both isomers, dose-response curves indicated that the L-isomer has greater activity, with an induction threshold of about 0.5 micrograms/ml. N-(3-Oxohexanoyl)-L-homoserine lactone is, therefore, an autoregulator of carbapenem biosynthesis rather than a biosynthetic intermediate. This compound is already known for its role in autoinduction of bioluminescence in the marine bacterium Vibrio fischeri. It is also structurally-related to the A- and I-factors which are known to regulate production of antibiotics in some Streptomyces species. Its association in this work with the regulation of carbapenem biosynthesis implies a broader role for autoregulator-controlled gene expression in prokaryotes.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • 4-Butyrolactone / analogs & derivatives*
  • 4-Butyrolactone / chemical synthesis
  • 4-Butyrolactone / isolation & purification
  • 4-Butyrolactone / pharmacology
  • Carbapenems / biosynthesis*
  • DNA Transposable Elements / genetics
  • Magnetic Resonance Spectroscopy
  • Mutagenesis, Insertional
  • Pectobacterium carotovorum / drug effects
  • Pectobacterium carotovorum / genetics
  • Pectobacterium carotovorum / metabolism*
  • Spectrum Analysis
  • Stereoisomerism

Substances

  • Carbapenems
  • DNA Transposable Elements
  • N-(3-oxohexanoyl)-3-aminodihydro-2(3H)-furanone
  • 4-Butyrolactone