N-(3-oxohexanoyl)-L-homoserine lactone regulates carbapenem antibiotic production in Erwinia carotovora.
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.
Bainton
N J
NJ
Department of Pharmaceutical Sciences, University of Nottingham, U.K.
Stead
P
P
Chhabra
S R
SR
Bycroft
B W
BW
Salmond
G P
GP
Stewart
G S
GS
Williams
P
P
D015107:4-Butyrolactone / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000302:isolation & purification / Q000494:pharmacology; D015780:Carbapenems / Q000096:biosynthesis*; D004251:DNA Transposable Elements / Q000235:genetics; D009682:Magnetic Resonance Spectroscopy; D016254:Mutagenesis, Insertional; D016973:Pectobacterium carotovorum / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013057:Spectrum Analysis; D013237:Stereoisomerism
D015780:Carbapenems; D004251:DNA Transposable Elements; C030654:N-(3-oxohexanoyl)-3-aminodihydro-2(3H)-furanone; D015107:4-Butyrolactone