Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving nucleic acid
Patent
1993-10-18
1997-01-14
Ketter, James S.
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving nucleic acid
435 34, 540202, 548124, 549321, 549322, C12Q 168
Patent
active
055938272
DESCRIPTION:
BRIEF SUMMARY
An autoinducer is a chemical molecule, often quite a small one, which is produced by a microorganism during metabolism and which then acts to increase the expression of genes of the microorganism.
N-(.beta.-ketocaproyl) homoserine lactone [3-oxo-N-(tetrahydro-2-oxo-3-furanyl)hexanamide (formula 2) has long been recognised as an autoinducer regulating expression of lux genes and hence the bioluminescent phenotype in the marine microorganism, Vibrio fischeri (Eberhard et al., 1981). Although characterised as a bacterial pheromone (Eberhard, 1972), it has been identified only in the one species of bioluminescent bacteria and any broader role in signalling, such as communicating nutritional viability to other bacteria (Eberhard et al., 1981) has previously had no foundation in scientific evidence. It has been observed that the autoinducer of Vibrio fischeri is similar in structure to A-factor (formula 4), a regulatory molecule which is produced by Streptomyces griseus (Silverman et al., 1989; Meighen, 1991) and which causes a self-induction of sporulation and streptomycin synthesis. Intellectually, this has been assimilated by several workers as suggestive of a broader role for such molecules. To establish precisely the current level of understanding, we quote from two recent reviewers:
"Perhaps this chemical relationship is an indication that mechanisms used by bacteria to sense their environments have a common origin and that there is a large class of signalling molecules or bacterial hormones similar in structure and mode of action." (Silverman et al., 1989).
"The possibility that the lux autoinducers are part of a larger class of signalling molecules (allomones, pheromones or hormones) used to sense the local nutritional or chemical environment has been suggested." (Meighen, 1991).
While these two statements establish the possibility of a large class of signalling molecules, it must be re-emphasised that there is no basis in experimentation for confirming the above hypothesis and certainly no indication that N-(.beta.-ketocaproyl) homoserine lactone (formula 2) may be directly involved in gene regulation of microorganisms other than Vibrio fischeri and the closely related Vibrio logei. In addition, a study of other bacteria, including nonluminous species, for their ability to provide autoinducer for the related Vibrio harveyi system (N-.beta.-hydroxybutyryl homoserine lactone) (formula 3) failed to identify any terrestrial sources for complementation (Greenberg et al., 1979). ##STR2##
In a research programme directed at the study of carbapenem synthesis in prokaryotes, we have recently discovered that-the compound of formula 2 regulates the expression of carbapenem synthesis in Erwina. It appears that there is a family of compounds, including those of formulae 2 and 3 and analogues thereof, which control (increase or decrease) gene expression in a variety of microorganisms. This family is sometimes hereinafter referred to as "N-(.beta.-ketocaproyl) homoserine lactone or analogue". Some of this family of compounds, including specifically those of formulae 2 and 3, are produced by various microorganisms for which they act as autoinducers.
BRIEF SUMMARY OF THE INVENTION
We have synthesised various members of this family of compounds, including optically active isomers thereof. This invention includes as new compounds those members of the family that have not been previously described. The invention also includes use of the compounds of the family to control gene expression in microorganisms. Some of the practical implications of this use are discussed below.
Thus in one aspect the invention provides use of a compound having the formula 1 to control gene expression in microorganisms other than V. fischeri, V. logei and V. harveyi, wherein formula 1 is ##STR3## where n is 2 or 3
Preferably n is 2, so that the ring is five-membered. Although it is not necessary for Y and X to be the same, both are preferably O as in the compounds of formulae 2 and 3. Preferably R is C2 to C6 acyl. Preferably R carries a keto
REFERENCES:
patent: 4861709 (1989-08-01), Ulitzur et al.
patent: 5196318 (1993-03-01), Baldwin et al.
Devine et al., "Proc. Natl. Acad. Sci. USA", 86 5688-5692 (Aug. 1989) Biochemistry Identification of the Operator of the lux regulon from the Vibrio fischeri Strain ATCC7744.
Eberhard et al., "Arch. Microbiol." 146 35-40 (1986), Analogs of the Autoinducer of Bioluminescence in Vibrio fischeri.
Eberhard et al., "Biochemistry", 20 2444-2449 (1981) Structural Identification of Autoinducer of Photobacterium fischeri Luciferase.
Greenberg et al., "Arch. Microbiol.", 120 87-91 (1979), Induction of Luciferase Synthesis in Beneckea harveyi by Other Marine Bacteria.
Jie-Gang Cao et al., The Journal of Biological Chemistry, pp. 21670-21676 (1989) vol. 246(136).
Mar. (1968) "Advanced Organic Chemistry: Reactions, Mechanisms, and Structure", pp. 71-75, 92-94, McGraw-Hill, N.Y.
Meighen (1991) Microbl. Rev. 55(1), 123-142.
Bainton Nigel J.
Bycroft Barrie W.
Chhabra Siri R.
Hill Philip J.
Rees Catherine E. D.
Ketter James S.
The University of Nottingham
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