Streptomyces strains and process to produce single...

Details Streptomyces strains and process to produce single... Streptomyces strains and process to produce single...

1994-11-10

2001-01-30

Marx, Irene (Department: 1651)

Chemistry: molecular biology and microbiology

Micro-organism, per se ; compositions thereof; proces of...

Bacteria or actinomycetales; media therefor

C435S440000, C435S071200, C435S071300

Reexamination Certificate

active

06180392

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to new microorganisms, to a method for preparing them and also to their use. More especially, the invention relates to microorganisms that produce antibiotics.
BACKGROUND OF THE INVENTION
Of the many antibiotics described in the prior art, some possess the feature of consisting of several active components acting together synergistically. This is the case, in particular, with the antibiotics of the streptogramin family, which are composed of a macrolactone (group A component) and a depsipeptide (group B component). The antimicrobial activity and the mode of action of these antibiotics have been the subject of studies, in particular by Tanaka (Antibiotics, vol. III p. 487, Springer, Berlin (1975)) and Vasquez (Antibiotics, vol. III p. 521, Springer, Berlin (1975)). The general structure of the molecules of groups A and B is shown in
FIGS. 1 and 2
.
Among the known antibiotics of the streptogramin family, there may be mentioned, more especially:
pristinamycins,
mikamycins,
virginiamycins,
vernamycins,
ostreogrycins,
synergistins,
plauracins,
etamycins,
streptogramins,
viridogriseins,
griseoviridins, or
neoviridogriseins.
The active form of each of these antibiotics consists of a synergistic combination of molecules belonging to group A as shown in FIG.
1
and molecules belonging to group B as shown in
FIG. 2
, or of related molecules.
Related molecules are understood, in the sense used in the present invention, to mean molecules possessing the general skeleton of those shown in
FIGS. 1 and 2
but which may differ from the latter by substitutions or other secondary variations, and possessing an activity of the same nature.
The antibiotics of the streptogramin family are produced by a wide variety of microorganisms, and especially by bacteria of the genus Actinomycete and by certain fungi. These microorganisms are characterised in that they synthesise both components A and B simultaneously.
Table 1 lists the main productive microorganisms, together with the corresponding antibiotics.
Studies have been carried out with the object of increasing the levels of production of these microorganisms. There may be mentioned, in particular, the works of Biot (Biotechnology of Industrial Antibiotics, vol. 22 (1984) p. 695) or of Prikrylova et al. (Biotechnology and Bioindustry/2 (1988) 20) concerning improvement in the culture conditions and the effect of mutagenic agents on the levels of production of virginiamycin by
S. virginiae.
As the authors state, the overproductive mutants obtained always produce components A and B simultaneously.
However, the fact that the streptogramin-producing microorganisms which are available in the prior art synthesise both synergistic components A and B of the antibiotic simultaneously, in the same fermentation medium, constitutes a considerable drawback in some cases.
In effect, to optimise the use of these antibiotics and to be able to use them as pharmaceutical agents, it is preferable to be able to separate and purify the A and B components of the streptogramins. This is also essential in order to be able to carry out chemical studies on streptogramins, especially with the object of preparing semisynthetic derivatives such as, for example, those described in Patents FR 2,549,063, FR 2,549,065, EP 191,662 or EP 248,703.
However, accessibility to these different components is difficult as a result, in particular, of their simultaneous production and of the similarity of their physicochemical properties. Furthermore, these microorganisms generally synthesise several different molecules of each component, leading to a mixture of many compounds, in highly variable proportions, in the fermentation must. In effect, many molecules belonging to groups A and B of streptogramins, possessing very different biological activities and which are produced simultaneously by the microorganisms, are known at the present time. Thus, the following molecules belonging to group A are known in the prior art: pristinamycins PIIA and PIIB, virginiamycins M1 and M2, mikamycin A or ostreogrycins A and G. Likewise, the following molecules belonging to group B are known in the prior art: pristinamycins PIA, PIB and PIC, virginiamycins S1, S2, S3, S4 and S5, mikamycin B, vernamycins B&agr;, B&bgr;, B&ggr; and B&dgr;, ostreogrycin B, B1, B2 and B3 or neoviridogriseins I, II, III and IV.
For these reasons, it is difficult to obtain active and pharmaceutically acceptable synergistic mixtures of streptogramins satisfactorily at industrial level. It is also difficult to carry out chemical studies on streptogramins (structure-function relationship, development of water-soluble forms, and the like). The present invention enables the drawbacks of the prior art in this field to be remedied.
SUMMARY OF THE INVENTION
The Applicant has now shown that it is possible to obtain microorganisms that produce components A and B of streptogramins separately in a stable manner. The Applicant has hence developed, and this constitutes a subject of the present invention, microorganisms capable of selectively producing components A and B of streptogramins. The invention relates both to microorganisms capable of selectively producing molecules of group A of streptogramins or molecules of group B of streptogramins, and to microorganisms capable of selectively producing a molecule specific to one of these groups.
The invention thus makes possible the separate production of streptogramin A or B in large quantities.
The invention also makes it possible to use methods for purification of streptogramins which are simpler and hence more efficacious and more economical, since there are no longer, or are fewer, interactions between the different components during the extraction.
The invention also makes it possible to vary the respective quantities of components A and B in a mixture, and hence to produce antibiotic compositions which are optimal in respect of both purity and synergistic efficiency.
The invention also makes it possible to obtain products in sufficient quantity and purity to carry out chemical studies in order to improve further the properties of streptogramins.
The invention thus provides a system for production of streptogramins that permits a much more efficacious industrial exploitation of these antibiotics.
More especially, the invention relates to microorganisms capable of selectively producing components A and B of streptogramins chosen from the group comprising pristinamycin, virginiamycin, mikamycin, ostreogrycin, synergistin, viridogrisein, vernamycin, plauracin, etamycin, griseoviridin, neoviridogrisein and streptogramin.
BRIEF DESCRIPTION OF DRAWINGS
In a preferred embodiment, the invention relates to microorganisms capable of selectively producing the components A of streptogramins corresponding to the general formula shown in
FIG. 1
, in which:
Y represents a D-proline, a 4,5-dehydroproline, a D-alanine or a D-cysteine,
R0 represents a C═O or CHOH group,
R1 is a hydrogen atom or a methyl group,
R2 is a hydrogen atom or a methyl group, and
R3 is a methyl or isopropyl group.
In another preferred embodiment, the invention relates to microorganisms capable of selectively producing the components B of streptogramins corresponding to the general formula shown in FIG.
2
(
a
), in which:
Z represents an L-proline, an L-aspartic acid, a pipecolic acid, a 4-oxopipecolic acid, a 4-hydroxy-L-pipecolic acid or a 5-hydroxy-4-oxo-L-pipecolic acid,
R4 is a hydrogen atom or an amine of formula NH(CH3) or N(CH3)2,
R5 is a hydrogen atom or a methyl group, and
R6 is a methyl or ethyl group.
Still in a preferred embodiment, the invention relates to microorganisms capable of selectively producing the components B of streptogramins corresponding to the general formula shown in FIG.
2
(
b
), in which:
R7 represents a hydrogen atom or a hydroxyl group, and
R8 represents a methyl or ethyl group.
More preferably, the invention relates to microorganisms capable of selectively producing, alone or mixed, components A or B of streptogramins chosen from the

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