Streptogramins for preparing same by mutasynthesis

Details Streptogramins for preparing same by mutasynthesis Streptogramins for preparing same by mutasynthesis

1997-03-20

2002-03-05

Nashed, Nashaat T. (Department: 1652)

Chemistry: molecular biology and microbiology

Micro-organism, tissue cell culture or enzyme using process...

C435S106000, C435S117000, C435S232000, C435S252350, C435S320100, C536S023100, C536S023200, C536S023700

Reexamination Certificate

active

06352839

ABSTRACT:

The present invention relates principally to novel compounds which are related to the group B streptogramins, and to a process for preparing streptogramins by mutasynthesis. It also relates to novel genes which are involved in the biosynthesis of precursors of the group B streptogramins, and to their uses.
The streptogramins form a homogeneous group of antibiotics consisting of an association of two types of chemically different molecules; on the one hand polyunsaturated macrolactones (group A components) and, on the other hand, depsipeptides (group B components). This group comprises numerous antibiotics which are known under different names according to their origin and includes pristinamycins, mikamycins and virginiamycins (Cocito 1979, 1983).
The A and B components have a synergistic antibacterial activity which can amount to 100 times that of the separate components and which, contrary to that of each component, is bactericidal (Cocito 1979). This activity is more particularly effective against Gram positive bacteria such as Staphylococci and Streptococci (Cocito 1979, Videau 1982). Components A and B inhibit protein synthesis by binding to the 50S subunit of the ribosome (Cocito 1979; Di Gianbattista et al., 1989).
While knowledge of the routes by which each of the components is biosynthesized still remains partial to date, earlier studies, presented in Patent Application PCT/FR93/0923, have made it possible to identify several proteins, and the corresponding structural genes, which are involved in the biosynthesis of the two types of component.
Two parts can be distinguished in the process for biosynthesizing group B streptogramins:
1) Biosynthesis of the precursors, or their analogues, of the macrocycle: 3-hydropicolinic acid, L-2-aminobutyric acid, 4-dimethylamino-L-phenylalanine, L-pipecolic acid and L-phenylglycine.
2) Formation of the macrocycle from the precursors listed above, from L-threonine and from L-proline, or their analogues, with (a) possible subsequent modification(s) of the peptide N-methylation, epimerisation, hydroxylation and oxidation type.
Patent Application PCT/FR93/0923 relates, in particular, to the enzymes which catalyze incorporation of the precursors into the peptide chain of B streptogramins in the process of elongation, and also to their structural genes. These results have demonstrated the non-ribosomal peptide synthesis character of the type B components.
The present invention relates, more particularly, to novel compounds which are related to group B streptogramins and, more precisely, to novel compounds of the pristinamycin I family (FIGS.
1
and
2
), termed PI below, or of the virginiamycin S family (FIG.
3
).
The major constituent of the I pristinamycins (PI) is PI
A
(FIG.
1
), which represents approximately 94% of the PI, with the remaining approximately 6% being represented by minor constituents of the depsipeptide (PI
B
to PI
I
) whose structures are depicted in FIG.
2
. PI results essentially from the condensation of amino acids, certain of which are essential for protein synthesis (threonine and proline) and others of which are novel and themselves considered to be secondary metabolites (L-2-aminobutyric acid, 4-dimethylamino-L-phenylalanine (DMPAPA), L-pipecolic acid and L-phenylglycine for PI
A
), and also of an aromatic precursor, 3-hydroxypicolinic acid.
The virginiamycin S derivatives result from condensation of the same acids as in the case of PI, apart from 4-DMPAPA, which is replaced by a phenylalanine (see FIG.
3
).
Production of these different compounds by biosynthesis therefore requires preliminary synthesis, by a producer strain, of the novel precursors identified above.
The present invention results specifically from a novel process for preparing streptogramins which employs, as a strain for producing streptogramins, a microorganism strain which is mutated so as to alter the biosynthesis of the precursors of the group B streptogramins. According to this process, the said mutant strain is cultured in a medium which is supplemented with a novel precursor which is different from the precursor whose biosynthesis is altered. Unexpectedly, this results in the production of novel compounds which are related to the group B streptogramins and which are of value in the therapeutic sphere.
More precisely, the present invention relates to novel compounds which are represented by the general formula I:
in which:
R
2
and R
4
represent, independently of each other, a hydrogen atom or a methyl group,
R
3
represents a hydrogen atom or a hydroxyl group,
X represents a CO, CHOH or CH
2
group, and
R
1
represents:
with
For the Meta Derivatives
A, C, D and E representing a hydrogen atom, and B being able to represent
a halogen, and preferably a fluorine atom,
a monoalkylamino or dialkylamino group, with alkyl preferably representing a methyl or ethyl group,
an ether group; more particularly an OR group with R being preferably selected from among the methyl, ethyl, trifluoromethyl and allyl groups,
a thioether group, preferably represented by an alkylthio group with alkyl preferably representing a methyl group,
a C
1
to C
3
alkyl group, or
a trihalogenomethyl group, preferably trifluoromethyl
For the Para Derivatives
A, B, D and E representing a hydrogen atom, and C being able to represent:
a halogen,
an NR
1
R
2
group with R
1
and R
2
representing, independently of each other, a group selected from among
hydrogen,
a straight-chain or branched C
1
to C
4
alkyl group where, when one of the substituents R
1
or R
2
represents a methyl group, the other necessarily represents an ethyl group,
an alkyl-cycloalkylmethyl group with a C
3
to C
4
cycloalkyl,
an optionally substituted C
3
to C
4
cycloalkyl group,
a straight-chain or branched C
1
to C
4
alkenyl group where, when one of the substituents R
1
or R
2
represents an alkenyl group, the other is different from a methyl group or a C3 to C6 cycloalkyl,
a substituted or unsubstituted N-pyrrolidinyl group,
an ether group; preferably an OR group with R preferably being selected from among the methyl and ethyl groups, where appropriate substituted by a chlorine atom, or trifluoromethyl and alkenyl groups
a thioether group, preferably represented by an alkylthio group with alkyl preferably representing a C
1
to C
3
alkyl group,
an acyl or alkoxycarbonyl group and, more particularly, a COR group with R preferably representing a C
1
to C
3
alkyl group or a C
1
to C
3
alkoxy group,
a C
1
to C
6
alkyl group which is straight-chain or branched and which is preferably selected from among the methyl, isopropyl and tert-butyl groups,
an alkylthiomethyl group and, more preferably, a CH2SR group with R preferably representing a C
1
to C
3
alkyl group,
an aryl group, preferably a phenyl group, or
a trihalogenomethyl group, preferably trifluoromethyl
For the Meta-para Disubstituted Derivatives
A, D and E representing a hydrogen atom, and B being able to represent:
a halogen, preferably a fluorine atom,
a monoalkylamino or dialkylamino group with alkyl preferably representing a methyl or ethyl group,
an ether group and preferably an OR group with R preferably selected from among the methyl, ethyl and trifluoromethyl groups,
a thioether group and preferably alkylthio with alkyl preferably representing an ethyl group, or
a C
1
to C
3
alkyl group, and C being able to represent:
a halogen, preferably a fluorine atom,
an amino, monoalkylamino or dialkylamino group with alkyl preferably representing a methyl group with the proviso that B is different from a bromine or chlorine atom, or a substituted or unsubstituted allyl group,
an ether group and preferably an OR group with R preferably selected from among the methyl, ethyl and trifluoromethyl groups,
a thioether group and preferably an alkylthio group with alkyl preferably representing a methyl group,
a C
1
to C
6
alkyl group, or
a trihalogenomethyl group, preferably trifluoromethyl, and
For the Ortho-para Disubstituted Derivatives
B, E and D representing a hydrogen atom and A and C a methyl group.
The following may be

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