Antibiotics RK-1061 and process for preparing the same

Organic compounds -- part of the class 532-570 series – Organic compounds – Unsubstituted hydrocarbyl chain between the ring and the -c-...

Reexamination Certificate

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C514S218000

Reexamination Certificate

active

06455694

ABSTRACT:

TECHNICAL FIELD
The present invention relates to a novel antibiotic RK-1061s named as liposidomycins and pharmacologically acceptable salts thereof and a method of producing them.
1. Prior Art
In the case of development of a highly specific antibacterial agent with little side-effects, an agent which can target a specific site present in bacteria of prokaryotes but absent in human of eukaryotes is desired. As such a specific site, peptidoglycan which is one of bacterial cell wall components can be exemplified and penicillins, cephems, carbapenems, monobactams, cycloserine, bacitracin, vancomycin, phosphomycin are known as launched antibiotics which act on peptidoglycan.
2. Disclosure of the Invention
It is well known that any excellent antibiotic will induce resistant bacteria by using it for a long time. In addition, some antibiotics have side-effects such as neuropathy, nephropathy and/or hepatopathy. Recently, infection of MRSA (Methicillin resistant
Staphylococcus aureus
) in a hospital and
Helicobacter pylori
which is thought to play a role as a cause of gastric ulcer and/or gastric cancer become the topics in the field. From these points of view, development of an antibiotic having a novel structure and action mechanism is desired. Antibiotic liposidomycins (RK-1061s) were found by using screening system of inhibiting peptidoglycan synthesis. This antibiotic has an action of specifically inhibiting phospho-N-acetylmuramyl-pentapeptide transferase (E.C.2.7.8.13)(Phospho-MurNAc-pentapeptide translocase, UDP-MurNAc-pentapeptide phosphotransferase, (common name) translocase I) (Agri. Biol. Chem., 53(7), 1811-1815 (1989)) and structural characteristic of being a fatty acyl nucleoside antibiotic with sulfate group and unique aminosugar group. Though Tunicamycin (“Tunicamycin”, Japan Scientific Societies Press, 1982, Tokyo) and Mureidomycin (J. Antibiot., 42, 662-679 (1989)) are known to have the same action as liposidomycins, according to the above references, liposidomycins has an antibacterial spectrum different from those of the other two antibiotics and powerful inhibitory activity thereof on peptidoglycan synthesis. Therefore, liposidomycin theoretically has a possibility of being effective against the all bacteria having peptidoglycan if it has not problem on permeability or stability.
Liposidomycins has a potent antibacterial activity especially on Mycobacterium belonging to acid-fast bacteria (J. Antibiot., 38, 1617-1621 (1985)) and is expected to be effective against
Mycohacterium tuberculosis
resistant to known anti-tuberculotic agent such as rifanpicin etc. against which any agent is not effective. Further, opportunistic infectious disease such as pneumocystis carinii becomes serious problem according to the explosive increase in the number of patient with AIDS and liposidomycins can be expected to be effective against adventitious anti-fast bacterium Mycobacterium avium complex (MAC) which causes the aforementioned opportunistic infectious disease.
The present inventors investigated to produce high yield of RK-1061s which are antibiotics composed of many components and to isolate novel components therefrom and found novel substances different from RK-1061A (liposidomycins A), RK-1061B (liposidomycins B), RK-1061C (liposidomycin C) (Japanese unexamined patent application No. 282088/1986), RK-1061G (liposidomycins G), RK-1061H (liposidomycins H) (Japanese unexamined patent application No. 306992/1990) which were already reported. Though the all reported substances can be classified into general formula (II) as will be described below, liposidomycins obtained by the present invention are novel compounds which have a structure with novel group at R
1
group of formula (II) and can be classified into 3 different types which belong to structure (III), (IV) and (V). Further, novel antibiotic liposidomycins (RK-1061s) obtained by the present invention, especially compounds without sulfate group having structure (IV) or (V), demonstrated significantly higher antibacterial activity than the other compounds. Then, the present invention was accomplished.
An object of the present invention is to provide novel antibiotic liposidomycins (RK-1061s), highly productive cell lines thereof and a method of producing them.
The present invention relates to liposidomycins (RK-1061s) represented in the following general formula (I) or pharmacologically acceptable salts thereof.
A in the formula represents R
1
or R
1
CH(OR
2
)CH
2
.
R
2
represents 3-methylglutaric acid residue(—CO—CH
2
—CH(CH
3
)—CH
2
—COOH), R
3
represents hydrogen atom (H) or sulfate group(SO
3
H). Further, in the case of R
1
CH(OR
2
)CH
2
, R
1
represents C
n
H
2n+1
(n represents an integer between 1-20), C
n
H
2n−1
(n represents an integer between 2-21) or C
n
H
2n−3
(n represents an integer between 3-22). And in the case of R
1
, R
1
represents C
n
H
2n−1
(n represents an integer between 2-21), C
n
H
2n−3
(n represents an integer between 3-22) or C
n
H
2−5
(n represents an integer between 4-23).
As for the compounds, liposidomycins represented in the following formula (II)-(V) can be exemplified.
R
1
represents the same as described before.
According to species of substituted group A and R
3
, liposidomycins RK-1061s of the present invention can be classified into the following types. That is, they can be classified into 2 types, that is, one type in which A is R
1
CH(OR
2
)CH
2
(wherein R
2
is 3-methylglutaric acid residue) and another type in which A is R
1
(wherein R
2
is not present, R
1
directly binds to 2a position). And also they can be classified as R
3
is sulfate group and hydrogen atom.
Substituent
Structural
R
2
R
3
Formula
Type I
3-methylglutaric acid
sulfate group
Formula II
Type II
direct bonding
sulfate group
Formula III
Type III
3-methylglutaric acid
hydrogen atom
Formula IV
Type IV
direct bonding
hydrogen atom
Formula V
As a pharmacologically acceptable salt of these RK-1061s of the present invention, hydrochloride, sulfate, alkaline metal salt such as sodium or potassium etc., alkaline earth metal salt such as magnesium or calcium etc. other metal salt such as aluminium etc. and organic amine salt such as alkyl amine salt or pyridinium salt can be exemplified.
Further, the present invention relates to a method of producing liposidomycins (RK-1061s) represented as the above formula.
That is, the producing method of the present invention is a method of producing liposidomycins (RK-1061s) comprising the following steps:
1) culturing microorganism which belongs to Streptomyces and which has a capability to produce the aforementioned liposidomycins (RK-1061s) in culture medium;
2) producing said liposidomycins (RK-1061s); and
3) collecting said liposidomycins (RK-1061s) from the cultured products.
These compounds of the present invention can be isolated by utilizing the difference of retention time of each compound by HPLC etc.
In addition, these compounds such as liposidomycins (RK-1061) whose R
3
is sulfate group or hydrogen atom can be selectively produced by selecting carbon source of culture medium. For example, liposidomycins (RK-1061s) with R3 of sulfate group can be highly produced using glucose or maltose as carbon source, while liposidomycins (RK-1061s) with R
3
of hydrogen atom can be highly produced using at least one carbon source selected from the group consisting of xylose, lactose, D-fructose, sucrose, inositol and D-mannitol and wheat germ or malt extract as nitrogen source.
As actinomycetes producing liposidomycins (RK-1061s) of the present invention, soil bacterium Streptomyces sp. RK-1061 (hereinafter referred to RK-1061 cell line) found in soil at Misaka-cho, Yamanashi prefecture by the present inventors can be exemplified. This cell line was deposited at National Institute of Bioscience and Human Technology Agency of Industrial Science and Technology Ministry of International Trade and Industry with deposit number of FERM P-8278. A patent application claimed this FERM P-8278 cell line was already registered as Patent numbe

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