JPH10114778A - New compound f-12517 - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new compound comprising a spiro-ketal structure having a decalone skeleton collected from a culture medium of Vibrissea filisporia strain and expressing excellent antibacterial activity on gram-positive bacteria, especially bacteria belonging to the genus Staphylococcus. SOLUTION: This compound is represented by the formula or its salt. The compound of the formula is obtained by retaining Vibrissea filisporia SANK 18796 bacterial strain in a culture medium at pH5.0 to 7.0 at 15-37 deg.C, preferably 22-26 deg.C culture temperature, culturing the bacterium by spinner culture method, shaking culture method or aerating cultivation method, preferably shaking culture method, industrially submerged culture method, subjecting the cultured solution to filtration and centrifugation, etc., and subjecting the filtrate or supernatant and bacterial cell to solvent extraction, treatment by absorbent and separation and purification with column chromatography, etc.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to F-12517 or a salt thereof which is useful as an antibacterial agent.

[0002]

2. Description of the Related Art Spiro ketal derivatives having a decalone skeleton include, for example, Preucia isomera (Preu isomera).
ssia isomera (Preussomerin, J. Org. Chem,
56, 4355-4360 (1991))
And Natrassia Mangiferae (Natrassia)
Sch50673 produced by C.mangiferae),
Sch50676 (J. Antibiotics, 48
Vol. 329-331 (described in 1995)) and CJ-12371, C produced by an unidentified mold (N983-46)
J-12372 (J. Antibiotics, 48
Vol., 134-142 (1995)).

[0003] Pleusomerin has been reported as an antifungal active, but its activity is not very strong. Also, S
ch50673, Sch50676 has been reported as an antitumor active. Further, CJ-12371, CJ
-12372 is a DNA gyrase (DNA Gyrase)
It is known as an inhibitor of e).

[0004] To date, there has been no report that the genus Vibrsea, a bacterium, produces spiro-ketal derivatives having a decalone skeleton.

[0005]

DISCLOSURE OF THE INVENTION The present inventors have conducted intensive studies on compounds having antibacterial activity for many years, and as a result, have found that Vibrissea phyllosporia (Vibrissea) has been developed.
filisporia) in a culture of a strain belonging to
The present inventors have found that there is a compound having antibacterial activity, and completed the present invention.

[0006]

According to the present invention, there is provided the following formula:

[0007]

Embedded image

Or a salt thereof.

Further, the present invention provides the following physicochemical properties: (1) property of substance: acidic fat-soluble powder (2) molecular formula: C ₂₀ H ₈ O ₈ Cl ₂ (3) molecular weight: 446 (high resolution EI- High-resolution EI-MS (M ⁺ ) (as C ₂₀ H ₈ O ₈ Cl ₂ ) Actual value: 445.9588 Calculated value: 445.9596 (4) Elemental analysis value: (%) C ₂₀ H Obtained value for ₈ O ₈ Cl ₂ : C 53.05 H 2.51 Cl 14.87 Calculated value: C 53.72 H 1.80 Cl 15.86 (5) Ultraviolet absorption spectrum (λ _max nm (ε)): The ultraviolet absorption spectrum is as follows: .

In methanol: 232 (22250), 270 (sh), 395 (8090) In acidic methanol: 215 (sh), 260 (13030), 360 (5840) In alkaline methanol: 240 (29670), 273 (sh) ), 315 (sh), 420 (8990) (6) Infrared absorption spectrum (ν _max cm ^-1 ) The infrared absorption spectrum measured by the potassium bromide (KBr) tablet method is as follows.

3341,1663,1606,1441,1346,1328,1244,117
8,1110,1074,1032,998,949,908,885, (7) ¹ H-nuclear magnetic resonance spectrum: (δ, ppm) Nuclear magnetic resonance spectrum (360 MHz) measured in heavy methanol using tetramethylsilane as an internal standard
Is as follows.

7.86 (1H, s), 7.14 (1H, s), 4.34 (1H, d), 4.25
(1H, d), 4.02 (1H, d), 3.87 (1H, d), (8) ¹³ C-nuclear magnetic resonance spectrum: (δ, ppm) In heavy methanol, using tetramethylsilane as an internal standard. Measured nuclear magnetic resonance spectrum (90MHz)
Is as follows.

196.8 (s), 193.9 (s), 156.1 (s), 152.5 (s), 14
2.9 (s), 138.9 (s), 135.3 (s), 128.9 (d), 127.0 (d), 126.0
(s), 124.0 (s), 123.8 (s), 111.7 (s), 110.0 (s), 105.6 (s), 8
5.5 (s), 54.7 (d), 54.6 (d), 53.3 (d), 53.1 (d), (9) High performance liquid chromatography: Separation column: Senshupack ODS H-2151 (registered trademark, column φ6 × 150 mm) Moving layer: acetonitrile-0.2% trifluoroacetic acid = 58.42 Flow rate: 1.5 ml / min Retention time: 9.2 minutes, or F-12517 or a salt thereof.

Further, the present invention relates to a vibrisse (Vibrisse).
a) culturing an F-12517 producing bacterium belonging to the genus, and collecting F-12517 from the culture;
Regarding the production method of 12517, preferably, an F-12517-producing bacterium belonging to the genus Vibricea is produced by Vibricea sp.
brissea sp.) SANK18796 strain (FERM BP-
5885).

The present invention also relates to a medicament comprising F-12517 or a pharmacologically acceptable salt thereof.
The present invention relates to an antibacterial agent containing F-12517 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0016] The present invention relates to Vibris sp.
sea sp.) SANK18796 strain (FERM BP-56
85) Relating to itself.

The F-12517 of the present invention can be converted into a salt according to a conventional method. As the salt of F-12517,
There is no particular limitation as long as it is used medically and is pharmacologically acceptable. It should be noted that there is no limitation for uses other than pharmaceuticals, for example, when used as an intermediate. Such salts preferably include alkali metal salts such as sodium, potassium and lithium salts; alkaline earth metal salts such as calcium and magnesium salts; aluminum salts, iron salts, zinc salts and copper lead. , Nickel salts, metal salts such as cobalt salts; ammonium salts; t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts, ethylenediamine salts, N
-Methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt,
N, N'-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-
Amine salts such as organic salts such as benzyl-phenethylamine salt, piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt; Pharmacologically acceptable salts are preferably alkali metal salts such as sodium salt, potassium salt and lithium salt; and alkaline earth metal salts such as calcium salt and magnesium salt.

Further, F-12517 of the present invention has various stereoisomers. In the present invention, all equal and unequal mixtures of these isomers are represented by a single formula. The present invention includes all these isomers and mixtures of these isomers.

Further, in the present invention, when F-12517 forms a solvate (for example, a hydrate), these are all included.

For example, when the F-12517 of the present invention is left in the atmosphere or recrystallized, it may absorb moisture, adhere to adsorbed water, or form a hydrate. The present invention includes such a solvate.

Further, in the present invention, all compounds that are metabolized in vivo and converted into F-12517, so-called prodrugs, are also included.

The above-mentioned SANK18796 strain producing the novel compound F-12517 of the present invention was isolated from the fruiting bodies of bacilli which had formed on the decayed trees collected in the Hanuki Valley, Ibaraki Prefecture.

The bacteriological properties of SANK18796 strain are as follows.

[0024] Ascus discs are superimposed on the matrix and are scattered from the colony. It has a clear handle and a height of 1.5 mm. The diameter of the board is about 2.5 mm, and it is yellow-brown when fresh. When dried, it is dark brown but often white due to the emitted spores. The sac is pale to dark brown. The encrustation layer presents a rectangular fungal tissue, with cells arranged almost perpendicular to the outer surface. Its outermost layer is thin-walled, has a darker brown color, and projects slightly outward. The ascus is an elongated cylindrical shape with a size of about 120 × 5μ
m. The tip of the ascus is thick and not stained with Melzer reagent. The ascospores are filamentous and have a size of about 120 × 1.
5 μm, formed in bundles in the asci. After the injection, a large number of partition walls are formed and divided. Lateral thread is thread-like, 20 μm from the ascus
It is elongated and has a width of 2 μm. It has a septum and may be somewhat voluminous at the tip.

The colonies on the PDA medium reach 16 mm in diameter at 23 ° C. for 2 weeks. Form a mat of dense mycelium with colloids. Navel-shaped bulges at the center, and others are flat. The color of the surface is dark green, pale toward the edges, and green-grey near the edges. The back has an olive color and becomes darker toward the center. The aerial hyphae develop velvety and are thick fluffy in the center. It turns black at the center, but is colorless elsewhere, and forms a mycelial bundle near the center.
Slight secretion of a soluble pigment similar in color to the back side is observed. No conidia are formed.

The colonies on the WSH medium reach 18 mm in diameter at 23 ° C. for 2 weeks. Form a mat of dense mycelium with colloids. It is flat, dark green at the center, and pale toward the edges. The back surface is yellow-brown in the vicinity of the center, becomes lighter toward the edges, and is almost white at the edges.
The aerial hyphae are fluffy and colorless. It becomes black at the center and forms a hyphal bundle. No secretion of soluble pigment is observed. No conidia are formed. The composition of the medium is as follows.

PDA medium: PDA powder (Nissui Pharmaceutical Co., Ltd.)
(1 g) was made up to 1 L with distilled water. WSH medium: 10 g of oatmeal, 1 g of magnesium sulfate heptahydrate, 1 g of monopotassium dihydrogen phosphate, 1 g of sodium nitrate, and 1 g of agar were adjusted to 1 L with water (pH was not adjusted).

Based on the above mycological properties, a search was made for a substance corresponding to the present bacterium, and it was found that “The sections A
postmium and Microstemiu
mof the genus Vibrissea (f
ungi), The Journal of Agri
culture of The University
of Pureto Pico 51: 79-93
P. (1967). And "Vibrisea filisporia" described in
This was in good agreement with the description in ia). Therefore, this bacterium is transferred to Vibr
isseafilisporia (Bon.) Korf
& Sanchez SANK18796 strain (hereinafter referred to as “
Abbreviated as "SANK 18796 strain".

The SANK18796 strain is Vibricea philisporia (Bon) Corfu and Sanchietsu SANK1.
No. 8796 was deposited with the Institute of Biotechnology and Industrial Technology of the Ministry of International Trade and Industry on October 1, 1996 (Heisei 8), and given the accession number FERM BP-5885.

As is well known, bacilli can be produced in nature or by artificial manipulation (for example, ultraviolet irradiation, irradiation,
Mutation is likely to occur due to chemical treatment or the like, and the same applies to the SANK18796 strain of the present invention. The SANK18796 strain referred to in the present invention includes all the mutant strains. These mutants also include those obtained by genetic methods, for example, recombination, transduction, transformation and the like. That is, S producing F-12517
The ANK18796 strain, mutants thereof and strains not clearly distinguished therefrom are all included in the SANK18796 strain.

[0031]

DETAILED DESCRIPTION OF THE INVENTION To obtain the F-12517 of the present invention, the culture of these microorganisms is carried out in a medium such as that used to produce other fermentation products. Such a medium contains a carbon source, a nitrogen source and inorganic salts that can be assimilated by the microorganism.

In general, carbon sources include glucose, fructose, maltose, sucrose, mannitol, glycerin, dextrin, oats, rye, corn starch, potato, corn flour, soybean oil, cottonseed oil, molasses, citric acid, tartaric acid and the like. I can give it. These carbon sources may be used alone in the medium, or several carbon sources may be used in combination in the medium.

Although the exact amount of the carbon source used in the medium depends on other components in the medium, it is usually 1-10% by weight of the medium amount.
Random.

As the nitrogen source, a substance containing a protein is generally used in the fermentation step. Suitable nitrogen sources include soybean flour, bran, peanut flour, cottonseed flour, casein hydrolyzate,
Pharmamin, fish meal, corn steep liquor, peptone, meat extract, yeast, yeast extract, malt extract, sodium nitrate, ammonium nitrate, ammonium sulfate and the like. 0.2-6% by weight of various nitrogen sources
Can be used alone or in combination.

The carbon and nitrogen sources are generally used in combination, but need not be in pure form. Less pure ones containing trace amounts of growth factors, vitamins and mineral nutrients may be used. Ordinary salts from which ions such as sodium, potassium, magnesium, ammonium, calcium, phosphate, sulfate, chloride and carbonate can be obtained may be added to the medium. In addition, when a sulfur compound that can be assimilated by bacteria is added to the medium, the production amount of the target product may increase. For example, zinc sulfate, copper sulfate, ferrous sulfate, sulfates such as ammonium sulfate, thiosulfates such as ammonium thiosulfate,
Inorganic sulfur compounds such as sulfites such as ammonium sulfite; sulfur-containing amino acids such as cystine, cysteine and L-thiazolidine-4-carboxylic acid; organic sulfur compounds such as sulfur-containing peptides such as pipetaurine and glutathione; Heavy metal salts such as iron and copper sulfate, vitamins such as vitamin B ₁ and bition, and cell growth promoting substances such as thiamine may be added as necessary. It also contains manganese, iron, molybdenum, zinc and other trace metals. If necessary, an antifoaming agent such as silicone oil, polyalkylene glycol ether, vegetable oil, animal oil, or a surfactant may be added to the medium, particularly if the nutrient medium is considerably foamed (especially during liquid culture). Is preferred).

Vibrisia philisporia SANK18
796 strain, and the culture medium producing F-12517
H can be varied from 5.0 to 7.0.

The growth temperature of the bacterium is from 15 ° C. to 37 ° C., but the growth is good in the range of 22 ° C. to 35 ° C. Further, 22 ° C. to 26 ° C. is suitable for the production of F-12517.

The culture method is not particularly limited and may be any culture method generally used for microorganisms, such as a stirring culture method,
A shaking culture method, aeration culture method, or the like can be used. Preferably, an aerobic liquid culture method, such as a stirring culture method, a shaking culture method, or an aeration culture method, is more preferably a shaking culture method. In addition, the aeration stirring culture method is suitable industrially.

In a small-scale culture, it is preferable to carry out shaking culture at 23 ° C. for several days. The culture is started in an Erlenmeyer flask with a 1-2 stage seed development process.
The medium at the stage of seed development can use a combination of carbon and nitrogen sources. Seed flasks were kept in a constant temperature incubator at 23 ° C, 7
Shake for days or until fully grown.
The grown seed is used to inoculate a second seed or production medium. If an intermediate development step is used, it is grown in essentially the same way and is partially used to inoculate the production medium. The inoculated flask is shaken at constant temperature for several days, and after the incubation is completed, the contents of the flask are centrifuged or filtered.

In the case of mass cultivation, it is preferable that after stirring, the culture is carried out in a suitable tank equipped with an aeration device. According to this method, the nutrient medium can be prepared in the tank. The nutrient medium is sterilized by heating to 121 ° C., and after cooling, the sterile medium is inoculated with seeds that have been previously grown. Culture is 23
C. with aeration and stirring. This method is suitable for obtaining large amounts of compounds.

F-125 produced as the culture proceeds
The change with time of the amount of 17 can be measured using high performance liquid chromatography. Normally, the production of F-12517 reaches the maximum value after culturing for 120 hours to 200 hours.

After the completion of the culture, the liquid portion in the culture solution and F-12517 present in the cells are separated from the cells and other solid portions by a filtration operation using diatomaceous earth as a filter aid or by centrifugation. It is obtained by extracting and purifying F-12517 present in the solution or supernatant and in the cells using its physicochemical properties. For example, F-12517 present in the filtrate or supernatant can be formed by an organic solvent immiscible with water under acidic pH conditions, such as ethyl acetate, chloroform, ethylene chloride, methylene chloride, butanol, etc., alone or in combination. It can be extracted and purified. Alternatively, as an adsorbent, for example, activated carbon or Amberlite XAD-2, XAD which is a resin for adsorption
-4 (registered trademark, manufactured by Rohm and Haas),
Diaion HP-10, HP-20, CHP-20,
HP-50 (registered trademark, manufactured by Mitsubishi Chemical Corporation) or the like is used. The liquid containing F-12517 is passed through a layer of the adsorbent as described above to adsorb and remove impurities, or after adsorbing F-12517, eluted with methanol water, acetone water, butanol water, or the like. Thereby, F-12517 can be obtained. In addition, F-12517 existing in the cells can be obtained by extracting with 50-90% aqueous acetone or aqueous methanol to remove the organic solvent, and then performing the same extraction and purification operation as the filtrate.

The thus obtained F-12517
Further, adsorption column chromatography using a carrier such as silica gel, magnesium-silica gel type florisil, distribution column chromatography using Sephadex LH-20 (registered trademark, manufactured by Pharmacia) or the like, Cosmoseal 140C ₁₈ − It can be purified by column chromatography using a reversed-phase carrier such as OPN (registered trademark, manufactured by Nacalai Tesque, Inc.) or high-performance liquid chromatography using a normal-phase or reverse-phase column.

F-12517 can be separated and purified by using the above separation and purification means alone or in an appropriate combination and repeated.

The F-12517 of the present invention has an antibacterial effect and is useful as an antibacterial agent.

When F-12517 of the present invention is used as an antibacterial agent, it is administered in various forms. The administration form is not particularly limited, and is determined according to various preparation forms, patient age, sex and other conditions, degree of disease, and the like. For example, tablets, pills, powders, granules, syrups, solutions, suspensions, emulsions, granules and capsules are orally administered. In the case of an injection, it is administered intravenously, alone or as a mixture with a normal replenisher such as glucose or amino acid, and if necessary, intramuscularly, intradermally, subcutaneously or intraperitoneally. In the case of suppositories, they are administered rectally.

These various preparations can be used in the conventional pharmaceutical preparations such as excipients, binders, disintegrants, lubricants, dissolving agents, flavoring agents, coating agents and the like in accordance with the conventional method. It can be formulated with auxiliaries.

In the case of molding into tablets, carriers conventionally known in the art can be widely used, such as lactose, sucrose, sodium chloride, glucose, urea, starch, and the like.
Binding of excipients such as calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc., water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, polyvinylpyrrolidone, etc. Agent, dried starch, sodium alginate, agar powder, laminaran powder, sodium hydrogen carbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, disintegrators such as lactose, sucrose, stearin, cacao Disintegration inhibitors such as butter and hydrogenated oil, quaternary ammonium salts, absorption promoters such as sodium lauryl sulfate, humectants such as glycerin and starch, and adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid , Ltd. talc, stearates,
Lubricants such as boric acid powder and polyethylene glycol can be exemplified. Furthermore, tablets are tablets coated with normal skin as needed,
For example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets or double tablets or multilayer tablets can be prepared.

For molding into pill form, carriers conventionally known in this field can be widely used, for example, excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, talc, and the like. Examples thereof include rubber powder, tragacanth powder, binders such as gelatin and ethanol, and disintegrants such as laminaran agar.

In shaping into a suppository form, carriers conventionally known in the art can be widely used, for example, polyethylene glycol, cocoa butter, higher alcohols and the like.
Esters of higher alcohols, gelatin, semi-synthetic glycerides and the like can be mentioned.

When prepared as an injection, the solution and suspension are preferably sterilized and isotonic with blood. When formed into the form of these solutions, emulsions and suspensions, they may be diluted. All agents commonly used in this field can be used as the agent, for example, water, ethyl alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol,
Examples thereof include polyoxyethylene sorbitan fatty acid esters. In this case, a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and ordinary dissolution aids, buffers, soothing agents and the like may be added. May be.

If necessary, a coloring agent, a preservative, a fragrance,
Flavoring agents, sweeteners and the like and other pharmaceuticals may be included.

The amount of the active ingredient compound contained in the above-mentioned pharmaceutical preparation is not particularly limited and may be appropriately selected in a wide range, but is usually 1-70% by weight, preferably 1-30% by weight in the whole composition. Is appropriate.

The dosage varies depending on the condition, age, body weight, administration method and dosage form, but is usually 1 dose for adults.
2000 mg as the upper limit per day (preferably 200 m
g, more preferably 20 mg), with a lower limit of 0.1 mg.
001 mg (preferably 0.01 mg, more preferably 0.1 mg) can be administered.

[0055]

EXAMPLES Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited to these examples.

Example 1 F-12517 (1) Culture A 500 ml volume of 80 ml of a medium having the composition described below, which was obtained by aseptically sterilizing Vibricea philisporia SANK18796 strain (accession number FERMBP-5885) (121 ° C., 20 minutes). One loopful of a loop was inoculated into an Erlenmeyer flask, and cultured at 23 ° C. for 7 days in a rotary shaking incubator at 210 rpm (rotation radius of 7 cm). The culture solution obtained in this manner was used as a seed culture solution for a medium 80 of the same composition.
10% of the seed culture solution was inoculated into 13 500 ml Erlenmeyer flasks containing 500 ml, and cultivated at 23 ° C. for 7 days in a 210 rpm (rotational radius of 7 cm) rotary shaking incubator.

[0057]

[Table 1] Medium composition ────────────────────────────────── glycerin 30 g glucose 30 g soybean flour (day Seiya Soya Flower Co., Ltd.) 10 g Yeast Extract (manufactured by Difco) 2.5 g Soluble starch (Kanto Chemical Co., Ltd.) 20 g Gelatin (Kanto Chemical Co., Ltd.) ^* 2.5 g Ammonium nitrate 2.5 g Defoamer ^** 0.5 ml １０００ 1000 ml with tap water And (PH 6.5: before sterilization) ^* Dissolve in hot water before use.

^** Nissan Deform CB-442
(Registered trademark, manufactured by NOF Corporation) in a 10% acetone solution.

(2) Isolation and Purification 1000 ml of the obtained culture was adjusted to pH 3 with hydrochloric acid, and extracted with equal amounts of acetone and ethyl acetate. The extracted ethyl acetate layer is composed of water, saturated saline,
Washed with water and dried over anhydrous sodium sulfate. The extract was concentrated to dryness under reduced pressure to obtain 1.8 g of an oil. The obtained oil was dissolved in 10 ml of 50% methanol, and the mixture was subjected to Cosmoseal column (registered trademark, size φ3.5).
× 25 cm). Then, after developing with the same solvent, developing with 50% acetonitrile and further eluting with 70% acetonitrile. Fraction 14 containing F-12517
4 mg were collected. 1.4 ml of the obtained powder in methanol
And subjected to high performance liquid chromatography and fractionated (fractionation conditions, column: Senshupack ODS H-
4251 (registered trademark, size φ10 × 250mm),
Eluent: acetonitrile-0.2% trifluoroacetic acid =
6: 4, flow rate: 5 ml / min). Fractions containing F-12517 were collected and concentrated. Then, when subjected to lyophilization, F-1
33 mg of 2517 were obtained.

[Test Example] Test Example 1 Antibacterial activity of F-12517 F-12517 against general Gram positive and negative bacteria
The minimum inhibitory concentration (MIC) was measured by an agar medium dilution method using an ordinary agar medium (manufactured by Eiken Chemical Co., Ltd.).

Table 2 shows the results.

[0062]

[Table 2] 菌 Test bacteria Minimum inhibitory concentration (MIC) (μg / ml) ─────────────────────────────────── Staphylococcus aureus 209P 0.8 Staphylococcus aureus 56R 3.1 Filococcus aureus 535 (MRSA) ^*** 3.1 Enterococcus faecalis 681 25 Escherichia coli NHIJ> 200 Salmonella enterititis> 200 Klebsiella Nyumonje 806> 200 ─────────────────── ─────────────── ^*** Methicillin-resistant Staphylococcus aureus As is clear from Table 2, F-12517 is a common gram-positive bacterium, particularly against Staphylococcus and Enterococcus sp. The effect was shown.

[Formulation Examples] Next, formulation examples will be given.

Formulation Example 1 Oral Capsule

[0065]

Table 3 Formulation F-12517 30 mg Lactose 170 mg Corn starch 150 mg Magnesium stearate 2 mg ──── 352 mg The powder of the above formulation is mixed and passed through a 30-mesh sieve, and then this powder is placed in a gelatin capsule to prepare a capsule.

[0066]

Industrial Applicability The novel compound F-12517 or a salt thereof of the present invention has an antibacterial activity and is useful as an antibacterial agent for preventing or treating various bacterial infectious diseases.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁶ Identification code FI C12R 1:01) (C12P 17/18 C12R 1: 645)

Claims (7)

[Claims] 1. The following formula: Or a salt thereof. 2. The following physicochemical properties: (1) Properties of substance: acidic fat-soluble powder (2) Molecular formula: C ₂₀ H ₈ O ₈ Cl ₂ (3) Molecular weight: 446 (measured by high-resolution EI-MS method) ) High-resolution EI-MS (M ⁺ ) (as C ₂₀ H ₈ O ₈ Cl ₂ ) Found: 445.9588 Calculated: 445.9596 (4) Elemental analysis: (%) C ₂₀ H ₈ O ₈ Cl Found as _2: C 53.05 H 2.51 Cl 14.87 calculated: C 53.72 H 1.80 Cl 15.86 ( 5) UV absorption spectrum _{(λ max nm (ε))} : UV absorption spectra are as shown below. In methanol: 232 (22250), 270 (sh), 395 (8090) In acidic methanol: 215 (sh), 260 (1303
0), 360 (5840) in alkaline methanol: 240 (29670), 273 (s
h), 315 (sh), 420 (8990) (6) Infrared absorption spectrum (ν _max cm ^-1 ) The infrared absorption spectrum measured by the potassium bromide (KBr) tablet method is as follows. 3341,1663,1606,1441,1346,1328,1244,1178,1110,1074,
1032,998,949,908,885, (7) ¹ H-nuclear magnetic resonance spectrum: (δ, ppm) Nuclear magnetic resonance spectrum (360 MHz) measured in heavy methanol using tetramethylsilane as an internal standard
Is as follows. 7.86 (1H, s), 7.14 (1H, s), 4.34 (1H, d), 4.25 (1H, d), 4.02 (1
(H, d), 3.87 (1H, d), (8) ¹³ C-nuclear magnetic resonance spectrum: (δ, ppm) Nuclear magnetic resonance spectrum (90 MHz) measured in heavy methanol using tetramethylsilane as an internal standard. )
Is as follows. 196.8 (s), 193.9 (s), 156.1 (s), 152.5 (s), 142.9 (s), 138.9
(s), 135.3 (s), 128.9 (d), 127.0 (d), 126.0 (s), 124.0 (s), 1
23.8 (s), 111.7 (s), 110.0 (s), 105.6 (s), 85.5 (s), 54.7
(d), 54.6 (d), 53.3 (d), 53.1 (d), (9) High Performance Liquid Chromatography: Separation column: Senshupack ODS H-2151 (registered trademark, column φ6 × 150 mm, Senshuyu Kagaku Co., Ltd.) Mobile layer: acetonitrile-0.2% trifluoroacetic acid = 58.42 Flow rate: 1.5 ml / min Retention time: 9.2 minutes F-12517 or a salt thereof. 3. An F- member belonging to the genus Vibrissea.
12517-producing bacteria were cultured, and F-125 was obtained from the culture.
17. A method for producing F-12517, wherein 17 is collected. 4. An F-12517-producing bacterium belonging to the genus Vibricea is derived from Vibrissea sp.
The method according to claim 3, which is 18796 strain (FERM BP-5885). 5. A medicament comprising F-12517 or a pharmaceutically acceptable salt thereof. 6. An antibacterial agent comprising F-12517 or a pharmaceutically acceptable salt thereof as an active ingredient. 7. Vibrissea sp.
SANK18796 strain (FERM BP-5885).