WO2016111574A1 - Novel cyclic depsipeptide-based compound, method for preparing same, and antibacterial pharmaceutical composition containing same as active ingredient - Google Patents

Abstract

The present invention relates to a novel cyclic depsipeptide-based compound, a method for preparing same, and an antibacterial pharmaceutical composition containing same as an active ingredient, the novel cyclic depsipeptide-based compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof, according to the present invention, exhibiting inhibitory activity against Staphylococcus aureus and Salmonella typhimurium, thereby being able to be usefully employed for an antibacterial composition, antibacterial pharmaceutical composition, antibacterial feed composition, or antibacterial cosmetic composition, and for the treatment of bacterial infectious diseases.

Description

Novel cyclic depsipeptide compounds, preparation method thereof and antimicrobial pharmaceutical composition containing the same as an active ingredient

The present invention relates to a novel cyclic depsipeptide-based compound, a method for preparing the same, an antimicrobial pharmaceutical composition containing the same as an active ingredient, and a method for treating a bacterial infectious disease.

The classical meaning of antibiotics is a secondary metabolite produced by microorganisms, which means that they kill or inhibit growth at very low concentrations. The term antibiotic is to be started is first used by only (Waksman) 1940's wax, penicillin (Penicillin) produced by initially synthetic material of the release, mainly used at the time of sulfone amides (sulfonamide) and penicillin mold (Penicillium sp.) Used to distinguish. Since the discovery and synthesis of many substances that exhibit antimicrobial activity, it has become difficult to uniquely define the meaning of antibiotics. Currently, antibiotics generally have a natural, semisynthetic or It is taken to mean a compound of synthesis.

Research on the exploration and use of natural products is the exploration and utilization of the biosynthetic ability of the organism, so far, mainly plants and microorganisms have been the target species. In particular, microorganisms have produced a variety of species and unique and interesting bioactive substances, short generation period, easy mass production and high industrial availability, has become an attractive search source for bioactive substances. The exploration of useful substances produced by microorganisms has been actively conducted mainly on terrestrial microorganisms, and many of them have found usefulness in fermentation industry and medicine. In addition, antibiotic-resistant bacteria that are resistant to conventional antibiotics and appear to be ineffective are emerging, and as new diseases such as AIDS are increasing, the development of new drugs that can replace existing antibiotics is urgently required. It is becoming.

In this regard, Patent Document 1 (Korean Patent Laid-Open Publication No. 10-2007-0086038) discloses a compound having a depsi peptide parent nucleus and an antimicrobial composition containing the same. In addition, Patent Document 2 (Korean Patent Laid-Open Publication No. 10-1986-0000382) discloses a compound having a depsi peptide parent nucleus, and an antitumor or antibiotic composition containing the same.

Previously developed antibiotics are classified as beta-lactam class of antibiotics, and there is methicillin (methicillin), which is recognized to be superior to penicillin, and has become resistant to methicillin. Bacteria, specifically vancomycin, which has been developed to have an antimicrobial effect on methicillin resistance staphyllococus aureus (MRSA).

However, vancomycin resistance staphyllococus has recently been called superbacteria. As resistance bacteria against existing antibiotics such as aureus and VRSA increase, the need for development of a substance or a drug having resistance to antibiotics is being emphasized more. That is, attention is focused on the development of a medicament with a new mechanism of action that can replace existing antibiotics. Therefore, there is a need for a target-specific search method and securing new resources for the development of new active substances.

The inventors of the present invention while studying a compound having excellent inhibitory activity against a particular bacterium, the novel cyclic depsipeptide-based compound, the optical isomer thereof, or a pharmaceutically acceptable salt thereof according to the present invention is Staphylococcus aureus And excellent anti-inflammatory activity against Salmonella typhimurium ( Salmonella typhimurium ) confirmed that it is useful for antimicrobial composition, antimicrobial pharmaceutical composition, antimicrobial feed composition or antimicrobial cosmetic composition, and bacterial infectious treatment using the same and completed the present invention. .

An object of the present invention is to provide a compound having an inhibitory activity against Staphylococcus aureus and Salmonella typhimurium , an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the compound, optical isomer thereof, or pharmaceutically acceptable salt thereof.

Still another object of the present invention is to provide an antimicrobial composition containing the compound, the optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide a pharmaceutical composition for antimicrobial containing the compound, the optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide an antimicrobial feed composition containing the compound, the optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Still another object of the present invention is to provide an antimicrobial cosmetic composition containing the compound, the optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another object of the present invention is to provide a Streptomyces sp . KCB13F003 strain producing the compound.

Another object of the present invention is to provide a method of treating bacterial infectious diseases, comprising administering the pharmaceutical composition to a subject.

Since the novel cyclic depsipeptide compounds, optical isomers thereof, or pharmaceutically acceptable salts thereof according to the present invention exhibit inhibitory activity against Staphylococcus aureus and Salmonella typhimurium , The composition, the antimicrobial pharmaceutical composition, the antimicrobial feed composition or the antimicrobial cosmetic composition, and can be usefully used for the treatment of bacterial infectious diseases.

1 shows a ¹ H NMR spectrum (800 MHz, DMSO-d ₆ ) of the compound represented by Formula A prepared in Example 4. FIG.

Figure 2 shows a ¹³ C NMR spectrum (200 MHz, DMSO-d ₆ ) of the compound represented by Formula A prepared in Example 4.

3 shows a ¹ H NMR spectrum (700 MHz, DMSO-d ₆ ) of the compound represented by Formula B prepared in Example 4. FIG.

Figure 4 shows a ¹³ C NMR spectrum (225 MHz, DMSO-d ₆ ) of the compound represented by Formula B prepared in Example 4.

One aspect of the present invention for achieving the above object is a compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1]

In Chemical Formula 1,

R ¹ is —H, —OH, halogen, nitrile, C _1-10 straight or branched chain alkyl, or C _1-10 straight or branched chain alkoxy.

Preferably,

R ¹ is —H, —OH, halogen, C _1-5 straight or branched alkyl, or C _1-5 straight or branched alkoxy.

More preferably,

R ¹ is -H or -OH.

The compound represented by Formula 1 of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid, aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioate, aromatic acids, aliphatic and aromatic sulfonic acids, and organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically nontoxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, eye Odide, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suve Latex, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitro benzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobene Sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycolate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1 Sulfonates, naphthalene-2-sulfonates, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, a precipitate produced by dissolving a derivative of Formula 1 in an organic solvent such as methanol, ethanol, acetone, methylene chloride, acetonitrile and adding an organic or inorganic acid. The solvent may be prepared by filtration and drying, or by distillation under reduced pressure of the solvent and excess acid, followed by drying and crystallization in an organic solvent.

Bases can also be used to make pharmaceutically acceptable metal salts. Alkali metal or alkaline earth metal salts are obtained, for example, by dissolving a compound in an excess of alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is pharmaceutically suitable to prepare sodium, potassium or calcium salt as the metal salt. Corresponding salts are also obtained by reacting alkali or alkaline earth metal salts with a suitable negative salt (eg silver nitrate).

Furthermore, the present invention includes not only the compound represented by Formula 1 and pharmaceutically acceptable salts thereof, but also solvates, optical isomers, hydrates, and the like that can be prepared therefrom.

The novel cyclic depsipeptide compounds of the present invention are compounds prepared from terrestrial soil actinomycetes, preferably Streptomyces sp., More preferably Streptomyces sp. KCB13F003 strain. It has a chemical structure that is unknown to.

In another embodiment, Streptomyces sp . ) Culturing the KCB13F003 strain to obtain a strain culture (step 1);

Extracting the strain culture obtained in step 1 to obtain an extract (step 2); And

Purifying the extract obtained in step 2 (step 3); It is a method of producing a compound represented by the formula (1) comprising.

Hereinafter, a method for preparing a compound represented by Chemical Formula 1 according to the present invention will be described in detail step by step.

ㅍ displayed and by the general formula (1) according to the present invention is a process for producing the compound, the step 1 is genus Streptomyces (Streptomyces sp . ) Is a step of obtaining a strain culture by culturing the KCB13F003 strain. Specifically, the culture of the strain is cultured in a medium containing a nutrient source that can be used by conventional microorganisms. As a nutrient source, the well-known nutrient source conventionally used for the culturing of actinomycetes is used. For example, as a carbon source, glucose, starch syrup, dextrin, starch, molasses, animal oil, vegetable oil, etc. may be used, and as nitrogen sources, bran, soybean meal, wheat, malt, cottonseed gourd, fishmeal, corn steep liquor, gravy, yeast Extracts, ammonium sulfate, sodium nitrate, urea and the like can be used. If necessary, it is very effective to add salts, potassium, magnesium, cobalt, chlorine, phosphoric acid, sulfuric acid and other inorganic salts that promote ion generation. As a culture method, shaking culture or political culture is possible under aerobic conditions.

The culture temperature is slightly different depending on the conditions when incubated in each of the above conditions, but in general it is preferable to culture at 20 to 37 ℃, more preferably at 25 to 30 ℃.

In the method for preparing a compound represented by Formula 1 according to the present invention, Step 2 is a step of extracting the strain culture obtained in Step 1 with a solvent to obtain an extract. In general, the cyclic depsipeptide compound is present in the culture part of the strain as well as in the cell part. Therefore, a solvent is added to the culture medium and the cells of the strain to extract the active ingredient from the culture medium and the cells, and the obtained extract is concentrated by a vacuum evaporation method.

At this time, the solvent is preferably ethyl acetate.

In the method for preparing a compound represented by Formula 1 according to the present invention, Step 3 is a step of purifying the extract obtained in Step 2. Specifically, the extract obtained in step 2 is subjected to flash column chromatography using a methanol: water mixed solvent, and then purified by high performance liquid chromatography to prepare a compound represented by Chemical Formula 1.

Another embodiment is an antimicrobial composition containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Here, the bacteria may be Staphylococcus sp . Bacteria or Salmonella sp . Bacteria, and more preferably, the Staphylococcus sp . Bacteria or Salmonella sp . The bacteria may be Staphylococcus aureus or Salmonella typhimurium, respectively, but are not limited thereto.

Another embodiment is an antimicrobial pharmaceutical composition containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In this regard, as a result of experiments to evaluate the antimicrobial activity of the compounds represented by Formula A and Formula B according to the present invention, the compounds represented by Formula A and Formula B according to the present invention are Salmonella and Staphylococcus aureus It was shown to have a specific antibiotic effect against (see Table 4 of Experimental Example 2).

Therefore, the novel cyclic depsipeptide compounds, optical isomers, or pharmaceutically acceptable salts thereof according to the present invention exhibit inhibitory activity against Staphylococcus aureus and Salmonella typhimurium . It can be usefully used as a composition for use, an antimicrobial pharmaceutical composition, an antimicrobial feed composition or an antimicrobial cosmetic composition.

The compounds according to the invention are generally administered in the form of a pharmaceutical composition comprising the active compound of the invention and comprising a pharmaceutically acceptable carrier or carrier suitable for use in pharmaceutical preparations.

Another embodiment is a method of treating a bacterial infectious disease comprising administering the pharmaceutical composition to a subject having a disease caused by various bacteria at a therapeutically effective dosage. At this time, the composition may be used alone or in combination with other pharmaceutical compositions.

Specifically, the bacteria may be Staphylococcus aureus or Salmonella typhimurium , and the bacterial infectious diseases include dermatitis, skin infection, food poisoning, pneumonia, meningitis, osteomyelitis, endocarditis, Toxic shock syndrome (TSS), Bacteremia, or sepsis, but may be a bacterium exhibiting antimicrobial activity through the pharmaceutical composition of the present invention and the disease caused by the type is not particularly limited.

As used herein, the term "treatment" means any action that improves or benefits the symptoms of bacterial infectious diseases caused by various bacteria by administration of the composition.

The term "therapeutically effective dosage", "therapeutically effective amount" or "effective amount" as used herein means an amount of pharmaceutical composition that is sufficiently contained to result in a therapeutic response. A therapeutic response may be any response that a user (ie, a clinical investigator) will recognize as an effective response to treatment by evaluating symptoms and surrogate clinical markers. Thus, the therapeutic response will generally be alleviation of one or more symptoms of the disease or disorder.

The term "individual" in the present invention means a living organism, and means a mammal, although not particularly limited thereto.

The term "mammal" of the present invention includes, for example, mice, rats, rabbits, dogs, cats, and especially humans, and "mammals" of higher vertebrates that nourish their offspring with milk secreted by the mammary glands. "Means any organism of the class.

The preferred dosage of the pharmaceutical composition of the present invention depends on the condition and weight of the patient, the extent of the disease, the form of the drug, the route of administration and the duration, and may be appropriately selected by those skilled in the art. However, for the desired effect, the pharmaceutical composition of the present invention is preferably administered at 0.01 to 100 mg / kg (body weight) per day, preferably 0.001 to 100 mg / kg. Administration may be once a day or may be divided several times.

The pharmaceutical composition may be administered to various mammals such as rats, mice, livestock, humans, and the like. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.

Another embodiment is an antimicrobial feed composition containing the compound represented by Chemical Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another embodiment is an antimicrobial cosmetic composition containing the compound represented by Formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

Another embodiment, the Streptomyces genus ( Streptomyces ) for producing a compound represented by the formula sp . ) KCB13F003 strain.

Hereinafter, the present invention will be described in more detail with reference to the following examples. These examples are only for illustrating the present invention, and the scope of the present invention is not to be construed as being limited by these examples.

< Example  1> Genus Streptomyces ( Streptomyces sp . ) KCB13F003  Isolation of Strains

This strain was isolated from Ulleungdo soil samples in August 2013. Collected soil samples were stored in a sterilized plastic bag immediately after collection and refrigerated until use. Soil samples were diluted 10-fold with sterile distilled water. 1 ml of the diluent was smeared on Starch-Yeast extract agar medium and incubated at 28 ° C. for 5 days to purely separate colonies.

< Example  2> Identification and Naming of Strains

GenBack search results of the nucleotide sequence obtained through rRNA sequence analysis of the strain, Streptomyces sp . ) Was 99.58% homology to (SEQ ID NO: 1). Therefore, this strain was identified as Streptomyces genus, Streptomyces genus sp . KCB13F003, and the strain was deposited on December 9, 2014, with the accession number KCTC12731BP to the Korean Collection for Type Cultures (KCTC), an international depository institution under the Budapest Treaty.

< Example  3> Genus Streptomyces ( Streptomyces sp . ) KCB13F003  Cultivation of Strains

In order to culture the actinomycetes strain, a medium containing a nutrient source normally used by microorganisms was prepared. As crude and production medium of actinomycetes 2.0% (w / v) glycerol, 1.0% (w / v) lactose, 0.5% (w / v) malt extract, 0.5% (w / v) yeast extract, 0.1% (w / v) GLY medium containing calcium carbonate was used.

After sterilizing a 500 ml Erlenmeyer flask containing 100 ml of the medium for 15 minutes at 121 ° C., Streptomyces sp . ) Platinum was inoculated from the slope culture tube of KCB13F003 strain, shake cultured for 3 days, and seed culture. 30 ml of a 1,000 ml Erlenmeyer flask containing 250 ml of production medium was inoculated with 3 ml of each species culture medium, followed by shaking culture at 28 ° C. for 5 days.

< Example  4> annular Depsi Peptides  Preparation of the compound

Streptomyces genus cultured in Example 3 sp . ) The culture of KCB13F003 strain was extracted with ethyl acetate (15 L), and the obtained extract was concentrated by a reduced pressure evaporator using a vacuum dryer. The concentrated solution was adsorbed on ODS18 and subjected to ODS RP-18 flash column chromatography, where methanol / water (8: 2-10 / 0, v / v) was mixed. The solvent was eluted with increasing methanol concentration step by step. At this time, the fraction containing the compound represented by the following formula A (named Ulleungamide A) and formula B (named Ulleungamide B) was eluted in 80% methanol. After concentrating the fraction under reduced pressure, using a high performance liquid chromatography (column: Optimapak C18, length 25 mm, diameter 10 mm), acetonitrile and water were dissolved in a 40:60-80:20 concentration gradient as a solvent. Elution was carried out in ml / min conditions to prepare a compound represented by the formula (A) showing a UV absorption peak of 210 nm at 17 minutes.

[Formula A]

The same fraction was eluted with acetonitrile and water using a same column at a concentration gradient of 40:60-52:48 at an elution rate of 3 ml / min, and the 210 nm UV absorption peak was shown by the following Chemical Formula B at 19 minutes. The resulting compound was prepared.

[Formula B]

< Experimental Example  1> annular Depsi Peptides  Structural Analysis of Compounds

Streptomyces of the Actinomycetes Streptomyces sp . The molecular weight and molecular formula of the compound represented by Formula A prepared from the culture medium of KCB13F003 strain were determined using an ESIMS mass spectrometer. In addition, ¹ H NMR, ¹³ C NMR, Correlation Spectroscopy (COSY), HMQC (Nuclear Magnetic Resonance (NMR) analysis (Bruker Biospin Advance II 900 NMR spectrometer, Bruker AVANCE HD 800 NMR spectrometer, Bruker AVANCE HD 700 NMR spectrometer) 1H-Detected heteronuclear Multiple-Quantum Coherence (HMBC), Heteronuclear Multiple-Bond Coherence (HMBC), Distortionless Enhancement by Polarization (DEPT), and Nuclear Overhauser effect spectroscopy (NOESY) spectra were obtained and the molecular structure of the compound was determined.

Was measured result is equal to the genus Streptomyces (Streptomyces sp . A material prepared from the culture solution of the KCB13F003 strain was identified as a novel cyclic depsipeptide compound represented by Formulas (A) and (B).

Compound represented by the formula (A) is phenylalanine, glycine, threonine, N-methyl-phenylalanine, 2-isopropylsuccinic acid, 5-hydroxy-6-methyl-2,3-dehydropipecolic acid, pipecolic acid, 4-hydroxy It was identified that this is a novel depsipeptide compound composed of pipecolic acid ( ¹ H, ¹³ C NMR data is shown in Table 1 below).

Compound represented by formula A: white powder; [α] _D +88.4 ( c 0.05, MeOH); UV (MeOH) λ _max (log ε) 204 (3.6), 210 (3.3); HRESIMS m / z 986.4861 [M + H] ⁺ (calcd for C ₅₁ H ₆₈ N ₇ O ₁₃ , 986.4875).

	δ C b , type	δ H c , mult ( J in Hz)		δ C b , type	δ H c , mult ( J in Hz)
5-hydroxy-6-methyl- 2,3-dehydropipecolic acid			Glycine
One	162.3, C		29	168.0, C
2	129.4, C		30	40.5, CH 2	4.54, m
3	120.2, CH	5.98, s			3.48, m
4	27.3, CH 2	2.28, ovl a 2.01, ovl a	30-NH		8.04, d (7.5)
			Threonine
5	65.2, CH	3.75, s	31	167.4, C
6	53.6, CH	3.93 d (5.7)	32	54.6, CH	4.77, d (9.1)
7	14.5, CH 3	0.97, ovl a	33	71.4, CH	5.48, bd (3.1)
5-OH		4.79, ovl a	34	15.9, CH 3	0.97, ovl a
Pipecolic acid			32-NH		7.69, d (8.1)
8	170.6, C		N- methyl -Phenylalanine
9	50.2, CH	5.56, ovl a	35	170.9, C
10	26.7, CH 2	1.94, m1.59, ovl a	36	56.7, CH	5.57, ovl a
			37	34.7, CH 2	3.20, dd (14.4, 5.4)
11	19.6, CH 2	1.53, ovl a 1.31, m			2.90, dd (13.8, 11.0)
			38	137.8, C
12	24.7, CH 2	1.52, ovl a 1.24, m
			39	129.4, CH	7.20, ovl a
			40	128.8, CH	7.23, ovl a
13	42.7, CH 2	3.89, bd (13.3) 3.10, t (12.5)
			41	126.1, CH	7.16, ovl a
Phenylalanine			42	128.8, CH	7.23, ovl a
14	170.0, C		43	129.4, CH	7.20, ovl a
15	48.4, CH	5.15, dd (16.2, 8.4)	44	31.3, CH 3	2.94, s
16	37.6, CH 2	3.00, ovl a 2.82, dd (13.6, 8.5)	2- Isopropyl Succinate
			45	172.0, C
17	137.6, C		46	31.8, CH 2	2.52, ovl a
18	129.4, CH	7.20, ovl a			2.10, d (14.9)
19	128.8, CH	7.23, ovl a	47	46.8, CH	2.48, ovl a
20	126.2	7.16, ovl a	48	29.2, CH	1.73, m
21	128.8	7.23, ovl a	49	19.7, CH 3	0.78, d (6.4)
22	129.4	7.20, ovl a	50	19.7, CH 3	0.76, d (6.4)
15-NH		8.90, d (9.4)	51	175.6, C
4- Hydroxypipecolic acid
23	170.8, C
24	52.4, CH	4.29, m
25	33.2, CH 2	1.82, ovl a 1.41, m
26	61.9, CH	3.65, bs
27	31.3, CH 2	1.59, ovl a 1.45, m
28	34.1, CH 2	4.17, m3.19, ovl a
26-OH		4.43, bs

In Table 1 above,

^a represents an overlapping signal;

^b shows a measurement at 200 MHz; And

^c indicates a measurement at 800 MHz.

Compound represented by the formula (B) is phenylalanine, glycine, threonine, N-methyl-phenylalanine, 2-isopropyl succinic acid, pipecolic acid, 4-hydroxy pipecolic acid is the same as the compound represented by the formula A, A novel structure in which 5-hydroxy-6-methyl-2,3-dehydropipecolic acid of the compound represented by 4 is converted into 4,5-dihydroxy-6-methyl-2,3-dehydropipecolic acid ( ¹ H, ¹³ C NMR data is shown in Table 2 below).

Compound represented by formula B: white powder; [α] _D +69.6 ( c 0.05, MeOH); UV (MeOH) λ _max (log ε) 204 (3.6); HRESIMS m / z 1002.4818 [M + H] ⁺ (calcd for C ₅₁ H ₆₈ N ₇ O ₁₄ , 1002.4824).

	δ C b , type	δ H c , mult ( J in Hz)		δ C b , type	δ H c , mult ( J in Hz)
4,5- Dihydroxy -6- methyl - 2,3- Dehydropipecolic acid			Glycine
One	162.4, C		29	168.1, C
2	130.4, C		30	40.4, CH 2	4.56, dd (18.0, 7.4) 3.43, ovl a
3	121.4, CH	5.73, s
4	62.9, CH	4.16	30-NH		8.04, d (7.7)
5	66.9, CH	3.60, bs	Threonine
6	56.0, CH	4.08, m	31	167.3, C
7	14.5, CH 3	1.09, d (6.6)	32	54.5, CH	4.77, dd (9.1, 2.3)
4-OH		Not detected	33	71.7, CH	5.49, dd (6.0, 3.1)
5-OH		4.82, ovl a	34	15.7, CH 3	0.97, d (6.2)
Pipecolic acid			32-NH		7.79, d (8.2)
8	170.9, C		N- methyl -Phenylalanine
9	50.2, CH	5.54, ovl a	35	170.9, C
10	26.9, CH 2	1.89, m 1.57, m	36	56.8, CH	5.53, ovl a
			37	34.8, CH 2	3.22, dd (14.1, 5.7)
11	19.6, CH 2	1.54, ovl a 1.28, ovl a			2.89, dd (14.1, 10.5)
			38	137.8, C
12	24.7, CH 2	1.50, ovl a 1.24, ovl a
			39	129.3, CH	7.20, ovl a
			40	128.8, CH	7.26, ovl a
13	42.6, CH 2	3.91, t (14.0) 3.08, t (12.2)
			41	126.2, CH	7.16, ovl a
Phenylalanine			42	128.8, CH	7.26, ovl a
14	169.8, C		43	129.3, CH	7.20, ovl a
15	48.4, CH	5.13, ovl a	44	31.5, CH 3	2.92, s
16	37.6, CH 2	3.00, ovl a 2.82, dd (13.6, 8.5)	2- Isopropyl Succinate
			45	171.9, C
17	137.6, C		46	31.9, CH 2	2.53, ovl a
18	129.3, CH	7.20, ovl a			2.09, dd (16.1, 3.5)
19	128.8, CH	7.26, ovl a	47	46.8, CH	2.46, m
20	126.2, CH	7.16, ovl a	48	29.3, CH	1.73, m
21	128.8, CH	7.26, ovl a	49	19.7, CH 3	0.78, ovl a
22	129.3, CH	7.20, ovl a	50	19.7, CH 3	0.76, ovl a
15-NH		8.95, d (9.8)	51	175.6, C
4- Hydroxypipecolic acid
23	170.8, C
24	52.5, CH	4.27, m
25	33.3, CH 2	1.81, m 1.39, m
26	61.9, CH	3.65, bs
27	31.3, CH 2	1.60, m1.43, m
28	34.3, CH 2	4.17, m 3.16, t (12.8)
26-OH		4.43, ovl a

In Table 2 above,

^a represents an overlapping signal;

^b shows a measurement at 200 MHz; And

^c indicates measurement at 800 MHz.

< Experimental Example  2> Antimicrobial Activity Evaluation

Strains obtained from the accumulation culture collection of the Korea Gene Bank (KCTC) were used for the antimicrobial activity evaluation study, which is shown in Table 3 below.

Strain	badge
Salmonella typhimurium (KCTC 1926)	NA
Staphylococcus aureus , KCTC 1916)	LB agar
Enterococcus faecalis , KCTC 3206)	Brain Heart Infusion Agar
Bacillus subtilis (KCTC 1022)	NA
Escherichia coli coli , KCTC 1039)	Brain Heart Infusion Agar
Micrococcus luteus , IAM 1056)	ENB Agar
Candida albicans (Candida albicans , KCTC 7678)	YM Agar
Penicillium penicillium griseofulvum , KCTC 6435)	Malt Extract Agar

In Table 3 above,

NA (Nutrient Agar): [0.3% (w / v) meat extract, 0.5% (w / v) peptone, 1.5% (w / v) agar];

LB (Lysogeny broth) Agar: [1% (w / v) tryptone, 0.5% (w / v) yeast extract, 1% (w / v) NaCl, 1.5% (w / v) agar;

Brain Heart Infusion Agar: shows [3.7% (w / v) BHI medium (brain heart infusion broth, Difco 0037), 1.5% (w / v) agar];

ENB (Enriched Nutrient Broth) Agar: [1.25% (w / v) HI medium (heart infusion broth, difco 0038), 0.54% (w / v) nutrient broth (Difco 0003), 0.25% (w / v) yeast extract];

YM Agar: [0.3% (w / v) yeast extract, 0.3% (w / v) malt extract, 0.5% (w / v) peptone, 1% (w / v) dex Troose, 2% (w / v) agar]; And

Malt Extract Agar: [2% (w / v) malt extract, 2% (w / v) glucose, 0.1% (w / v) peptone, 2% (w / v) agar].

The antimicrobial activity was evaluated by the paper disc method. Pour agar medium containing each test bacteria solution into a petri dish, make a flat medium, and absorb 100 grams, 50 ug, and 30 ug of the compound represented by the formula (A) and the formula (B) into the sterilized paper disc. Put on the prepared activity evaluation plate medium, 37 ℃ (S. Salmonella, Staphylococcus aureus, Enterococcus faecalis, Escherichia coli) and 28 ° C (Bacillus subtilis, Microcaucasus Luteus, Candida Albicans, 18 hours of incubation in the penicillium griseoprum) was used to measure the clear zone (mm) around the disc. The results are shown in Table 4 below.

Strain	Clear zone (mm)
	Compound A (μg / disc)			Compound B (μg / disc)
	100	50	30	100	50	30
Salmonella typhimurium (KCTC 1926)	12.7	9.8	-	-	-	-
Staphylococcus aureus , KCTC 1916)	17.6	13.7	10.8	13.0	-	-
Enterococcus faecalis , KCTC 3206)	-	-	-	-	-	-
Bacillus subtilis (KCTC 1022)	-	-	-	-	-	-
Escherichia coli coli , KCTC 1039)	-	-	-	-	-	-
Micrococcus luteus , IAM 1056)	-	-	-	-	-	-
Candida albicans (Candida albicans , KCTC 7678)	-	-	-	-	-	-
Penicillium penicillium griseofulvum , KCTC 6435)	-	-	-	-	-	-

In Table 4 above,

The symbol "-" indicates no activity against the strain.

As shown in Table 4, the compounds represented by Formula A and Formula B according to the present invention were shown to have a specific antibiotic effect against Salmonella and Staphylococcus aureus.

Therefore, the novel cyclic depsipeptide compounds, optical isomers, or pharmaceutically acceptable salts thereof according to the present invention exhibit inhibitory activity against Staphylococcus aureus and Salmonella typhimurium . It can be usefully used for the treatment of a composition for use, an antimicrobial pharmaceutical composition, an antimicrobial feed composition or an antibacterial cosmetic composition, and a bacterial infectious disease.

On the other hand, the compounds of the present invention can be formulated in various forms according to the purpose. Examples of preparations for the compositions of the present invention are illustrated below.

< Formulation example  1> Preparation of flexible lotion

Butylene glycol, glycerin, polyoxyethylene (60) hardened castor oil, betaine, citric acid, sodium citrate, and preservatives were added to the purified water, followed by stirring and dissolving. The compound represented by the formula (1) according to the present invention was added thereto, sufficiently stirred, and aged to prepare a flexible lotion. Table 5 shows the content of each component.

Raw material	Content (w / w%)
Compound represented by formula (1)	50.0
Butylene Glycol	7.0
glycerin	5.0
Polyoxyethylene (60) hardening castor oil	0.2
ethanol	5.0
Betaine	2.0
Citric acid	0.02
Sodium citrate	0.06
antiseptic	a very small amount
Spices	a very small amount
Purified water	a very small amount

< Formulation example  2> Manufacture of nutritional lotion

The compound represented by the formula (1), butylene glycol, glycerin, carboxyvinyl polymer, arginine, preservative and purified water according to the present invention were heated with stirring at 70 to 75 ℃. Squalane, butylene glycol dicaprylate / dicaprate, sorbitan stearate, polysorbate 60, glyceryl stearate and stearyl glycerate mixture, which were heated by stirring at 75 to 80 ° C. were added thereto, followed by emulsification. While stirring, the fragrance was added and cooled to about 45 degreeC. Thereafter, the mixture was cooled to 30 ° C., and aged to prepare nutrient cosmetics. Table 6 shows the content of each component.

Raw material	Content (w / w%)
Compound represented by formula (1)	40.0
Butylene Glycol	8.0
glycerin	5.0
Squalane	10.0
Butylene Glycol Dicaprylate / Dicaprate	5.0
Sorbitan stearate	1.5
Polysorbate 60	1.0
Glyceryl Stearate	0.5
Stearyl glycyrrhetinate	0.2
Carboxy Vinyl Polymer	0.1
Arginine	0.1
antiseptic	a very small amount
Spices	a very small amount
Purified water	a very small amount

< Formulation example  3> Preparation of Essence

Agitate and mix the cytositrol, polyglyceryl 2-oleate, ceramide, ceteareth-4 and cholesterol, and then stir the cytositrol, polyglyceryl 2-oleate, ceramide, ceteareth-4 and cholesterol It was mixed and emulsified by adding a compound represented by the formula (1) of the present invention, dicetyl phosphate, concentrated glycerin and purified water. Then, when it cooled to 45 degreeC, stirring, the fragrance was added, it stirred, it cooled to 30 degreeC, and it aged. Essence was prepared by stabilizing and adding carboxyvinyl polymer, xanthan gum and preservatives thereto. Table 7 shows the content of each component.

Raw material	Content (w / w%)
Compound represented by formula (1)	10.0
Sito stero	1.7
Polyglyceryl 2-oleate	1.5
Ceramide	0.7
Ceteares-4	1.2
cholesterol	1.5
Dicetylphosphate	0.4
Concentrated glycerin	0.5
Carboxy Vinyl Polymer	0.2
Xanthan Gum	0.2
antiseptic	a very small amount
Spices	a very small amount
Purified water	a very small amount

< Formulation example  4> Manufacture of ointments

According to the formulation shown in Table 8 below, ointment was prepared by a conventional method.

Ingredient Name	role	Compounding amount (% by weight)
vaseline		40.0
Stearyl alcohol		15.0
Wood		15.0
POE (10) Olate		0.25
Glyceryl Monostearate		0.25
Allantoin	Anti-inflammatory Ingredients (Whitening Ingredients)	1.0
Sorbitol	Moisturizing ingredients	5.0
Propylene glycol		5.0
Gentiana Extract * 1	Moisturizing ingredients	0.3
Compound represented by formula (1)		6.0
antiseptic		A reasonable amount
Ion exchange water		Remaining amount

^{* 1} : Gentiana extract BG (made by Maruzen Pharmaceutical Co., Ltd.) was used as a gentian extract.

From the above description, those skilled in the art will appreciate that the present application can be implemented in other specific forms without changing the technical spirit or essential features. In this regard, it should be understood that the embodiments described above are exemplary in all respects and not limiting. The scope of the present application should be construed that all changes or modifications derived from the meaning and scope of the following claims and equivalent concepts rather than the detailed description are included in the scope of the present application.

Claims (13)

1. A compound represented by formula 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:

   [Formula 1]

   

   (In Formula 1,

   R ¹ is —H, —OH, halogen, nitrile, C _1-10 straight or branched chain alkyl, or C _1-10 straight or branched chain alkoxy).
2. The method of claim 1,

   R ¹ is -H, -OH, halogen, compound, its enantiomer, or a pharmaceutically acceptable salt thereof as straight or branched chain alkyl, or wherein the linear or branched C _1-5 alkoxy C _1-5 of .
3. The method of claim 1,

   R ¹ is —H or —OH, the optical isomer thereof, or a pharmaceutically acceptable salt thereof.
4. Streptomyces sp . ) Culturing the KCB13F003 strain to obtain a strain culture (step 1);

   Extracting the strain culture obtained in step 1 to obtain an extract (step 2); And

   Purifying the extract obtained in step 2 (step 3); Method of producing a compound represented by the formula (1) comprising a.
5. An antimicrobial composition comprising the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
6. The method of claim 5,

   The bacterium is an antimicrobial composition, characterized in that Staphylococcus aureus or Salmonella typhimurium .
7. A pharmaceutical composition for antimicrobial containing a compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
8. An antimicrobial feed composition comprising the compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
9. An antimicrobial cosmetic composition containing a compound represented by Formula 1 of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
10. The genus Streptomyces that produces a compound of claim 1 (Streptomyces sp . ) KCB13F003 strain.
11. A method of treating bacterial infectious disease, comprising administering to a subject a pharmaceutical composition of claim 7.
12. The method of claim 11, wherein the bacterium is Staphylococcus aureus or Salmonella typhimurium.
13. The method of claim 11, wherein the bacterial infectious disease is dermatitis, skin infection, food poisoning, pneumonia, meningitis, osteomyelitis, endocarditis, Toxic shock syndrome, bacteremia, or sepsis.

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