WO2012086889A1 - Novel hispidin-based compound having an enoyl-reductase-inhibiting and an antimicrobial activity - Google Patents

Abstract

The present invention relates to a hispidin-based compound represented by chemical formula 1 or chemical formula 2, which exhibits an enoyl-reductase-inhibiting activity and an antimicrobial activity, and relates to a use therefor. The compound of the present invention strongly inhibits the activity of the Fab I and Fab K enzymes and therefore has a strong antimicrobial action against pathogenic microorganisms and antibiotic-resistant microbes, and, more particularly, exhibits a powerful antimicrobial action against MRSA and therefore can advantageously be used in the treatment of infectious diseases caused by superbacteria.

Description

Novel Hispidine Compounds with Enoyl Reductase Inhibition and Antimicrobial Activity

The present invention relates to hispidine-based compounds represented by the formula (1) or formula (2) showing the anoyl reductase inhibitory activity and antimicrobial activity and its use.

In general, direct or indirect damage caused by pathogenic microorganisms causes many economic, environmental and medical problems. Loss due to corruption during food distribution in the food industry, human health and environmental pollution from the use of excessive chemical pesticides on crops in the agricultural industry, and the emergence of antibiotic resistant strains due to the misuse of antibiotics. I'm making it. Although rational antibiotic therapy in the treatment of infectious diseases is an important factor in determining the patient's prognosis, the emergence of such antibiotic resistant strains has made it difficult to select effective antibiotics unlike the past.

For example, after the treatment of methicillin-resistant S. aureus (MRSA), which is only treated with vancomycin, the last treatment for staphylococcus, the most common cause of human infection, has been questioned since the 1970s, In 1988, vancomycin resistant Enterococcus (VRE) was first discovered in Europe, and in late 1990, vancomycin intermediate-resistant S. was resistant to vancomycin in Japan, the United States, France and Korea. aureus, VISA). Furthermore, vancomycin-resistant Staphylococcus aureus (VRSA), a highly resistant to vancomycin, was reported for the first time in the world by the Centers for Disease Control in 2002, suggesting the possibility of the so-called "superbacteria" spread. This is very high. Accordingly, the problem of antibiotic resistance has emerged as a global crisis, and the development of a new concept of antibiotics is urgently required.

Meanwhile, as a result of research into hospital microbial genomes, which began in the mid-1990s, new antibiotic targets were discovered and the possibility of developing a new concept of antibiotics began to open. One of the new antibiotic targets discovered and validated using microbial genome information, enoyl-ACP reductase, is responsible for the growth of microorganisms, responsible for the end of the elongation phase of the fatty acid synthesis cycle. As an essential enzyme, it is present in both Gram-positive and negative bacteria and is attracting attention as a new antibiotic target because of its very low homology with humans. In particular, as the action target of the fungicide triclosan and tuberculosis isoniazid, which have not been previously identified, has been reaffirmed as an antibiotic development point.

There are three isoforms of the enoyl reductase enzyme, Fab I, Fab K, and Fab L. Staphylococcus aureus, E. coli, etc. Fab I is common in most major pathogenic bacteria, and only Fab K is present in pneumococci.

Therefore, new Fab I inhibitors are promising as a new concept of therapeutic agent capable of treating existing antibiotic resistant bacteria. In addition, new Fab K inhibitors are promising as therapeutics for pneumococci.

Accordingly, the present inventors have made intensive efforts to develop Fab I and Fab K inhibitors from natural products such as microorganisms and plants, and as a result, novel Felinstatin compounds isolated from Phellinus linteus 08090-29 strains strongly inhibit Fab I and Fab K. As well as confirming that it exhibits antimicrobial activity against resistant bacteria, the present invention was completed. In addition, the present inventors confirmed that the hispidine compound not only strongly inhibits Fab I and Fab K but also exhibits antibacterial activity against resistant bacteria, and completed the present invention.

An object of the present invention is to provide an antimicrobial composition comprising a compound represented by Formula 1 or Formula 2, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof.

It is another object of the present invention to provide an inhibitor of an anoyl reductase activity comprising a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof.

Another object of the present invention to provide an antimicrobial composition for antimicrobial comprising a compound represented by the formula (1) or (2) as an active ingredient.

Another object of the present invention comprises administering a compound represented by the formula (1) or (2), or a pharmaceutically acceptable salt thereof to an individual who has developed an infectious disease caused by a pathogenic microorganism or resistant bacteria. It is to provide a method for treating a disease.

Another object of the present invention is to inhibit the anoyl reductase activity of pathogenic microorganisms or resistant bacteria in a subject, comprising administering to the subject a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof. To provide a way.

Another object of the present invention is to provide a use for the preparation of the antimicrobial agent of the compound represented by the formula (1) or (2), or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a method for preparing the compound.

Another object of the present invention is to provide a compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.

The compound of the present invention strongly inhibits the activity of Fab I and Fab K enzymes, thereby having a strong antimicrobial activity against pathogenic microorganisms and antibiotic resistant bacteria, and particularly exhibiting a strong antimicrobial activity against MRSA to treat infectious diseases caused by superbacteria. It can be useful.

As one embodiment for achieving the above object, the present invention provides an antimicrobial composition comprising a compound represented by the following formula (1) or (2), isomers, derivatives thereof, or a pharmaceutically acceptable salt thereof.

[Formula 1: Pelinstatin]

[Formula 2: Hispidine]

Compounds of the present invention include not only pelinstatin or hispidine, but also isomers, derivatives, or pharmaceutically acceptable salts thereof. The pelinstatin was first discovered by the present inventors as a hispidine-based compound.

In the present invention, the 'isomer' refers to a relationship between compounds having the same chemical formula but not identical, and the kind of such isomers includes structural isomers, geometric isomers, optical isomers, and geometric isomers. A stereoisomer means a compound having the same chemical composition but different in terms of the arrangement of atoms or groups in space, and an optical isomer (enantiomer) means two stereoisomers of a compound having mirror images that do not overlap each other, and diastereomers Isomers refer to stereoisomers that have two or more asymmetric centers and whose molecules are not mirror images of each other.

In the present invention, "derivative" means a compound obtained by substituting a part of the structure of a pelinstatin or hispidine compound with another atom or group of atoms, and a "pharmaceutically acceptable salt" means a relatively non-toxic inorganic and organic acid addition of the compound. Salt.

The compound of the present invention has excellent anoyl reductase inhibitory activity. In particular, the compounds of the present invention show good inhibitory activity against Fab I or Fab K. In the present invention, the term "Fab I" or "Fab K" refers to the heterostructure of the anoyl reductase, which is an enzyme that is currently attracting attention as an antibiotic target, and the compound of the present invention effectively reduces the Fab I or Fab K. By inhibiting it can be used as an antimicrobial material.

In one embodiment of the present invention, for example, the enzyme inhibitory ability of Felinstatin to Fab I of Staphylococcus aureus, which is a major pathogen, was measured. As a result, IC ₅₀ of Felinstatin was 6 μM, indicating strong Fab I activity. Suppression. In addition, IC ₅₀ of the pellinstatin against Fab K of Streptococcus pneumoniae, the causative agent of pneumonia, was found to strongly inhibit Fab K activity as 5.8 μM (Example 3 and Table 2).

In addition, in one embodiment of the present invention, the enzyme inhibitory ability of hispidine to Fab I of Staphylococcus aureus, an exemplary pathogen, was measured. As a result, IC ₅₀ of hispidine was 12.6 μM and Fab I activity. It can be seen that the strong inhibition. In addition, the IC ₅₀ of hispidine against Fab K of Streptococcus pneumoniae, the causative agent of pneumonia, was found to strongly inhibit Fab K activity as 6.4 μM (Example 3 and Table 2). These results support that the compound of the present invention can be used as an antimicrobial composition.

The compounds of the present invention can be synthesized according to methods commonly used in the art, and can also be obtained as natural compounds produced from strains. The compound of the present invention may preferably be produced from a Pelinus linteus strain, more preferably from a Pelinus linteus strain 08090-29. In the present invention, the term "pellinus linteus" refers to a situation mushroom strain, and the inventors of the present invention was first isolated from the situation mushroom strain of the pellinstatin of the formula (1), the hispidine of formula (2) has an antimicrobial effect First identified.

As another aspect, the present invention provides an inhibitor of the anoyl reductase activity comprising a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof.

In the present invention, the enoyl-ACP reductase is the reduction of the enoyl-acyl carrier protein (ACP) at the last stage of the four reactions included in each cycle of the fatty acid biosynthesis of the bacteria. By bacterial enzyme is believed to function as an enzyme.

The enzyme is widely distributed in bacteria and plants, and is a protein enzyme necessary for synthesizing the lipids constituting the bacterial biofilm, and three isoforms of Fab I, Fab K, and Fab L exist. Fab I is commonly present in pathogenic bacteria such as Staphylococcus aureus, methicillin-resistant staphylococci and quinolone-resistant staphylococci, and Fab K is known to be mainly present in pneumonia strains.

Preferably, the enoyl reductase may be Fab I or Fab K, and in one embodiment of the present invention, the compound represented by Formula 1 or Formula 2 has inhibitory activity against Fab I and Fab K. It confirmed (Example 3 and Table 2).

As another aspect, the present invention is a pathogenic comprising administering a compound represented by the formula (1) or (2), or a pharmaceutically acceptable salt thereof to an individual suffering from an infectious disease caused by a pathogenic microorganism or resistant bacteria Provided are methods for treating infectious diseases caused by microorganisms or resistant bacteria.

In still another aspect, the present invention comprises the step of administering to a subject a compound represented by the formula (1) or (2), or a pharmaceutically acceptable salt thereof, the enoyl of the pathogenic microorganism or resistant bacteria in the subject Provided are methods for inhibiting reductase activity.

As used herein, the term "treatment" refers to any action that improves or advantageously changes the symptoms caused by an infectious disease caused by a pathogenic microorganism or resistant bacteria by administration of a pharmaceutical composition. As well as all animals, including humans, who may develop or may develop infectious diseases caused by resistant bacteria, as well as cells, blood, urine, water, soil, food, flora and intestines, flora and tissues or organisms themselves, and the composition of the invention By administering to, it is possible to effectively treat the disease or to inhibit the anoyl reductase activity of pathogenic microorganisms or resistant bacteria.

In the present invention, the pathogenic microorganisms are all microorganisms that cause disease or harm while invading the living organisms of animals and plants, and include bacteria, yeasts and fungi of Gram-positive bacteria and Gram-negative bacteria, preferably Staphylococcus aureus. Reus, Staphylococcus epidermis, Bacillus subtilis, Streptococcus pneumoniae or Candida albicans.

In the present invention, the resistant bacteria means that the bacterium exhibits resistance to antibiotics as a result of continuous use of the drug for treating or preventing any disease and complications thereof, or any bacterial disorders and complications thereof. Examples of such antibiotics include cephalosporins, quinolones and fluoroquinolones, penicillins, beta lactamase inhibitors, carbepenems, monobactams, macrolides and lincosamines, glycopeptides, rifampins, oxazolidinones, tetracyclines, aminoglycoses Seeds, streptogramamine and sulfonamides, and antibiotic-resistant bacteria are resistant even when the antibiotics listed above are treated, so that the disease is maintained continuously in the subject, preferably MRSA (methicillin-resistant Staphylococcus aureus) or QRSA ( Quinolone-resistant Staphylococcus aureus).

In one embodiment of the present invention, for example, the antimicrobial activity of the pellelin statin against Staphylococcus aureus, MRSA and Streptococcus pneumoniae was measured, and the MIC for each bacterium of the pellelin statin was all 128 μg. It was confirmed that the strong antimicrobial activity as / ml (Example 4 and Table 3).

In addition, in one embodiment of the present invention, the antimicrobial activity of hispidine against Staphylococcus aureus, MRSA and Streptococcus pneumoniae was measured. As 64 μg / ml, strong antimicrobial activity was confirmed (Example 4 and Table 3). Therefore, the antimicrobial composition of the present invention can be usefully used for the prevention or treatment of infectious diseases caused by pathogenic microorganisms or resistant bacteria.

For the treatment of the disease, the composition of the present invention may contain not only the compound of the present invention, but also at least one known active ingredient having antimicrobial activity against pathogenic bacteria. In addition, the composition of the present invention may further comprise a pharmaceutically acceptable carrier.

The term "pharmaceutically acceptable carrier" in the present invention refers to liquid or solid fillers involved in the transport or transport of any subject composition or component from one organ or part of the body to another organ or part of the body. Refers to a pharmaceutically acceptable material, composition or vehicle, such as a diluent, excipient, solvent or encapsulating material, wherein the composition of the present invention further comprises a pharmaceutically acceptable carrier, excipient or diluent in addition to the active ingredients described above for administration. It may include. The carrier, excipient and diluent may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, Polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.

In addition, the compositions of the present invention can be used in the form of powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, oral dosage forms, external preparations, suppositories, or sterile injectable solutions, respectively, according to conventional methods. have. Specifically, when formulated, it may be prepared using conventional diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrating agents, and surfactants. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like. Such solid preparations may be prepared by mixing at least one excipient such as starch, calcium carbonate, sucrose, lactose, gelatin and the like with the compound of Formula 1. In addition to simple excipients, lubricants such as magnesium stearate and talc may also be used. Liquid preparations for oral use include, but are not limited to, suspending agents, solvents, emulsions, syrups, and the like, and various excipients, such as wetting agents, sweeteners, fragrances, It can be prepared by adding a preservative or the like. Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and suppositories. As the non-aqueous solvent and suspending agent, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, injectable esters such as ethyl oleate and the like can be used. As the base of the suppository, utopsol, macrogol, tween 61, cacao butter, laurin butter, glycerogelatin and the like can be used.

In addition, the compositions of the present invention can be administered orally or parenterally (eg, intravenously, subcutaneously, intraperitoneally or topically) according to the desired method, and the dosage is determined by the condition and weight of the patient, disease Depending on the degree, drug form, route of administration, and duration, it may be appropriately selected by those skilled in the art. It may be administered once or several times daily as needed, and used alone or in combination with methods using surgery, hormone therapy, drug treatment and biological response modifiers for the prevention or treatment of pathogenic bacteria and resistant bacteria. Can be.

As another aspect, the present invention provides an antimicrobial composition for antimicrobial comprising the compound represented by the formula (1) or formula (2) as an active ingredient. That is, the present invention provides a quasi-drug composition for the purpose of preventing or improving infectious diseases caused by pathogenic microorganisms or resistant bacteria.

The quasi-drug composition of the present invention can be used together with other quasi-drugs or quasi-drug components, and can be suitably used according to a conventional method. The mixed amount of the active ingredient may be appropriately determined depending on the purpose of use (prevention, health or therapeutic treatment).

The quasi-drug composition may be a disinfectant cleaner, a shower foam, gagreen, wet tissue, detergent soap, hand wash, humidifier filler, mask, ointment or filter filler.

As another aspect, the present invention provides a use of the compound represented by the formula (1) or formula (2), or a pharmaceutically acceptable salt thereof for the production of antimicrobial agents.

Felinstatin represented by Formula 1 and hispidine represented by Formula 2 exhibit excellent antimicrobial activity against major pathogenic microorganisms and resistant bacteria, so that the compound or a pharmaceutically acceptable salt thereof is used as an antimicrobial agent, It can be usefully used for the prevention and treatment of infectious diseases.

In another aspect, the present invention provides a method for producing a bacterium comprising 1) culturing a Felinus linteus strain or a mutant thereof; 2) extracting the culture medium and mycelium of the strain obtained in step 1) with an organic solvent and then extracting with ethyl acetate; And 3) performing chromatography on the ethyl acetate extract obtained in step 2) to provide a compound according to the present invention.

In step 1), as well as the strain of Felinus Linteus, may include a strain (natural mutation or mutant strain) derived from the strain, a strain newly produced by a conjugate or genetic engineering method. In addition, the strain of Felinus linteus may be preferably a strain of Felinus linteus 08090-29.

The culture of the Felinus linteus strain or mutant strain thereof is cultured in a medium containing nutrients that can be used by conventional microorganisms. As a nutrient source, the well-known nutrient source currently used for the cultivation of a mold 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 the culture in each of the above conditions, it is usually suitable to incubate at 20 ~ 37 ℃, in most cases it is incubated at 26 ~ 30 ℃. In addition, in the culture period of shaking and stationary culture, the production of the pellelin statin compound of the present invention reached the highest when cultured for 7 days to 10 days.

Step 2) is a step of extracting the culture medium and mycelium of the Felinus linteus strain or its mutant strain, and the pelinstatin compound is present not only in the culture medium of the strain but also in the mycelium part. Therefore, by adding an organic solvent such as acetone to the culture medium and mycelium of the strain, extracting the active ingredient from the culture medium and the mycelium, acetone is evaporated under reduced pressure, solvent extraction with ethyl acetate, and the ethyl acetate solvent layer is concentrated under reduced pressure to remove ethyl acetate. do.

Step 3) is a step of separating the compound of the present invention, the purification and separation of the compound can be used without limitation the methods commonly used in the art, if necessary, the type of medium, culture conditions, extraction purification method, etc. It is obvious that the yield and yield can be controlled by changing the. In one embodiment of the present invention, the compound of the present invention was prepared by performing chromatography on ethyl acetate extract by the following method.

The ethyl acetate concentrate obtained in step 2) was subjected to silica gel column chromatography using chloroform: methanol in a ratio of 20: 1 to 1: 1, and the active fraction thus obtained was concentrated under reduced pressure to obtain an oily crude active ingredient. Purified by Sephadex ODS column chromatography. Finally, the active fractions were subjected to ODS TLC under a solvent condition of methanol: water = 60: 40, and again subjected to ODS TLC under acetonitrile: water = 30: 70 containing 0.1% TFA. Palinstatin and hispidine were obtained (Example 2).

As another aspect, the present invention provides a pelinstatin compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.

The Pelinstatin is a novel compound obtained by culturing Felinus linteus 08090-29 strain, which was obtained as a yellow powder, and has a molecular formula of C ₃₉ H ₂₇ O ₁₅ , having a molecular weight of 734.

Hereinafter, the present invention will be described in more detail with reference to Examples and Experimental Examples. However, the following examples are merely to illustrate the present invention, but the content of the present invention is not limited to the following examples.

Example 1 Culture of Phellinus linteus 08090-29 Strains

Species medium for the culture of Phellinus linteus 08090-29 strain from the National Academy of Agricultural Science, RDA, was 2% glucose, 0.5% polypeptone, 0.2% yeast extract, 0.1% KH ₂ PO ₄ , Medium containing 0.05% MgSO ₄ · 7H ₂ O was used after adjusting the pH to 5.6 to 5.8 before sterilization. The 100 ml Erlenmeyer flask containing 20 ml of the seed medium was sterilized at 121 ° C. for 20 minutes, inoculated with 1 platinum from a slope-test tube of Phellinus linteus 08090-29 strain, and incubated at 28 ° C. for 3 days, followed by 1 Tea seed culture was used. A 500 ml Erlenmeyer flask (48) containing sterile medium containing 2% glucose, 0.5% polypeptone, 0.2% yeast extract, 0.1% KH ₂ PO ₄ , 0.05% MgSO ₄ .7H ₂ O. Dogs) were inoculated with the culture medium and shaken at 28 ° C. for 7 to 10 days.

Example 2 Isolation and Purification of Compounds of the Invention

The acetone extract of the culture solution and mycelium cultured in Example 1 was solvent extracted three times with ethyl acetate. The ethyl acetate solvent layer containing the active ingredient thus obtained was concentrated under reduced pressure to remove ethyl acetate, and then chloroform: methanol was subjected to silica gel column chromatography using a solvent of 20: 1-1: 1. The active fraction thus obtained was concentrated under reduced pressure to obtain an oily crude active ingredient, and then purified by Sephadex ODS column chromatography using methanol as a solvent. Finally, the active fractions were subjected to ODS TLC under a solvent condition of methanol: water = 60: 40, and again subjected to ODS TLC under acetonitrile: water = 30: 70 containing 0.1% TFA. Hispidine was obtained.

The physicochemical properties of the pelinstatin and hispidine isolated from the Phellinus linteus 08090-29 strain were as follows.

Compound 1: Felinstatin

1) Appearance of the substance: yellow powder;

2) molecular weight: 734;

3) High Resolution ESI-MS:

Found m / z 733.1196 (MH) ⁻ (C ₁₈ H ₁₇ O ₉ ), calcd 733.1199;

4) Molecular Formula: C ₃₉ H ₂₇ O ₁₅ ;

5) UV absorption spectrum [UV (MeOH) lambda max (logε)]: 202 (4.37), 284 (3.62), 372 (3.73) nm;

6) IR spectrum: 3432, 2924, 1635, 1500, 1251 cm ⁻¹ ;

7) polarization degree: [a] D = 5.7 ° (c0.14, MeOH);

8) Nuclear Magnetic Resonance (NMR) Data: ¹ H and ¹³ C NMR data using methanol (CD ₃ OD-d ₄ ) as a solvent are shown in Table 1 below.

Table 1

9) Chemical Structural Formula

Compound 2: Hispidine

1) Appearance of the substance: yellow powder;

2) molecular weight: 246;

3) molecular formula: C ₁₃ H ₁₀ O ₅ ;

4) Nuclear Magnetic Resonance (NMR) Absorption Spectrum: ¹ H data using methanol (CD ₃ OD-d ₄ ) as a solvent is as follows.

6.11 (1H, s, H-5), 6.58 (1H, d, 15.9, H-7), 7.31 91H, d, 15.9, H-8), 7.03 (1H, d, 2.1, H-10), 6.78 (1H, d, 8.1, H-14), 6.94 (1H, dd, 8.1, 1.8, H-13)

5) Chemical structure

Example 3 Fab I and Fab K Inhibitory Activity of the Pelinstatin and Hispidine Compounds

In order to confirm Fab I inhibitory activity of the compound according to the present invention, the following enzyme titer measurement experiments were performed.

Ward's method (Biochemistry 38, 12514 (1999)) was modified and used for the determination of enzyme titers. Fab I from Staphylococcus aureus prepared by genetic recombination technology was used. Titer measurements were performed in 50 mM sodium phosphate buffer (pH 7.5), and as substrate, 400 μM of trans-2-octennoyl N-acetylcysteamine thioester, NADPH ( nicotinamide adenine dinucleotide) 200 μM and Fab I 150 nM was used. After the enzyme was added and reacted at room temperature for 60 minutes, the absorbance decrease of NADPH was measured at 340 nm using a UV-spectrometer. Felinstatin and hispidine prepared in Example 2 were dissolved in dimethyl sulfoxide (DMSO) solvent and added within 2% of the total reaction solution to evaluate the enzyme inhibitory ability. Enzyme inhibition capacity is expressed as a percentage of the NADH loss in the presence of the test compound to the degree of NADH loss in the absence of the test compound, the concentration of each test compound that inhibits 50% enzyme activity was determined by IC ₅₀ . The results are shown in Table 2.

In addition, Zheng et al. (J. Antibiotics 59 (12): 808-812, 2006) were used to measure Fab K titers. Fab K enzyme from pneumococci prepared by genetic recombination technology was used. Titer measurements were performed in 50 mM sodium phosphate buffer (pH 6.5), using 50 μM trans-2-octenoyl N-acetylcysteamine thioester, 200 μM NADH, and 150 nM Fab K. It was. After adding the enzyme and reacting at room temperature for 60 minutes, the absorbance decrease of NADH was measured at 340 nm using a UV-spectrometer. The results are shown in Table 2.

TABLE 2

As shown in Table 2, the IC ₅₀ for Fab I of the pelinstatin and hispidine compounds showed good Fab I inhibitory activity as 6 μM and 12.6 μM, respectively. In addition, the IC ₅₀ for Fab K of the pelinstatin and hispidine compounds showed excellent Fab K inhibitory activity as 5.8 μM and 6.4 μM, respectively.

Example 4 Antimicrobial Activity of the Pelinstatin and Hispidine Compounds

In order to confirm the antimicrobial activity of the pelinstatin and hispidine compounds according to the present invention, the following experiment was performed.

Test strains were cultured in Mueller Hinton broth (MHB), and the antimicrobial activity was measured by broth microdilution. After diluting the test culture incubated overnight to 2 x 100,000 / ㎖, dispense 100 μl per well in a 96 well plate, and then gradually dilute the compound 2-fold from a concentration of up to 128 ㎍ / ㎖ Treated. The compound was diluted in dimethylsulxoside (DMSO), and the experiment was performed with the concentration of DMSO adjusted to 1/100. After incubation for 20 hours, the growth of bacteria was examined by measuring the OD value at 650 nm. The minimum concentration of the compound which completely inhibited the growth of bacteria was determined by MIC, and the results are shown in Table 3 below.

TABLE 3

As shown in Table 3, the pelinstatin compound of the present invention is the main pathogen Staphylococcus aureus, antibiotic resistant bacteria MRSA (methicillin-resistant Staphylococcus aureus) and Streptococcus pneumoniae (Steptococcus pneumoniae) Excellent antimicrobial activity was observed (128 μg / ml MIC). In addition, the hispidine compound of the present invention also showed excellent antimicrobial activity against Staphylococcus aureus, MRSA and Streptococcus pneumoniae, which are antibiotic resistant bacteria (64 µg / ml MIC).

Claims (15)

1. An antimicrobial composition comprising a compound represented by Formula 1 or Formula 2, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof.

   [Formula 1]

   

   [Formula 2]

   
2. The composition of claim 1, wherein the compound is produced from Pelinus linteus 08090-29 strain.
3. The method of claim 1, wherein the composition is Staphylococus aureus, Bacillus subtilis, Staphylococcus epidermis, Methicillin-resistant staphylococcus (methicillin-resistant) Staphylococcus aureus (MRSA), Quinolone-resistant Staphylococcus aureus (QSA) and Streptococcus pneumoniae (Steptococcus pneumoniae) A composition that exhibits antimicrobial activity against one or more bacteria selected from the group consisting of.
4. The composition of claim 1, wherein the compound has an anoyl reductase inhibitory activity.
5. 5. The composition of claim 4, wherein the anoyl reductase is Fab I or Fab K. 6.
6. The composition of claim 1, wherein the composition further comprises a pharmaceutically acceptable carrier.
7. Enoyl reductase activity inhibitor comprising a compound represented by the following formula (1) or (2), or a pharmaceutically acceptable salt thereof.

   [Formula 1]

   

   [Formula 2]

   
8. 8. The inhibitor according to claim 7, wherein said enoyl reductase is Fab I or Fab K.
9. The method of claim 7, wherein the inhibitor is Staphylococus aureus, Bacillus subtilis, Staphylococcus epidermis, Methicillin-resistant staphylococci (methicillin-resistant) An inhibitor that exhibits antimicrobial activity against one or more bacteria selected from the group consisting of Staphylococcus aureus, Quinolone-resistant Staphylococcus aureus, and Streptococcus pneumoniae.
10. Antimicrobial quasi-drug composition comprising the compound represented by the following formula (1) or (2) as an active ingredient.

    [Formula 1]

    

    [Formula 2]

    
11. A method for treating a pathogenic microorganism or an infectious disease, comprising administering a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof, to a subject having an infectious disease caused by a pathogenic microorganism or a resistant bacterium.

    [Formula 1]

    

    [Formula 2]

    
12. A method of inhibiting the anoyl reductase activity of a pathogenic microorganism or resistant bacteria in a subject, comprising administering to the subject a compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof.

    [Formula 1]

    

    [Formula 2]

    
13. Use of the compound represented by Formula 1 or Formula 2, or a pharmaceutically acceptable salt thereof for the preparation of an antimicrobial agent.

    [Formula 1]

    

    [Formula 2]

    
14. 1) culturing a Pelinus linteus strain or a mutant thereof;

    2) extracting the culture medium and mycelium of the strain obtained in step 1) with an organic solvent and then extracting with ethyl acetate; And

    3) performing the chromatography on the ethyl acetate extract obtained in the step 2) to obtain a compound represented by the following formula (1) or (2).

    [Formula 1]

    

    [Formula 2]

    
15. A compound represented by the following formula (1) or a pharmaceutically acceptable salt thereof.

    [Formula 1]