KR20190113720A - Leoidin compound having anti-virulence activity and use thereof - Google Patents

Abstract

The present invention relates to a novel use of a leoidin compound and, more specifically, to a leoidin compound having an antitoxic or antipathogenic activity and a pharmaceutical composition for preventing or treating a bacterial infection disease including a derivative of the leoidin compound or pharmaceutically acceptable salt thereof. According to the present invention, the leoidin or the derivative thereof is able to inhibit erythrocyte hemolysis by bacteria without affecting the growth of bacteria, inhibit the expression of sae and sarA regulators, and accordingly inhibit the expression of various toxic genes. In addition, bacterial internalization can be inhibited through the inhibition of bacterial attachment and/or invasion to host cells. Moreover, since the leoidin or the derivative thereof does not cause any toxicity to the host cells, the present invention is expected to be useful for cleaning medical containers and further be beneficially used for inhibiting bacteria by being resistant to antibiotics or bacteria which are toxic when treating with antibiotics as well as can be easily used for manufacturing pharmaceuticals for preventing, alleviating, or treating bacterial infection, cosmetic compositions, health food, animal feed, or additives for food or feed.

Description

Leoidin compound having anti-virulence activity and use thereof {Leoidin compound having anti-virulence activity and use thereof}

The present invention relates to a novel use of a rheidine compound, and more specifically, for the prevention or treatment of bacterial infections, including a rheidine compound having antitoxic or antipathogenic activity, a derivative thereof, or a pharmaceutically acceptable salt thereof. It relates to a pharmaceutical composition.

Bacterial pathogens continue to pose a serious threat to public health, as indicated by the worldwide re-emergence of bacterial diseases. In particular, Staphylococcus aureus ("S. aureus") is a bacterium that colonizes more than 25% of the human population symbiotically. Importantly, the organism breaks the initial site of colonization and can cause bacterial seeding and disease. Staphylococcus aureus (S. aureus) is the leading cause of nosocomial infections, is the most common causative pathogen of skin and soft tissue infections as well as infectious endocarditis, and is one of the four leading causes of food-borne diseases. In total, Staphylococcus aureus (S. aureus) infects more than 1.2 million patients each year in US hospitals.

Antibiotics are generally used to treat bacterial infections including Staphylococcus aureus (S. aureus). Antibiotics are metabolites produced by microorganisms, and are used all over the world because they show excellent efficacy in infection symptoms as drugs that inhibit or kill the development of other microorganisms in small amounts and treat infections caused by pathogens.

However, due to the abuse of antibiotics, a so-called super bacteria, which became able to resist any antibiotic by developing the strength to resist pathogens themselves, gradually became stronger, and it was first appeared in Japan in 1996. A problem occurred. In the case of antibiotics, mutations in bacteria are induced by the action of killing bacteria, and in the process of formation of these mutations, genes that cause antibiotic resistance are created, which can lead to drug-resistant mutant bacteria, and these resistant bacteria convert resistance genes into other bacteria. By passing them to the field, the expansion of resistant bacteria can be made quickly. Representative examples of such super bacteria include MRSA (Methicillin-resistant Staphylococcus aureus), VRSA (Vancomycin-resistant Staphylococcus aureus) and VRE (Vancomycin-resistant Enterococci), which have stronger antibiotic resistance, and antibiotic-resistant bacteria are resistant to antibiotics. With this, resistance gradually grows stronger, making it possible to resist any antibiotic.

Therefore, in order to prevent the emergence of such drug-resistant bacteria, in recent years, instead of treatment with antibiotics that kill infectious bacteria, anti-toxic agents that reduce pathogenicity by inhibiting the expression or activity of toxic factors that infiltrate the body to threaten the host. As an alternative, a method of treating bacterial infectious diseases by using is proposed. Bacteria that have lost their toxicity by these anti-toxic agents are killed by the immune function of the human body, and ultimately, a therapeutic effect can be expected. Since these anti-toxic agents actually act on a completely different mechanism from existing antibiotics, they can be used not only as susceptible bacteria, but also as a therapeutic agent for treating infectious diseases caused by infection with multidrug resistant bacteria that are already resistant. In addition, these antitoxic agents can be used to reduce the dosage or increase the activity of antibiotics by co-administration with existing antibiotics. Although studies on antitoxic agents of such a new mechanism have been reported (refer to Korean Patent Laid-Open Patent No. 10-2015-0045216), the development of a therapeutic agent using such a method is still insignificant.

The present invention was devised to solve the problems of the prior art as described above, and the present inventors target bacterial toxicity factors as a new method capable of treating infectious diseases of susceptible or multidrug resistant bacteria without generating resistance. As a result of research efforts to discover an anti-toxic natural material that inhibits the toxic activity of or inhibits the expression of toxic factors, Leoidin expresses toxic factors of bacteria without affecting the growth of strains, cells caused by the fungus. It was confirmed that it has an antitoxic activity that remarkably inhibits hemolysis and cell invasion, and it was also found that the antibiotic sensitivity of multidrug resistant bacteria when co-administered with an existing antibiotic was increased. Based on this, the present invention was completed. Became.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for preventing or treating bacterial infections, comprising as an active ingredient Leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

However, the technical problem to be achieved by the present invention is not limited to the problems mentioned above, and other problems that are not mentioned will be clearly understood by those skilled in the art from the following description.

In order to achieve the above object, the present invention provides a pharmaceutical composition for preventing or treating bacterial infections, comprising as an active ingredient Leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

In one embodiment of the present invention, the rheoidine may be a compound represented by Chemical Formula 1.

[Formula 1]

In another embodiment of the present invention, the rheoidine derivative may be a compound represented by the following formula (2).

[Formula 2]

In Chemical Formula 2,

R ₁ and R ₂ are each independently hydrogen, C1-C7 alkyl, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl, and ,

R ₃ is hydrogen, hydroxy, aldehyde, halide, CN, OR _a , NR _b , SR _c Or COOR _d ,

R ₄ is hydrogen, C1-C7 alkyl, C1-C7 thioalkyl, C1-C7 aminoalkyl, C1-C7 hydroxyalkyl, halide, CN, OR _a , NR _b Or SR _c ,

R _a , R _b , R _c And R _d each independently represent hydrogen, hydroxy, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl.

As a specific example, the rheoidine derivative may be a compound represented by the following formula (4).

[Formula 4]

In another embodiment of the present invention, the rheoidine derivative may be a compound represented by Formula 3 below.

[Formula 3]

In Chemical Formula 3,

R ₁ and R ₂ are each independently hydrogen, C1-C7 alkyl, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl, and ,

R ₃ is hydrogen, hydroxy, aldehyde, halide, CN, OR _a , NR _b , SR _c Or COOR _d ,

R ₄ and R ₅ are each independently hydrogen, C1-C7 alkyl, C1-C7 thioalkyl, C1-C7 aminoalkyl, C1-C7 hydroxyalkyl, Halide, CN, OR _a , NR _b Or SR _c ,

R _a , R _b , R _c And R _d each independently represent hydrogen, hydroxy, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl.

In another embodiment of the present invention, the composition may have anti-toxic or anti-pathogenic activity against bacteria.

In another embodiment of the present invention, the composition may inhibit the hemolytic action of red blood cells by bacteria.

In another embodiment of the present invention, the composition may inhibit the expression of a staphylococcal accessory effector (sae) or a staphylococcal accessory regulator (sar) gene.

In another embodiment of the present invention, the composition may inhibit internalization of bacteria.

In another embodiment of the present invention, the composition may protect host cells from damage to host cells caused by bacterial infection.

In another embodiment of the present invention, the bacteria are Staphylococcus aureus, Streptococcus ferus, Serratia marcescens, Vibrio parahaemolyticus ), Streptococcus pneumonia, Staphylococcus saprophyticus, Campylobacter jejuni, Helicobactor pylori, Pseudomonas aeruginosa, Pseudomosa aeruginosa Bacillus cereus, Enterococcus fecalis, Bacillus licheniformis, Staphylococcus epidermidis, Corynebacterium diphtheria, Corynebacterium diphthera Pneumoniae (Klebsiella pneumoniae), Listreia innocua (Listreia innocua), Burkholderia cepacia, Streptococcus parasanguinis, Salmonella typhimurium (Salmonella typhimurium), Streptococcus sobri Streptococcus sobrinus, Streptococcus sanguinis, Streptococcus iniae, Streptococcus pyogene, Streptococcus mitis, Streptococcus mitis, Listovii Ivanovii ), Listeria monocytog enes), Streptococcus suis, Crosstridium perfringens, Yersinia enterocolitica, Shigella boydii, Shigella flexneri ), Shigella sonnei, Salmonella choleraesuis subsp, Salmonella enteritidis, Salmonella bongori, Salmonella enteritiica, Mycobacte Mycobacterium tuberculosis, Mycobacterium leprae, Clostridium botulinum, Bacillus anthracis, Yersinia pestis, Chlamydia pneumoniae Chlamydia pneumonia, Borrelia burgdorferi, Coxiella burnetii, Mycobacterium avium, Escherichia coli, Borrelia sp.), Bartonella sp., Chlamydia trachomatis, and Mycoplasma pneumonia.

In another embodiment of the present invention, the composition may be formulated with antibiotics or used in combination.

In another embodiment of the present invention, the antibiotic is methicillin, oxacillin, norfloxacin, vancomycin, amikacin, gentamicin, kanamycin (Kanamycin), Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin, Spectinomycin, Geldanamycin, Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem, Imipenem/Cilastatin, Meropenem, Sephadroxil (Cefadroxil), Cefazoline, Cephalotin, Cephalexin, Cefachlor, Cefamandol, Cefamandol, Cefazolin, Cefprozil, Ceph Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidim Ceftazidime), Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil, Ceftobiprole, Teico Teicoplanin, Telavancin, Dalbavancin, Oritavancin, Clindamycin, Lincomycin, Deptomycin, Azit Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Troleandomycin, Terrisromycin, Telithromycin Spiamycin, Aztreonam, Furazolidone, Nitrofurantoin, Linezolid, Posizolid, Radezolid, Torrezolid (Torezolid), Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin ), Mezlocillin, Nafcillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin, Amoxicillin/ Clavulanic acid (Amoxicillin/clavulanate), Ampicillin/sulbactam, Piperacillin/tazobactam, Ticarcillin/clavulanate, Bacitracin , Colistin, Polymyxin B, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Levofloxacin, Lomefloxacin, Lomefloxacin ), Moxifloxacin, Nalidixic acid, Ofloxacin , Trobafloxacin, Grepafloxacin, Spafloxacin, Temafloxacin, Mapenide, Sulfacetamide, Sulfadiazine ), Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide, Sulfasalazine, Sulfisoxazole , Trimethoprim-Sulfamethoxazole (Co-trimoxazole), TMP-SMX), Sulfonamido chrysoidine, Demeclocycline, Doxycycline, Minocycline , Oxytetracycline, Tetracycline, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide ), Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Ripapentine, Arsphenamine, Chloramphenicol, Fosfomycin, Fosfomycin Fusidi cacid, Metronidazole, Mupirosin, Platensimycin, Quinupristin/Dalfopristin, Thiamphenicol, Tigecycl ine), tinidazole, and trimethoprim.

In addition, the present invention provides a method of treating a bacterial infection comprising administering to an individual Leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

Furthermore, the present invention provides the use of Leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof to prevent, ameliorate, or treat bacterial infection.

In addition, the present invention provides a method for inhibiting bacterial toxicity or pathogenicity, comprising administering to an individual Leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a cosmetic composition for preventing or ameliorating bacterial infections, including Leoidin, a derivative thereof, or a cosmetically acceptable salt thereof.

In addition, the present invention provides a health functional food composition for preventing or improving bacterial infection, including Leoidin or a derivative thereof.

In addition, the present invention provides a feed for animals containing Leoidin (Leoidin) or a derivative thereof.

Leoidin or a derivative thereof according to the present invention can inhibit the hemolytic action of red blood cells by bacteria without affecting the growth of bacteria, and suppress the expression of sae and sarA regulators, thereby inhibiting the expression of various virulence genes. Expression can be inhibited. In addition, bacterial internalization can also be inhibited through inhibition of adhesion and/or invasion of bacteria to host cells. Moreover, since Leoidin or a derivative thereof does not cause any toxicity to host cells, the manufacture of pharmaceuticals, cosmetic compositions, health foods, animal feeds, food or feed additives for the prevention, amelioration or treatment of bacterial infections. In addition to being able to be used easily, it is expected to be useful for cleaning medical containers or for inhibiting bacteria that are resistant to antibiotics or toxic when treated with antibiotics.

FIG. 1 shows the structure of a reoidine compound screened as a compound having potent toxicity inhibitory activity from a natural product-derived small molecule compound library.
FIG. 2 shows the structure of a gangaleoidin compound screened as a compound having potent toxicity inhibitory activity from a natural product-derived small molecule compound library.
3 is a result of confirming the anti-toxic effect of USA300 when treated with various concentrations of rheidine (1, 2, 4 and 8 μM).
Figure 4 is a result of confirming the anti-toxic effect of USA300 when treated with various concentrations of ganggaleoidine (1, 2, 5, 10, 15, 20 and 25 μM).
5 is a result of confirming the inhibitory effect of erythrocyte hemolysis by USA300 when treated with various concentrations of rheidine (1, 2, 4 and 8 μM).
6 is a result of confirming the effect of inhibiting erythrocyte hemolysis by USA300 when treated with various concentrations of ganggaleoidine (1, 2, 4, 8, 16 and 32 μM).
7 is a result of confirming the effect of inhibiting the expression of transcriptional regulatory factors by reoidine.
8 is a result of confirming the effect of inhibiting the expression of the toxic gene regulated by the sae regulatory factor by reoidine.
9 is a result of confirming the effect of suppressing the expression of toxic genes regulated by sarA regulatory factors by reoidine.
10 is a result of confirming the effect of suppressing the expression of other toxic genes by reoidine.
11 is a result of confirming the internalization inhibitory effect of USA300 in Hela epithelial cells by reoidine.
12 is a case in which the USA300 was not infected (A), when incubated with USA300 without treatment with rheidine (B), 4uM concentration in order to confirm the cell protective effect from cell damage caused by S. aureus of rheidine. These are the results of confirming the live cells and dead cells in the case of treatment with rheidine of (C), and the case of treatment with 8 uM of Leoidin (D).
13 is a case in which oxacillin is treated alone (A), when combined with 4 uM concentration of reoidine (B), when combined with 8 uM concentration of reoidine in order to confirm the synergistic effect of the combination of rheidine and oxacillin. This is the result of confirming the antitoxic effect in case (C).
Figure 14 is to confirm the synergistic effect of the combination of reoidine and norfloxacin, when norfloxacin is treated alone (A), when combined with 4uM concentration of reoidine (B), 8uM concentration of reoidine and This is the result of confirming the antitoxic effect in the case of combination (C).
15 is a case in which methicillin was treated alone (A), when combined with 4 uM concentration of rheidine (B), when combined with 8 uM concentration of rheidine in order to confirm the synergistic effect of the combination of reoidine and methicillin This is the result of confirming the antitoxic effect in case (C).
16 is a case where vancomycin was treated alone (A), when combined with 4uM concentration of reoidine (B), when combined with 8uM concentration of rheidine in order to confirm the synergistic effect of the combination of reoidine and vancomycin This is the result of confirming the antitoxic effect in C).
17 is a result of confirming the hemolytic inhibitory effect on 26 pathogenic strains of reoidine.

The present inventors screened a substance capable of suppressing toxicity and/or pathogenicity without affecting the growth of bacteria from a library of natural products-derived small molecule compounds. One use was identified, and the present invention was completed based on this.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for the prevention or treatment of bacterial infections, comprising as an active ingredient leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

As used herein, the term "prevention" refers to any action that suppresses or delays the onset of bacterial infection by administration of the composition of the present invention.

As used herein, the term "treatment" refers to any action in which symptoms caused by a bacterial infection are improved or advantageously changed by administration of the composition of the present invention.

In the present invention, leoidin can be obtained naturally or by artificially synthesized methods, regardless of whether it is produced by any raw material or manufacturing method, and can be represented by the following formula (1).

[Formula 1]

In the present invention, "a derivative of leoidin" is a compound that exhibits the same activity as that of leoidin and has an effect of inhibiting toxicity and/or pathogenicity without affecting the growth of bacteria, preferably May be a compound represented by the following Chemical Formula 2 or Chemical Formula 3, but is not limited thereto.

[Formula 2]

In Chemical Formula 2,

R ₁ and R ₂ are each independently hydrogen, C1-C7 alkyl, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl, and ,

R₃Silver hydrogen, hydroxy, aldehyde, halide, CN, OR_a, NR_b, SR_c Or COOR_dIs,

R ₄ is hydrogen, C1-C7 alkyl, C1-C7 thioalkyl, C1-C7 aminoalkyl, C1-C7 hydroxyalkyl, halide, CN, OR _a , NR _b Or SR _c ,

R _a , R _b , R _c And R _d each independently represent hydrogen, hydroxy, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl.

As a specific example, the rheoidine derivative may be a compound represented by the following formula (4).

[Formula 4]

[Formula 3]

In Chemical Formula 3,

R ₁ and R ₂ are each independently hydrogen, C1-C7 alkyl, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl, and ,

R ₃ is hydrogen, hydroxy, aldehyde, halide, CN, OR _a ,NR _b ,SR _c or COOR _d ,

R ₄ and R ₅ are each independently hydrogen, C1-C7 alkyl, C1-C7 thioalkyl, C1-C7 aminoalkyl, C1-C7 hydroxyalkyl, Halide, CN, OR _a , NR _b or SR _c ,

R _a , R _b , R _c And R _d each independently represent hydrogen, hydroxy, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl.

At this time, the compound represented by Formula 3 may be prepared from the compound represented by Formula 2 through the following conventional reaction.

Leoidin represented by Formula 1, or a Leoidin derivative represented by Formula 2 or Formula 3, which is included as an active ingredient in the composition according to the present invention, does not affect the growth of bacteria and does not affect the growth of bacteria. It may have antitoxic and/or antipathogenic activity against. More specifically, the compound of the present invention, Leoidin or a derivative thereof, inhibits the hemolytic action of red blood cells by bacteria, and has antitoxic and/or antipathogenic activity through the action of inhibiting the expression of transcriptional manipulators and virulence genes. Can have. At this time, the bacteria are Staphylococcus aureus, Streptococcus ferus, Serratia marcescens, Vibrio parahaemolyticus, and Streptococcus pneumoniae. Streptococcus pneumonia), Staphylococcus saprophyticus, Campylobacter jejuni, Helicobacter pylori, Pseudomonas aeruginosa, Bacillus ceruginosa, Bacillus ceruginosa Enterococcus fecalis, Bacillus licheniformis, Staphylococcus epidermidis, Corynebacterium diphtheriae, Krebsiella pneumoniae, Krebsiella pneumoniae Listreia innocua, Burkholderia cepacia, Streptococcus parasanguinis, Salmonella typhimurium, Streptococcus sobrinus, Streptococcus sobrinus Streptococcus sanguinis, Streptococcus iniae, Streptococcus pyogene, Streptococcus mitis, Listeria Ivanovii subsp ivanovii, Listeria monocytogene monocytogenes), Streptococcus number Streptococcus suis, Crostridium perfringens, Yersinia enterocolitica, Shigella boydii, Shigella flexneri, Shigella sonei (Shigella sonnei), Salmonella choleraesuis subsp, Salmonella enteritidis, Salmonella bongori, Salmonella enterica, Salmonella enterica, Mycobacterium tuberclosis tuberculosis), Mycobacterium leprae, Clostridium botulinum, Bacillus anthracis, Yersinia pestis, Chlamydia pneumonia, Borrelia burgdorferi, Coxiella burnetii, Mycobacterium avium, Escherichia coli, Borrelia sp., Barto It may be selected from the group consisting of Bartonella sp., Chlamydia trachomatis, and Mycoplasma pneumonia, but is not limited thereto.

According to an embodiment of the present invention, it was confirmed that the compound of the present invention, Leoidin, significantly inhibited hemolysis against S. aureus (see Example 3), and sae, a transcriptional regulator that regulates virulence genes. It was confirmed that not only the expression of and sarA, but also the expression of toxic genes mainly regulated thereto and other toxic genes were remarkably suppressed (see Examples 4 and 5).

In addition, the compound of the present invention, Leoidin (Leoidin) or a derivative thereof, also has anti-toxic and/or anti-pathogenic activity through the action of inhibiting bacterial internalization by inhibiting the adhesion and/or invasion of bacteria to host cells. Can have.

According to another embodiment of the present invention, it was confirmed that the compound of the present invention, Leoidin, significantly reduces internalization by S. aureus and protects cells in a concentration-dependent manner from cell damage caused by bacterial infection. See examples 6 and 8).

On the other hand, the composition according to the present invention may be formulated with or used in combination with an existing antibiotic, wherein the antibiotics are methicillin, oxacillin, norfloxacin, vancomycin, a Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin, Spec Spectinomycin, Geldanamycin, Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem, Imipenem/Silastatin /Cilastatin), Meropenem, Cefadroxil, Cefazoline, Cephalotin, Cepalothin, Cefaxin, Cefachlor, Cefamandole, Sepoxy Cefoxitin, Cefprozil, Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime ), Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline Fosamil fosamil), Ceftobiprole, Teicoplanin, Telavancin, Dalbavancin, Oritavancin, Clindamycin, Lincomycin (Lincomycin), Deptomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Trorindomycin (Troleandomycin), Terithromycin, Spiramicin, Aztreonam, Furazolidone, Nitrofurantoin, Linezolid, Posizolid ), Radezolid, Torezolid, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Declock Dicloxacillin, Flucloxacillin, Mezlocillin, Nafcillin, Penicillin G, Penicillin V, Piperacillin, Temocillin (Temocillin), ticarcillin, amoxicillin/clavulanate, ampicillin/sulbactam, piperacillin/tazobactam, ticacillin/clavulanate (Ticarcillin/clavulanate), Bacitracin, Colistin, Polymyxin B, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin ), Levofloxacin, Lomefloxacin, Moxifloxacin, Nalidic Nalidixic acid, Ofloxacin, Trobafloxacin, Grepafloxacin, Spafloxacin, Temafloxacin, Mapenide, Sulfa Acetamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilimide , Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), TMP-SMX), Sulfonamido chrysoidine, Demeclocycline Demeclocycline), Doxycycline, Minocycline, Oxytetracycline, Teracycline, Clofazimine, Dapsone, Capreomycin, Cycloserine , Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Ripapentine, Arsphenamine, Arsphenamine, Chloramphenamine (Chloramphenicol), Fosfomycin, Fusidi cacid, Metronidazole, Mupirosine, Platetensimycin, Quinupristin/Dalfopristin, Chi Amphenicol (Thiamphenicol), Tigecycline (Tigecycline), Tinidazole (Tinidazole), and it is preferably selected from the group consisting of trimethoprim (Trimethoprim), more preferably methicillin (methicillin), oxacillin ( oxacillin), norfloxacin, and vancomycin, but is not limited thereto.

According to another embodiment of the present invention, remarkably excellent antibiotics when treated with antibiotic-resistant bacteria by combining the compound of the present invention, Leoidin, and the existing antibiotics, methicillin, oxacillin, norfloxacin, and vancomycin. It was confirmed to have activity (see Example 9).

Leoidin represented by Formula 1 or derivatives thereof of the present invention may include all salts, hydrates, and solvates that can be prepared by conventional methods, as well as pharmaceutically acceptable salts. When used in the form of a pharmaceutically acceptable salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful as the salt. Acid addition salts include inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid or phosphorous acid, and aliphatic mono and dicarboxylates, phenyl-substituted alkanoates, hydroxy alkanoates and alkanes. It is obtained from non-toxic organic acids such as dioates, aromatic acids, aliphatic and aromatic sulfonic acids. Such pharmaceutically non-toxic salts include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate chloride, bromide, ioda Id, fluoride, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate , Sebacate, fumarate, maleate, butin-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methyl benzoate, dinitro benzoate, hydroxybenzoate, me Toxicbenzoate, phthalate, terephthalate, benzenesulfonate, toluenesulfonate, chlorobenzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, β-hydroxybutyrate, glycol Rate, malate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the present invention is prepared by a conventional method, e.g., leoidin is dissolved in an excess acid aqueous solution, and the salt is dissolved in a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile. It can be prepared by using and precipitating. It can also be prepared by heating the same amount of Leoidin and an acid or alcohol in water, and then evaporating the mixture to dryness, or by suction filtration of the precipitated salt.

In addition, a pharmaceutically acceptable metal salt can be made using a base. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess alkali metal hydroxide or alkaline earth metal hydroxide solution, filtering the undissolved 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. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (eg, silver nitrate).

The pharmaceutical composition of the present invention may be formulated and administered in various oral or parenteral dosage forms at the time of clinical administration, but is not limited thereto.

Formulations for oral administration include, for example, tablets, pills, hard/soft capsules, solutions, suspensions, emulsifiers, syrups, granules, elixirs, and the like. Rose, sucrose, mannitol, sorbitol, cellulose and/or glycine), lubricants (eg silica, talc, stearic acid and its magnesium or calcium salts and/or polyethylene glycol). Tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and/or polyvinylpyrrolidine, and optionally starch, agar, alginic acid or sodium salts thereof. It may contain disintegrants or boiling mixtures and/or absorbents, colorants, flavoring agents, and sweetening agents.

Pharmaceutical compositions containing Leoidin or a derivative thereof as an active ingredient can be administered parenterally, and parenteral administration can be performed by subcutaneous injection, intravenous injection, intramuscular injection, intrathoracic injection, or transdermal administration. And, preferably, it can be applied in a method of topical application by application.

At this time, in order to formulate a formulation for parenteral administration, Leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof is mixed in water with a stabilizer or buffer to prepare a solution or suspension, and this is prepared in an ampoule or vial unit. It can be prepared in a dosage form. The composition may be sterilized or contain adjuvants such as preservatives, stabilizers, wetting agents or emulsification accelerators, salts and/or buffers for controlling osmotic pressure, and other therapeutically useful substances, and conventional methods of mixing, granulation or It can be formulated according to the coating method.

In addition, the pharmaceutical composition according to the present invention is administered in a pharmaceutically effective amount. In the present invention, "pharmaceutically effective amount" means an amount sufficient to treat a disease at a reasonable benefit/risk ratio applicable to medical treatment, and the effective dose level is the type of disease, severity, and drug activity of the patient. , Sensitivity to drugs, time of administration, route of administration and rate of excretion, duration of treatment, factors including drugs used concurrently, and other factors well known in the medical field. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or administered in combination with other therapeutic agents, may be administered sequentially or simultaneously with a conventional therapeutic agent, and may be administered single or multiple. It is important to administer an amount capable of obtaining the maximum effect in a minimum amount without side effects in consideration of all the above factors, and this can be easily determined by a person skilled in the art.

Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the age, sex, condition, body weight of the patient, the absorption of the active ingredient in the body, the inactivation rate and excretion rate, the type of disease, and the drug to be used in combination.

In another aspect of the present invention, the present invention provides a method for preventing or treating a bacterial infection comprising administering to an individual Leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, the present invention provides a method for inhibiting the toxicity or pathogenicity of bacteria, comprising administering to an individual Leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

In the present invention, "individual" means a subject in need of treatment of a disease, and more specifically, human or non-human primates, mice, rats, dogs, cats, horses and cattle. Means mammals.

As another aspect of the present invention, the present invention provides a cosmetic composition for preventing or improving bacterial infections, including Leoidin, a derivative thereof, or a cosmetically acceptable salt thereof.

The cosmetic composition of the present invention may be prepared in any formulation conventionally prepared in the art, for example, solution, suspension, emulsion, paste, gel, cream, lotion, powder, soap, surfactant-containing cleansing , Oil, powder foundation, emulsion foundation, wax foundation, and may be formulated as a spray, but is not limited thereto. In more detail, it may be prepared in the form of a flexible lotion, nutritional lotion, nutritional cream, massage cream, essence, eye cream, cleansing cream, cleansing foam, cleansing water, pack, spray or powder.

The cosmetically effective carrier contained in the cosmetic composition of the present invention may be a carrier commonly used in the art, depending on the formulation. When the formulation of the present invention is a paste, cream or gel, animal oil, vegetable oil, wax, paraffin, starch, tracant, cellulose derivative, polyethylene glycol, silicone, bentonite, silica, talc, or zinc oxide may be used as a carrier component. I can.

When the formulation of the present invention is a powder or spray, lactose, talc, silica, aluminum hydroxide, calcium silicate, or polyamide powder may be used as a carrier component. In particular, in the case of a spray, additionally chlorofluorohydrocarbon, propane / May contain propellants such as butane or dimethyl ether.

When the formulation of the present invention is a solution or emulsion, a solvent, a solubilizing agent or an emulsifying agent is used as a carrier component, such as water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylglycol oil, glycerol aliphatic ester, polyethylene glycol or fatty acid ester of sorbitan.

When the formulation of the present invention is a suspension, as a carrier component, a liquid diluent such as water, ethanol or propylene glycol, an ethoxylated isostearyl alcohol, a suspending agent such as polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, and crystallites Sex cellulose, aluminum metahydroxide, bentonite, agar or tracanth, and the like can be used.

When the formulation of the present invention is a surfactant containing cleansing, as a carrier component, aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters may be used.

Ingredients included in the cosmetic composition of the present invention include ingredients commonly used in cosmetic compositions in addition to the active ingredient and the carrier ingredient, for example, conventional auxiliary agents such as antioxidants, stabilizers, solubilizers, vitamins, pigments and fragrances. It may include.

As another aspect of the present invention, the present invention provides a health functional food composition for preventing or improving bacterial infections, including Leoidin or a derivative thereof. In the present invention, Leoidin (Leoidin) or a derivative thereof can be easily used in the manufacture of health functional foods having an antitoxic and/or antipathogenic effect, such as a main ingredient, an auxiliary ingredient, a food additive, a functional food or a beverage. .

In the present invention, the term "health functional food" refers to the biological defense rhythm control of the food group or food composition in which an added value is given to the food to act and express the function of the food for a specific purpose by using physical, biochemical, and biotechnological techniques, It refers to a food processed by designing to sufficiently express the body's control functions related to disease prevention and recovery, etc. to the living body, which may further contain food additives acceptable for food, suitable carriers, excipients, and It may further include a diluent.

In addition, the health functional food composition of the present invention includes various nutrients, vitamins, minerals (electrolytes), flavors such as synthetic flavors and natural flavors, coloring agents and fillers (cheese, chocolate, etc.), pectic acid and salts thereof, alginic acid. And salts thereof, organic acids, protective colloidal thickeners, pH adjusters, stabilizers, preservatives, glycerin, alcohols, carbonates used in carbonated beverages, and the like, and the components may be used independently or in combination.

The amount of the Leoidin (Leoidin) or a derivative thereof may be included as 0.001% by weight to 90% by weight of the total weight of the functional food, preferably 0.1% by weight to 40% by weight, and for long-term intake In this case, it may be less than the above range, but the active ingredient is not limited to the above range because there is no problem in terms of safety and can be used in an amount greater than the above range.

In another aspect of the present invention, the present invention provides a feed for animals comprising Leoidin or a derivative thereof. The animal feed may be in any suitable form, such as a dry form, a semi-wet form or a wet form, which may be a refrigerated or long-term stored pet food product. The animal feed may contain any carbohydrate source, protein source, and lipid source, in addition to the leoidin or derivatives thereof according to the present invention. The animal feed may be prepared using a conventional manufacturing method well known in the art, that is, extrusion cooking, baking, and other suitable processing methods. When the animal feed is extruded, it can usually be provided in the form of a kibble. In the case of wet food or wet pet food, it can be provided in the form of a meat-mimicking product. Other methods for the manufacture of chunk type products can also be used, for example, when cooking in a steam oven. Alternatively, a meat emulsion may be prepared by emulsifying an appropriate meat material, adding an appropriate gelling agent, heating the meat emulsion, and then placing it in a can or other container to manufacture a loaf type product.

Hereinafter, a preferred embodiment is presented to aid the understanding of the present invention. However, the following examples are provided for easier understanding of the present invention, and the contents of the present invention are not limited by the following examples.

[Example]

Example 1. Experiment preparation and analysis method

1-1. Strain culture and reporter system production

Multidrug resistant Staphylococcus aureus (S. aureus) strain (USA300) was cultured in a rotary shaker equipped with aeration at 37°C, in TSB (tryptic soy broth) medium.

On the other hand, the virulence reporter strain (Virulence reporter strain) was produced by introducing the hla promoter fused with green fluorescent protein (GFP) to USA300. For selection of the reporter strain, 5 μg/ml chloramphenicol (Sigma-Aldrich, USA) was added to the culture medium. The number of viable cells was measured by spreading the diluted culture in tryptic soy agar (TSA).

1-2. Screening for candidate compounds

A library containing about 800 compounds derived from natural products was purchased from Microsource discovery systems, Inc., USA. All compounds had 95% purity and were used without further purification. The reporter strain prepared in Example 1-1 was used for high-throughput screening to measure the antibacterial and antitoxic activity of the library compound. That is, the reporter strain Colonies were collected from TSA plates and suspended in tubes with fresh TSB medium to an _{OD 600 of 1.} Then, incubate in a rotary shaker at 180 rpm and 37°C to the exponential phase, and in the early exponential phase, the cell density is ^{∼2×10 7} CFU ml ^-1. Diluted in fresh medium. The diluted culture solution was added to each well of a 48-well plate (Nunc, Wiesbaden, Germany). After treatment with 10 μM of the natural compound and incubation for 6 hours, absorbance at 600 nm and fluorescence at 480/520 nm were measured. At this time, it was recorded that the compound was active when GFP production was decreased without reducing the growth of bacteria compared to the vehicle (untreated control).

1-3. Determination of the effective concentration of a compound

The reporter strain prepared in Example 1-1 was cultured in TSB overnight, diluted 1:100 in fresh TSB medium, and cultured until the initial exponential phase, and then 100 μl of the culture solution ( ^{containing 2×10 7} bacteria) was added twice as much as the compound. -It was added to a 48-well plate made of sterilized polystyrene along with the continuous dilution and vehicle (untreated control). After incubating the plate at 37° C. for 6 hours, fluorescence was measured. The effective concentration of the compound was calculated by measuring _{IC 50} and IC _{90 compared to vehicle (control).}

1-4. Anti-virulent activity assay

USA300 was incubated overnight in TSB, diluted 1:100 in fresh TSB medium and grown to the initial exponential phase, and 500 μl of culture solution with or without various concentrations of Leoidin or derivatives thereof was added to sterilized polystyrene. It was dispensed into a 48-well plate made of material. The culture medium was grown at 37° C. for 6 hours in a 200 rpm rotary shaker, and the absorbance was measured at 595 nm for rheidine and 600 nm for its derivatives.

1-5. Hemolytic activity analysis

The anti-hemolytic activity of Leoidin or a derivative thereof was measured using human-derived red blood cells. _{USA300 was incubated overnight, diluted to an OD 600} =0.1 in 20 ml of fresh TSB medium, and then incubated at 37°C for 3 hours to an _{OD 600 =0.6.} Cells were collected by centrifugation at 10,000xg for 10 minutes at 4° C., and then resuspended in 20 ml of phosphate buffer saline (PBS). 2% red blood cells were obtained by centrifuging 1 ml of fresh defibrotic blood, which was resuspended in 1 ml of sterile PBS. Then, after repeated washing with PBS, it was resuspended in 0.75 ml of PBS, and a 2% red blood cell suspension was prepared for analysis. 100 μl of a culture solution with or without various concentrations of rheidine was mixed with 900 μl of 2% red blood cells and incubated at 37° C. for 3 hours. Aliquots were centrifuged and the hemolysis rate was measured by absorbance at 540 nm.

1-6. Quantitative real time RT-PCR analysis

USA300 strains with or without 8 μM of Leoidin were grown to the initial exponential phase. Total RNA was isolated and purified using Qiagen RNA Protect Bacteria Reagent and RNeasy Mini Kit (Qiagen), and mechanical and enzymatic pulverization was performed. RNA was purified using a silica column, and DNA contamination was removed by treatment with DNase. CDNA was obtained from RNA using Eco dry premix random hexamers (Clontech Laboratories, Inc.) and a thermocycler (Applied biosystem), at which time the reaction was set at 42°C for 60 minutes according to the manufacturer's instructions, and 10 at 72°C. Paused for a minute. Quantitative PCR was carried out using iTaq universal SYBR green supermix (Bio Rad) and BioRad Real-Time PCR system, and the reaction conditions are as follows: denaturation at 95°C for 5 seconds, binding at 60°C for 15 seconds ( annealing), more than 30 cycles. The reaction was carried out three times, and information on the primers used at this time is shown in Table 1 below. On the other hand, the results were expressed as how many times the transcription was increased relative to 16S and ProC.

division Sequence information Forward primer (FP) RP (reverse primer) agrA 5'-ACAGACTCATTGCCCATT-3' (SEQ ID NO: 1) 5'-AACGTTTCTCACCGATGC-3' (SEQ ID NO: 2) SaeS 5'-ACCGCACATTAGAAGTGA-3' (SEQ ID NO: 3) 5'-AATCCAATACCTTCATC-3' (SEQ ID NO: 4) sarA 5'-CAATGGTCACTTATGCTG-3'
(SEQ ID NO: 5) 5'-TCTTTCATCATGCTCATTAC-3'
(SEQ ID NO: 6) sigB 5'-AGTGAGCGATGAACTAACC-3'
(SEQ ID NO: 7) 5'-CTTGTTGCCCATAATATC-3'
(SEQ ID NO: 8) hla 5'-CAACAACACTATTGCTAGGTTCCATATT-3'
(SEQ ID NO: 9) 5'-CCTGTTTTTACTGTAGTATTGCTTCCA-3'
(SEQ ID NO: 10) ent 5'-AGTTGCTGGCAGAGTGTA-3'
(SEQ ID NO: 11) 5'-GTAGCTCTTTATGCGACTC-3'
(SEQ ID NO: 12) coa 5'-TAATGTAGATTGGGCAATTACA-3'
(SEQ ID NO: 13) 5'-ATGCTTTAATTCAGTTAGAAGC-3'
(SEQ ID NO: 14) plc 5'-TTCAATGGGCAGACAATGCG-3'
(SEQ ID NO: 15) 5'-CCTCCAGACGCTACACTCAA-3'
(SEQ ID NO: 16) sspB 5'-GGAAGGTCTTGCTCACTTACTT-3'
(SEQ ID NO: 17) 5'-CTCATGGTGTGCAGGATTCA-3'
(SEQ ID NO: 18) sspA 5'-TCCCACATTGTTGCTACAGG-3'
(SEQ ID NO: 19) 5'-TCAGGCGAAGGTGATTTAGC-3'
(SEQ ID NO: 20) nuc 5'-ATGGTCCTGAAGCAAGTG-3'
(SEQ ID NO: 21) 5'-GCCAAGCCTTGACGAACTA-3
(SEQ ID NO: 22) sak 5'-GCTCTGATAAATCTGGGACAAC-3'
(SEQ ID NO: 23) 5'-TGGGCATTAGATGCGACAG-3'
(SEQ ID NO: 24) aur 5'-TGTCTGCGTGTACTTTCACTTC-3'
(SEQ ID NO: 25) 5'-AAGAGTGATGCGGTCAAAGC-3'
(SEQ ID NO: 26) lukS 5'-GTCTGGAACAAAATAGTCTCTCGG-3'
(SEQ ID NO: 27) 5'-GGTCCATCAACAGGAGGTAATG-3'
(SEQ ID NO: 28) lukF 5'-TGTGCTTCAACATCCCAACC-3'
(SEQ ID NO: 29) 5'-ACGGTAGGTTATTCTTATGGTGGAG-3
(SEQ ID NO: 30) hlgA 5'-ATCAATCGGAGGCAGTGGC-3'
(SEQ ID NO: 31) 5'-GCAGATACTTGACCATTCGGTG-3'
(SEQ ID NO: 32) hlgB 5'-CTATCACACAGACAAGATGGCG-3'
(SEQ ID NO: 33) 5'-CCCAGTAGAAGCCATTCCAAC-3
(SEQ ID NO: 34) hlgC 5'-TCCAATCAGCCCCATCAC-3'
(SEQ ID NO: 35) 5'-TTTGACGCCCCATAAAACAC-3'
(SEQ ID NO: 36) chp 5'-ACACACCATCATTCAGCGA-3'
(SEQ ID NO: 37) 5'-AGCGTTGTAGGAAGACCAC-3'
(SEQ ID NO: 38) Cap5 5'-ATGACGATGAGGATAGCG-3'
(SEQ ID NO: 39) 5'-CTCGGATAACACCTGTTGC-3'
(SEQ ID NO: 40) sdrE 5'-TCAGTAAGAACAGATGCTAATGGTC-3'
(SEQ ID NO: 41) 5'-GAGTCTTTTTCACCATCAGTTGTTC-3'
(SEQ ID NO: 42) isdH 5'-AGATCAAGCGTCAAGCCAAC-3'
(SEQ ID NO: 43) 5'-TCATCTGCTGGTGGATACTG-3'
(SEQ ID NO: 44) clfA 5'-TTTCAACAACGCAAGATA-3'
(SEQ ID NO: 45) 5'-GCTACTGCCGCTAAACTA-3'
(SEQ ID NO: 46) clfB 5'-TTTGGGATAGGCAATCATCA-3'
(SEQ ID NO: 47) 5'-TCATTTGTTGAAGCTGGCTC-3'
(SEQ ID NO: 48) fnbA 5'-TACCCGTTTCCACTTTCGC-3'
(SEQ ID NO: 49) 5'-GGCTACACAAAATCAAGTCGC-3'
(SEQ ID NO: 50) fnbB 5'-GTGTTGATTGTGATGGTTGCTC-3'
(SEQ ID NO: 51) 5'-GTAGAGGAAAGTGGGAGTTCAG-3'
(SEQ ID NO: 52) psma 5'-GCCATCCCAACTTAATAACCATGT-3'
(SEQ ID NO: 53) 5'-TATCAAAAGCTTAATCGAACAATTC-3'
(SEQ ID NO: 54) geh 5'-AGGCGTGGTGTCAGTGTTAG-3'
(SEQ ID NO: 55) 5'-TCGCATTCCCTTGTTCTCCC-3'
(SEQ ID NO: 56) eap 5'-GTTACTGCCACTTTAGCATTGG-3'
(SEQ ID NO: 57) 5'-AGGAACAGTGTGATAACCATCC-3'
(SEQ ID NO: 58) cap8 5'-CAGCAGTTAAAGTCGCACCA-3'
(SEQ ID NO: 59) 5'-GAACCCAATACAGGCAATCCT-3'
(SEQ ID NO: 60)

1-7. Cell viability assay

Hela cells were cultured in DMEM supplemented with 10% FBS (fetal bovine serum, Invitrogen) in a 5% CO _{2 chamber.} After treatment with Leoidin (the _{same concentration as IC 50} and IC ₉₀ ) and incubation for 1 hour, it was added to a cover glass placed on a 12-well micro-titre plate. All experiments were repeated 3 times. The USA300 culture medium cultured overnight was centrifuged at 4000 rpm for 10 minutes at 4°C. The cells were washed 3 times with DMEM medium, and OD=1 ( ^{containing about 10 9} cfu/ml) was set. 2x10 ⁷ cfu/ml of USA300 was dispensed into a well and incubated for 6 hours. Cells were stained with fluorescein diacetate (FDA) and propidium iodide (PI), and the stained cells were confirmed using a confocal laser scanning microscope.

1-8. Cell proliferation assay

Cell proliferation analysis was performed using EZ-Cytox cell viability measurement reagent (Daeil lab services Co, Seoul, Korea) according to the manufacturer's instructions. That is, Hela cells were cultured in DMEM to which 10% FBS (fetal bovine serum, Invitrogen) was added in a _{5% CO 2 chamber.} Cells were inoculated into 96-well plates (1×10 ⁵ cells density per well), attached to wells, and cultured for 24 hours. 2 μM to 10 μM of Leoidin was added to each well, and after incubation for 72 hours, 20 μl of EZ-Cytox reagent was added to each well. Then, it was incubated for 3 hours at 37°C in a _{CO 2 humidified incubator.} After incubation, the absorbance was measured at 450 nm using a microplate absorption reader (Tecan infinite m200, Switzerland), and all experiments were repeated three times.

1-9. Cell internalization assay

Internalization analysis according to S. aureus-based cell invasion was performed using gentamicin protection assays. That is, Hela cells were cultured in a DMEM medium containing 10% FBS (fetal bovine serum, Invitrogen) _{in a 5% CO 2 chamber.} When the saturation (confluency) reached 70%, ⁵ ×10 5 cells per well were applied to a 24-well plate containing a glass cover slip, and the plate was incubated for 48 hours. USA300 was incubated overnight in TSB, and after centrifugation (4000 rpm, 10 minutes), bacterial cells were suspended in DMEM, and _{OD 600} ^{= 1 corresponding to 10 9} cfu/ml was adjusted. One hour before bacterial treatment, _{leoidin at IC 50} and IC ₉₀ concentrations was added to each well. About 1×10 ⁷ cells were treated _{on Hela cells, and cultured for 90 minutes at 37° C. for CO 2} , resulting in a multiplicity of infection (MOI) of 100. After incubation, the cells were washed, and gentamicin (10 μg/mL) was added for 60 minutes to dissolve extracellular or adherent staphylococcus. Thereafter, the cells were washed with PBS and plated on a TSA plate, and the plate was cultured for 24 hours, and the formed colonies were counted.

1-10. In combination with antibiotics Synergistic effect analysis

The combination of Leoidin and antibiotics was determined using the checkerboard method. _{First, the IC 50} of four drugs, methicillin, oxacillin, norfloxacin, and vancomycin, were calculated. USA300 was incubated in TSB with constant shaking at 180 rpm at 37° C. overnight, and diluted 1:100 in fresh TSB medium with antibiotics at various concentrations ranging from 0.1-10 μg/ml. Then, the IC ₅₀ of the four antibiotic drugs were treated alone or in combination with 4 μM or 8 μM of Leoidin.

The FIC (Fractional Inhibitory Concentration) of the antibiotic was determined using the following formula.

FIC of Drug (FIC _A ) = MIC of Drug in combination with leoidin/MIC of drug

1-11. Statistical analysis

Statistical analysis was performed using graph pad prism software (version 4.03). ANOVA was used, followed by a Newman-Keuls multiple comparison test using Graph Pad prism program version 6.0 (Graph Pad Software Inc., San Diego, CA). The minimum level of meaning was set to P ≤ 0.001. All analyzes were performed three times and statistical analysis was done.

Example 2. Anti-virulent activity effect verification

Among 800 compounds tested for screening through the method described in Example 1-2, Leoidin and Gangaleoidin having strong toxic inhibitory activity were identified (see Figs. 1 and 2), In the case of treatment with various concentrations of rheoidine (1, 2, 4 and 8 μM) or gangaloidine (1, 2, 5, 10, 15, 20 and 25 μM) by the method described in Examples 1-4 The antitoxic activity effect in was confirmed.

As a result, as shown in Figure 3, it was confirmed that Leoidin (Leoidin) inhibited the production of green fluorescent protein (GFP) to less than 50% while maintaining the bacterial growth 95% or more, in particular, 4 μM (IC ₅₀ ) And 8 μM (IC ₉₀ ), it was confirmed that the production of green fluorescent protein (GFP) was reduced by 50% and 90%.

In addition, as shown in Figure 4, it was confirmed that Gangaleoidin inhibited the production of green fluorescent protein (GFP) to less than 50% while maintaining the growth of bacteria by 95% or more, and in particular, 10 μM (IC _It was confirmed that 90% reduction in green fluorescent protein (GFP) production at a concentration of 90 ).

From the above results, it was found that Leoidin and Gangaleoidin can be used as antipathogenic agents.

Example 3. Verification of hemolytic inhibitory effect on S. aureus

In order to confirm whether or not Leoidin or Gangaleoidin has the activity of inhibiting the hemolytic action of S. aureus, various concentrations of rheidine (1, 2, 4 and 8 μM) or gangaloidine (1, 2, 4, 8, 16 and 32 μM) were analyzed for the inhibitory effect of hemolysis against S. aureus.

As a result, as shown in FIG. 5, it was confirmed that Leoidin significantly inhibited the hemolysis of red blood cells by S. aureus. More specifically, when 4 μM of reoidine was added, hemolytic activity was suppressed up to 50%, and in the case of 8 μM, no measurable hemolytic activity was found.

In addition, as shown in Fig. 6, it was confirmed that gangaleoidin significantly inhibited the hemolysis of red blood cells by S. aureus. More specifically, when 2 μM of reoidine was added, hemolytic activity was suppressed up to 30%, and in the case of 8 μM, no measurable hemolytic activity was found.

From the above results, it was found that Leoidin and Gangaleoidin are effective inhibitors of α-hemolysin, which causes hemolysis.

Example 4. Verification of the inhibitory effect on expression of transcriptional regulators of Leoidin

In previous studies, the production of α-hemolysin, one of the most essential exotoxins secreted by S. aureus, was reported to be regulated by a staphylococcal accessory effector (sae). In addition, it has been reported that the expression of hla is influenced by sar (staphylococcal accessory regulator) and agr (accessory gene regulator). Therefore, it was confirmed through the method described in Example 1-6 whether the expression of these transcriptional regulatory factors could be suppressed by treatment with Leoidin.

As a result, as shown in FIG. 7, when compared with the control group not treated with Leoidin, the saeS and sarA expression levels in the culture medium treated with Leoidin were reduced to 74% and 50%, respectively. I could confirm. On the other hand, other major regulatory factors such as agrA did not show inhibitory effects. From the above results, since Leoidin not only inhibits the expression of α-hemolysin, but also suppresses various virulence genes through sae and sarA modulators, anti-toxicity against other exotoxins It was found that it could be applied as a therapeutic agent.

Example 5. Of Leoidin Verification of the effect of suppressing the expression of toxic genes

It was confirmed through the method described in Example 1-6 whether the expression of the virulence gene of S. aureus (USA300) could be suppressed by treatment with Leoidin.

As a result, as shown in Figure 8, when compared to the control group not treated with Leoidin (Leoidin), when treated with Leoidin, hla, eap, nuc, lukS, isdH and various It could be seen that the expression of hemolytic (hlgA, hlgB and hlgC) was significantly suppressed. In particular, in the case of hla, the expression level was reduced to 82%. Likewise, in the case of treatment with Leoidin, as shown in FIG. 9, expression of cap8, clumping factors (clfA and clfB), and fibronectin binding proteins (fnbA, fnbB), which are regulated by sarA, is significantly suppressed. I could confirm. In addition, as shown in Figure 10, plc, psm (phenol-soluble modulins), geh (lipases), proteases (sspA, sspB) and sak (staphylokinases) in the case of treatment with Leoidin (Leoidin) expression It was confirmed that it was significantly suppressed (FIG. 10A). In addition, the expression of CHIPS (chemotaxis inhibiting protein) was also reduced by about two times, and the expression of aureolysin, which inhibits phagocytosis of bacteria by neutrophils, and sdrE (Serine-aspartate repeat protein), which play an important role in immune evasion, were 91, respectively. It was confirmed that the percentage and 38% decrease (FIG. 10B). On the other hand, the transcription of enterotoxin, SigB, cap5 (capsular polysaccharide) and coa (coagulase) had no significant effect.

Example 6. Verification of the inhibitory effect of Leoidin on internalization of S. aureus

Internalization of S. aureus in epithelial cells by adhesion and invasion is a basic and essential step for various infections to occur. Therefore, in order to confirm whether the internalization of S. aureus can be inhibited by treatment with Leoidin in the host cell, a gentamycin protection assay was performed. That is, in the presence of Leoidin, Hela cells were treated with USA300 to induce cellular internalization, and extracellular bacteria that were not internalized were removed using gentamicin. Thereafter, host cells were lysed and internalized USA300 was counted.

As a result, as shown in FIG. 11, ^{when 1×10 7} of USA300 cells ^{were treated with 5} ×10 5 Hela cells for 90 minutes, compared to the control, internalization was reduced when treated with Leoidin, especially 8 μM It was confirmed that internalization by USA300 was significantly reduced when treated with /ml of Leoidin. From the above results, it was found that by inhibiting the expression of surface-binding proteins required for adhesion and internalization of Leoidin, the invasion of bacteria can be suppressed.

Example 7. Cytotoxicity Verification of Leoidin

After confirming the efficacy of Leoidin in the internalization analysis according to Example 6, their toxicity to Hela cells was analyzed. As a result, it was confirmed that the addition of Leoidin in Hela cells did not show any toxic effect at the concentration of 8 μM, and the viability of Hela cells 72 hours after treatment was almost the same as that of the control group. From the above results, it was found that Leoidin can attenuate S. aureus infection without causing side effects in epithelial cells.

Example 8. Verification of the cytoprotective effect of Leoidin against cell damage by S. aureus

Since it was confirmed from Examples 3 to 5 that Leoidin can inhibit the expression of hemolytic and various toxic genes, Leoidin can protect host cells from damage to host cells caused by bacterial infection. It was confirmed through the method described in Examples 1-7.

As a result, as shown in FIG. 12, the control cells not infected with USA300 maintained green fluorescence (FIG. 12A), whereas when cultured with USA300 without treatment with Leoidin, dead cells were It was confirmed that it was dyed red (FIG. 12B). However, when 4 μM concentration of Leoidin was treated, dead cells were reduced (FIG. 12C), and when 8 μM of Leoidin was treated, it was confirmed that the cells remained green. It was confirmed that reoidine almost completely protects the cells from USA300 infection (FIG. 12D). From the above results, it was found that Leoidin concentration-dependently protects cells from cell damage caused by bacterial infection.

Example 9. Verification of synergistic effect according to the combination of Leoidin and antibiotics

Increased antibiotic effect by combination of four antibiotics, well known as S. aureus antibiotics, methicillin, oxacillin, norfloxacin, and vancomycin and leoidin The effect was confirmed through the method described in Examples 1-10. In the case of USA300, a multidrug resistant bacteria, since it has resistance to the antibiotics used in this experiment, the concentration (IC ₅₀ ) that reduces the growth of bacteria by 50% or more was first determined for each antibiotic (1 μg/ml methicillin, 1 μg/ ml oxacillin, 1 μg/ml norfloxacin or 5 μg/ml vancomycin). Thereafter, 4 μM and 8 μM of rheidine and _{antibiotics at an IC 50} concentration were combined and treated with the bacteria, and the degree of inhibition of the growth of the bacteria was observed.

As a result, as shown in Figs. 13 to 16, it was confirmed that the combination of antibiotics and leoidin showed remarkably superior growth inhibitory effect than the case of treatment with antibiotics alone. More specifically, the combination of 8 μM (IC ₉₀ ) of Leoidin and oxacillin, methicillin, and norfloxacin showed 72%, 70%, and 70.9% inhibition, respectively, and in the case of vancomycin, 4 μM It showed inhibition of 70% when combined with (IC ₅₀ ) of Leoidin and 88.22% when combined with 8 μM (IC ₉₀ ) of Leoidin.

Example 10. Verification of Hemolytic Inhibitory Effect of Leoidin on Other Pathogenic Bacteria

It was confirmed whether or not Leoidin has hemolytic inhibitory activity against various other bacteria in addition to S. aureus, and the types of bacteria in this experiment are shown in Table 2 below.

Strains Source/ Reference USA300 (FPR3757) Clinical strain Streptococcus ferus KCTC3637 Serratia marcescens KCTC42171 Vibrio parahaemolyticus KCTC2729 Streptococcus pneumoniae KCTC5080 Staphylococcus saprophyticus KCTC3345 Campylobacter jejuni KCTC5327 Helicobactor pylori KCTC12083 Pseudomonas aureginosa KCTC1637 Bacillus cereus KCTC13153 Enterococcus fecalis KCTC3511 Bacillus licheniformis KCTC1918 Staphylococcus epidermidis KCTC1917 Cornebactreium diptheria KCTC3075 Klepsella pneumoniae Samsung Hospital Infectious Medicine Listreia innocua KCTC3586 Burkholderia cepacia KCTC2966 Streptococcus parasanguinis KCTC15406 Salmonella typhimurium KCTC2058 Streptococcus sobrinus KCTC5809 Streptococcus sanguinis KCTC3284 Streptococcus iniae KCTC3657 Streptococcus Pyogene KCTC3208 Streptococcus mitis KCTC5650 Listeria Ivanovii subsp ivanovii KCTC3444 Listeria monocytogenes KCTC3569 Streptococcus suis Samsung Hospital Infectious Medicine

As a result, as shown in FIG. 17, among 26 pathogenic bacteria tested for hemolytic activity after treatment with 8 μM of reoidine, Streptococcus pneumonia and Streptococcus sobrinus The hemolytic activity was inhibited by more than 80%, and the hemolytic activity of Streptococcus ferus and Listreia innocua was decreased by 77.65% and 76.73%, respectively. In addition, a reduction of 50% or more was also confirmed in Klebsiella pneumoniae and Pseudomonas aeruginosa (Fig. 17A). In addition, when incubated with 8 μM reoidine, it significantly inhibits the hemolytic function of several bacterial species, as well as Campylobacter jejuni, Helicobacter pylori, Enterococcus fecalis. , Corynebacterium diphtheriae, S. parasanguinis, S. sanguinis, S. pyogene, S. suis. ), it was confirmed that there was also antibacterial activity (FIG. 17B).

The above description of the present invention is for illustrative purposes only, and those of ordinary skill in the art to which the present invention pertains will be able to understand that other specific forms can be easily modified without changing the technical spirit or essential features of the present invention. will be. Therefore, it should be understood that the embodiments described above are illustrative in all respects and are not limiting.

<110> RESEARCH & BUSINESS FOUNDATION SUNGKYUNKWAN UNIVERSITY <120> Leoidin compound having anti-virulence activity and use thereof <130> MP17-252 <150> KR 10-2017-0004125 <151> 2017-01-11 <160> 60 <170> KoPatentIn 3.0 <210> 1 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> agrA forward primer <400> 1 acagactcat tgcccatt 18 <210> 2 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> agrA reverse primer <400> 2 aacgtttctc accgatgc 18 <210> 3 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> SaeS forward primer <400> 3 accgcacatt agaagtga 18 <210> 4 <211> 17 <212> DNA <213> Artificial Sequence <220> <223> SaeS reverse primer <400> 4 aatccaatac cttcatc 17 <210> 5 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> sarA forward primer <400> 5 caatggtcac ttatgctg 18 <210> 6 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> sarA reverse primer <400> 6 tctttcatca tgctcattac 20 <210> 7 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> sigB forward primer <400> 7 agtgagcgat gaactaacc 19 <210> 8 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> sigB reverse primer <400> 8 cttgttgccc ataatatc 18 <210> 9 <211> 28 <212> DNA <213> Artificial Sequence <220> <223> hla forward primer <400> 9 caacaacact attgctaggt tccatatt 28 <210> 10 <211> 27 <212> DNA <213> Artificial Sequence <220> <223> hla reverse primer <400> 10 cctgttttta ctgtagtatt gcttcca 27 <210> 11 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> ent forward primer <400> 11 agttgctggc agagtgta 18 <210> 12 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> ent reverse primer <400> 12 gtagctcttt atgcgactc 19 <210> 13 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> coa forward primer <400> 13 taatgtagat tgggcaatta ca 22 <210> 14 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> coa reverse primer <400> 14 atgctttaat tcagttagaa gc 22 <210> 15 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> plc forward primer <400> 15 ttcaatgggc agacaatgcg 20 <210> 16 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> plc reverse primer <400> 16 cctccagacg ctacactcaa 20 <210> 17 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> sspB forward primer <400> 17 ggaaggtctt gctcacttac tt 22 <210> 18 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> sspB reverse primer <400> 18 ctcatggtgt gcaggattca 20 <210> 19 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> sspA forward primer <400> 19 tcccacattg ttgctacagg 20 <210> 20 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> sspA reverse primer <400> 20 tcaggcgaag gtgatttagc 20 <210> 21 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> nuc forward primer <400> 21 atggtcctga agcaagtg 18 <210> 22 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> nuc reverse primer <400> 22 gccaagcctt gacgaacta 19 <210> 23 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> sak forward primer <400> 23 gctctgataa atctgggaca ac 22 <210> 24 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> sak reverse primer <400> 24 tgggcattag atgcgacag 19 <210> 25 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> aur forward primer <400> 25 tgtctgcgtg tactttcact tc 22 <210> 26 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> aur reverse primer <400> 26 aagagtgatg cggtcaaagc 20 <210> 27 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> lukS forward primer <400> 27 gtctggaaca aaatagtctc tcgg 24 <210> 28 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> lukS reverse primer <400> 28 ggtccatcaa caggaggtaa tg 22 <210> 29 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> lukF forward primer <400> 29 tgtgcttcaa catcccaacc 20 <210> 30 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> lukF reverse primer <400> 30 acggtaggtt attcttatgg tggag 25 <210> 31 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> hlgA forward primer <400> 31 atcaatcgga ggcagtggc 19 <210> 32 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> hlgA reverse primer <400> 32 gcagatactt gaccattcgg tg 22 <210> 33 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> hlgB forward primer <400> 33 ctatcacaca gacaagatgg cg 22 <210> 34 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> hlgB reverse primer <400> 34 cccagtagaa gccattccaa c 21 <210> 35 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> hlgC forward primer <400> 35 tccaatcagc cccatcac 18 <210> 36 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> hlgC reverse primer <400> 36 tttgacgccc cataaaacac 20 <210> 37 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> chp forward primer <400> 37 acacaccatc attcagcga 19 <210> 38 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> chp reverse primer <400> 38 agcgttgtag gaagaccac 19 <210> 39 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> Cap5 forward primer <400> 39 atgacgatga ggatagcg 18 <210> 40 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> Cap5 reverse primer <400> 40 ctcggataac acctgttgc 19 <210> 41 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> sdrE forward primer <400> 41 tcagtaagaa cagatgctaa tggtc 25 <210> 42 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> sdrE reverse primer <400> 42 gagtcttttt caccatcagt tgttc 25 <210> 43 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> isdH forward primer <400> 43 agatcaagcg tcaagccaac 20 <210> 44 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> isdH reverse primer <400> 44 tcatctgctg gtggatactg 20 <210> 45 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> clfA forward primer <400> 45 tttcaacaac gcaagata 18 <210> 46 <211> 18 <212> DNA <213> Artificial Sequence <220> <223> clfA reverse primer <400> 46 gctactgccg ctaaacta 18 <210> 47 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> clfB forward primer <400> 47 tttgggatag gcaatcatca 20 <210> 48 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> clfB reverse primer <400> 48 tcatttgttg aagctggctc 20 <210> 49 <211> 19 <212> DNA <213> Artificial Sequence <220> <223> fnbA forward primer <400> 49 tacccgtttc cactttcgc 19 <210> 50 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> fnbA reverse primer <400> 50 ggctacacaa aatcaagtcg c 21 <210> 51 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> fnbB forward primer <400> 51 gtgttgattg tgatggttgc tc 22 <210> 52 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> fnbB reverse primer <400> 52 gtagaggaaa gtgggagttc ag 22 <210> 53 <211> 24 <212> DNA <213> Artificial Sequence <220> <223> psma forward primer <400> 53 gccatcccaa cttaataacc atgt 24 <210> 54 <211> 25 <212> DNA <213> Artificial Sequence <220> <223> psma reverse primer <400> 54 tatcaaaagc ttaatcgaac aattc 25 <210> 55 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> geh forward primer <400> 55 aggcgtggtg tcagtgttag 20 <210> 56 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> geh reverse primer <400> 56 tcgcattccc ttgttctccc 20 <210> 57 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> eap forward primer <400> 57 gttactgcca ctttagcatt gg 22 <210> 58 <211> 22 <212> DNA <213> Artificial Sequence <220> <223> eap reverse primer <400> 58 aggaacagtg tgataaccat cc 22 <210> 59 <211> 20 <212> DNA <213> Artificial Sequence <220> <223> cap8 forward primer <400> 59 cagcagttaa agtcgcacca 20 <210> 60 <211> 21 <212> DNA <213> Artificial Sequence <220> <223> cap8 reverse primer <400> 60 gaacccaata caggcaatcc t 21

Claims (16)

Leooid (Leoidin), derivatives thereof or pharmaceutically acceptable salts thereof as an active ingredient, a pharmaceutical composition for preventing or treating bacterial infections.
The composition of claim 1, wherein the leoidin is a compound represented by the following Chemical Formula 1.
[Formula 1]

The composition of claim 1, wherein the derivative of leoidin is a compound represented by the following Chemical Formula 2.
[Formula 2]

(In Formula 2,
R ₁ and R ₂ are each independently hydrogen, C 1 -C 7 alkyl, C 1 -C 7 thioalkyl, C 1 -C 7 aminoalkyl, or C 1 -C 7 hydroxyalkyl; ,
R ₃ is hydrogen, hydroxy, aldehyde, halide, CN, OR _a , NR _b , SR _c or COOR _d ,
R ₄ is hydrogen, C 1 -C 7 alkyl, C 1 -C 7 thioalkyl, C 1 -C 7 aminoalkyl, C 1 -C 7 hydroxyalkyl, halide, CN, OR _a , NR _b or SR _c ,
R _a , R _b , R _c And R _d each independently represent hydrogen, hydroxy, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl.)
The composition of claim 3, wherein the derivative of leoidin is a compound represented by the following formula (4).
[Formula 4]

The composition of claim 1, wherein the derivative of leoidin is a compound represented by the following Chemical Formula 3.
[Formula 3]

(In Chemical Formula 3,
R ₁ and R ₂ are each independently hydrogen, C 1 -C 7 alkyl, C 1 -C 7 thioalkyl, C 1 -C 7 aminoalkyl, or C 1 -C 7 hydroxyalkyl; ,
R ₃ is hydrogen, hydroxy, aldehyde, halide, CN, OR _a , NR _b , SR _c or COOR _d ,
R ₄ and R ₅ are each independently hydrogen, C 1 -C 7 alkyl, C 1 -C 7 thioalkyl, C 1 -C 7 aminoalkyl, C 1 -C 7 hydroxyalkyl, Halide, CN, OR _a , NR _b or SR _c ,
R _a , R _b , R _c And R _d each independently represent hydrogen, hydroxy, C1-C7 thioalkyl, C1-C7 aminoalkyl, or C1-C7 hydroxyalkyl.)
The composition of claim 1, wherein the composition has antitoxic or antipathogenic activity against bacteria.
The composition of claim 1, wherein the composition inhibits erythrocyte hemolysis by bacteria.
The composition of claim 1, wherein the composition inhibits the expression of a staphylococcal accessory effector (sae) or a staphylococcal accessory regulator (sar) gene.
The composition of claim 1, wherein the composition inhibits the internalization of bacteria.
The composition of claim 1, wherein the composition protects the host cell from damage to the host cell by bacterial infection.
According to claim 1, wherein the bacteria are Staphylococcus aureus, Streptococcus ferus, Serratia marcescens, Vibrio parahaemolyticus, Streptococcus Streptococcus pneumonia, Staphylococcus saprophyticus, Campylobacter jejuni, Helicobactor pylori, Pseudomonas aeruginosa basilus acerus (Bacillus cereus), Enterococcus fecalis, Bacillus licheniformis, Staphylococcus epidermidis, Corynebacterium diphtheriae, Crypnea neuramona (Klebsiella pneumoniae), Listreia innocua, Burkholderia Sephacia (Burkholderia cepacia), Streptococcus parasanguinis, Salmonella typhimurium, Streptococcus sobrinus, Streptococcus sanguiep icoccus striconis iniae, Streptococcus pyogene, Streptococcus mitis, Listeria Ivanovii subsp ivanovii, Listeria monocytogenes, Streptococcus suis (Streptococcus suis) Clostridium perfringens, Yersinia enterocolitica, Shigella boydii, Shigella flexneri, Shigella sonnei, Salmonella cholera Salmonella choleraesuis subsp, Salmonella enteritid is), Salmonella bongori, Salmonella enterica, Mycobacterium tuberculosis, Mycobacterium leprae, Crosstridium botulinum , Bacillus anthracis, Yersinia pestis, Chlamydia pneumonia, Borrelia burgdorferi, Coxiella burnetii, Mycobacte Mycobacterium avium, Escherichia coli, Borrelia sp., Bartonella sp., Chlamydia trachomatis, and Mycoplasma pneumoniae (Mycoplasma pneumonia), characterized in that the composition selected from the group consisting of.
The composition of claim 1, wherein the composition is formulated or used in combination with an antibiotic.
The method of claim 12, wherein the antibiotic is methicillin (methicillin), oxacillin (oxacillin), norfloxacin (norfloxacin), vancomycin, amikacin (Amikacin), gentamicin (Gentamicin), kanamycin (Kanamycin) Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin, Spectinomycin, Geldanamycin, Gelamymycin, Herbimycin Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem, Imipenem / Cilastatin, Meropenem, Cefadroxil Cefazolin, Cefalothin, Cefalothin, Cefalexin, Cefaclor, Cefacandole, Cefamandole, Cefoxitin, Cefprozil, Cefprozil, Cefprozil Cefuroxime, Cefixime, Cefdinir, Cefditoren, Three Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Ceftriaxone, Ceftriaxone Cefepime, Ceftaroline fosamil, Ceftobiprole, Teicoplanin, Telavancin, Dalbavancin, Oritavancin, Clinda Clindamycin, Lincomycin, Daptomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Erythromycin, Roxithromycin (Roxithromycin), Troleandomycin, Telithromycin, Spiramycin, Aztreonam, Furazolidone, Nitrofurantoin, Nitrofurantoin, Linezolidide ), Posizolid, Radezolid, Torezolid, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, Dicloxacillin Flucloxacillin, Mezlocillin, Nafcillin, Penicillin G, Penicillin V, Penicillin V, Piperacillin, Temocillin, Ticarcillin , Amoxicillin / clavulanate, Ampicillin / sulbactam, Piperacillin / tazobactam, Ticarcillin / clavulanate, Bacitracin (Bacitracin), Colistin, Polymyxin B, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Levofloxacin, Lomefloxacin Lomofloxacin, Moxifloxacin, Nalidixic acid idixic acid), Ofloxacin, Trovafloxacin, Grepafloxacin, Greflofloxacin, Spafloxacin, Temafloxacin, Mafenide, Sulfa Acetama Sulfurtamide, Sulfadiazine, Silver sulfadiazine, Sulfamethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanalimide (Sulfasalazine), Sulfixazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), TMP-SMX, Sulfonamido chrysoidine, Demeclocycline , Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Clofazimine, Dapsone, Capreomycin, Cyclorine ine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, Rifampicin, Rifabutin, Rifapentin, Arsphenamine Chloramphenicol, Chloramphenicol, Fosfomycin, Fusidi cacid, Metronidazole, Mupirocin, Platinsimycin, Quinupristine / Dalfopristin, Dalfopristin Thiamphenicol (Thiamphenicol), Tigecycline (Tigecycline), Tinidazole (Tinidazole), and trimethoprim (Trimethoprim), characterized in that the composition.
A cosmetic composition for preventing or ameliorating a bacterial infection, including a leoidin, a derivative thereof, or a cosmetically acceptable salt thereof.
Food composition for preventing or ameliorating bacterial infection, including Leooid (Leoidin) or derivatives thereof.
Animal feed comprising Leooid (Leoidin) or derivatives thereof.

Images