KR20180082973A - Leoidin compound having anti-virulence activity and use thereof - Google Patents

Abstract

The present invention relates to a new usage purpose of Leoidin compound, and specifically, to a pharmaceutical composition for treating or preventing bacterium infection, including Leoidin compound having antitoxic or antivirulence activity, a derivative thereof, or pharmaceutically allowable salt of the same. According to the present invention, the Leoidin or the derivative thereof does not influence growth of bacteria but can suppress hemolytic action of red blood cells due to the bacteria. Also, the Leoidin or the derivative thereof can suppress revelation of various toxic genes by suppressing the revelation of sae and sarA modulators. Also, the Leoidin or the derivative thereof can suppress bacteria internalization by suppressing adhesion and/or infiltration of the bacteria to a host cell. Also, the Leoidin or the derivative thereof does not cause any toxicity to the host cell and can be easily used for manufacture of food or feed additives, feed for an animal, health food, a cosmetic compound, and a medicine for preventing, improving, or treating the bacteria infection. Also, the Leoidin or the derivative thereof can be usefully used to clean a medical container or to suppress the bacteria having the toxicity or a tolerance to antibiotics.

Description

Reoidin compounds having antitoxic or anti-pathogenic activity and their use {

The present invention relates to a novel use of a leuidine compound, and more particularly, to a novel use of a leuidine compound for the prevention or treatment of a bacterial infectious disease comprising a leuidine compound having an anti-toxic or anti-pathogenic activity, a derivative thereof or a pharmacologically acceptable salt thereof To a pharmaceutical composition.

As shown by the worldwide reappearance of bacterial diseases, bacterial pathogens continue to present a serious threat to public health. In particular, Staphylococcus aureus ("S. aureus") is a bacterium that symbiologically colonizes more than 25% of the human population. Importantly, the organism can break the initial site of colonization and cause bacterial seeding and disease. S. aureus is a leading cause of hospital infection and is the most common causative agent of skin and soft tissue infections as well as infectious cardiomyopathies and is one of the four leading causes of food-mediated disease. Overall, S. aureus infects over 1.2 million patients every year in US hospitals.

Antibiotics are commonly used to treat bacterial infections, including S. aureus. Antibiotics are metabolites produced by microorganisms, which inhibit or kill the growth of other microorganisms in a small amount and are used to treat infectious diseases caused by pathogens, and are used worldwide because they exhibit excellent efficacy against infection.

However, due to the abuse of antibiotics, the ability to resist the pathogens themselves has become stronger, and resistance to certain antibiotics has become increasingly strong. As superb bacteria first appeared in Japan in 1996, the use of antibiotics A problem has occurred. In the case of antibiotics, the mutation of the bacteria is induced by the action of killing the bacteria. In the course of such mutation, a gene which causes antibiotic resistance is produced, and a drug-resistant mutant bacteria can be produced. And the spread of resistant bacteria can be done quickly. These superb bacteria are exemplified by MRSA (Methicillin-resistant Staphylococcus aureus), VRSA (Vancomycin-resistant Staphylococcus aureus) and VRE (Vancomycin-resistant Enterococci) with stronger antibiotic resistance and antibiotic resistant bacteria , The tolerance gradually becomes stronger so that it can resist any antibiotic.

In order to prevent the emergence of such drug-resistant bacteria, recently, instead of treating antibiotics that kill infecting bacteria, an antibacterial agent that reduces pathogenicity by inhibiting the expression or activity of toxic factors used by bacteria that infiltrate in vivo, A method of treating bacterial infectious diseases is suggested as an alternative. Bacteria that have lost their toxicity by these antidote agents can be killed by the immune function of the human body and ultimately can be expected to have a therapeutic effect. These antidote agents act in a totally different mechanism from existing antibiotics, so they can be used not only as a susceptible strain but also as a therapeutic agent for infectious diseases caused by multidrug-resistant bacteria that already have resistance. These antidotes may also be used in combination with existing antibiotics to reduce the dose of antibiotics or to increase their activity. Studies on the anticancer agent of this new mechanism have been reported (see Korean Patent Publication No. 10-2015-0045216), but the development of a therapeutic agent using such a method is still insufficient.

Disclosure of Invention Technical Problem [8] Accordingly, the present invention has been made to solve the above problems of the prior art, and the inventors of the present invention have found that a novel method for treating infectious diseases of susceptible or multidrug-resistant bacteria without generating tolerance, (Leoidin) has been shown to inhibit the toxic activity or inhibit the expression of toxic factors. As a result, it has been found that Leoidin does not affect the growth of the strain, Hematopoietic and cell-invasive activity, and found that the antibiotic-susceptibility of the multidrug-resistant microbes is increased when they are co-administered with existing antibiotics. Based on this finding, the present invention has been completed .

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

However, the technical problem to be solved by the present invention is not limited to the above-mentioned problems, and other matters not mentioned can 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 infection comprising leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In one embodiment of the present invention, the leione may be a compound represented by the formula (1).

[Chemical Formula 1]

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

(2)

In Formula 2,

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl or C 1 to C 7 hydroxyalkyl, ,

R ₃ is selected from the group consisting of hydrogen, hydroxy, aldehyde, halide, CN, OR _a , NR _b , SR _c Or COOR _d ,

R ₄ is selected from the group consisting of 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.

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

[Chemical Formula 4]

In another embodiment of the present invention, the derivative of the leodine may be a compound represented by the following general formula (3).

(3)

In Formula 3,

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl or C 1 to C 7 hydroxyalkyl, ,

R ₃ is selected from the group consisting of hydrogen, hydroxy, aldehyde, halide, CN, OR _a , NR _b , SR _c Or COOR _d ,

R ₄ and R ₅ are each independently selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl, C 1 to 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.

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 red blood cell hemolysis by bacteria.

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

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

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

In another embodiment of the present invention, the bacterium is selected from the group consisting of Staphylococcus aureus, Streptococcus ferus, Serratia marcescens, Vibrio parahaemolyticus ), Streptococcus pneumonia, Staphylococcus saprophyticus, Campylobacter jejuni, Helicobacter pylori, Pseudomonas aeruginosa, Pseudomonas aeruginosa, Bacillus cereus, Enterococcus fecalis, Bacillus licheniformis, Staphylococcus epidermidis, Corynebacterium diphtheriae, Klebsiella spp., Bacillus cereus, Bacillus cereus, Enterococcus fecalis, Bacillus licheniformis, Staphylococcus epidermidis, Klebsiella pneumoniae, Listreia innocua, Burkholdode Such as Burkholderia cepacia, Streptococcus parasanguinis, Salmonella typhimurium, Streptococcus sobrinus, Streptococcus sanguinis, Streptococcus sp., Streptococcus spp. For example, Streptococcus iniae, Streptococcus pyogene, Streptococcus mitis, Listeria Ivanovii subsp ivanovii, Listeria monocytogenes, Streptococcus suis ), Clostridium perfringens, Yersinia enterocolitica, Shigella boydii, Shigella flexneri, Shigella sonnei, and the like. , Salmonella choleraesuis subsp, Salmonella enteritidis (Sal montella enteritidis, Salmonella bongori, Salmonella enterica, Mycobacterium tuberculosis, Mycobacterium leprae, Clostridium botulinum, Clostridium botulinum, ), Bacillus anthracis, Yersinia pestis, Chlamydia pneumonia, Borrelia burgdorferi, Coxiella burnetii, Mycobacterium avium, Escherichia coli, Borrelia sp., Bartonella sp., Chlamydia trachomatis, and Mycoplasma pneumoniae. Mycoplasma pneumonia. ≪ / RTI >

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 selected from the group consisting of methicillin, oxacillin, norfloxacin, vancomycin, amikacin, gentamicin, But are not limited to, kanamycin, neomycin, netilmicin, tobramycin, paromomycin, streptomycin, spectinomycin, geldanamycin, Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem, Imipenem / Cilastatin, Meropenem, Sephadoxil, (Cefadroxil), Cefazolin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Cefacin, Cefuroxime, Cefixime, Cefdinir, Cefditoren (Ce femtosecond, fditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil, Ceftobiprole, Teicoplanin, Telavancin, Dalbavancin, Oritavancin, Oritavancin, ), Clindamycin, Lincomycin, Daptomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, , Roxithromycin, Troleandomycin, Telithromycin, Spiramycin, Aztreonam, Furazolidone, Nitrofurantoin, Rinse, Linezolid, Posizolid, Ladezol, But are not limited to, Radezolid, Torezolid, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, ), Flucloxacillin, Mezlocillin, Nafcillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin, amoxicillin / clavulanate, ampicillin / sulbactam, piperacillin / tazobactam, ticarcillin / clavulanate, ), Bacitracin, Colistin, Polymyxin B, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin Levofloxacin, Lomefloxacin, Moxifloxacin, Such as Nalidixic acid, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin, Mafenide, Sulfametamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethizole, Sulfamethoxazole, Sulfanilide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), TMP-SMX), Sulfonamido chrysoidine, Demeclocycline But are not limited to, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Clofazimine, Dapsone, Capreomycin, It has been reported that the antioxidant activity of cycloserine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, Arphenamine, Chloramphenicol, Fosfomycin, Fusidic acid, Metronidazole, Mupirocin, Platensimycin, Quinupristin / Dalfopristin, ), Thiamphenicol, Tigecycline, Tinidazole, and Trimethoprim.

The present invention also provides a method of treating a bacterial infection comprising administering to a subject a leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

Moreover, the present invention provides a use for the prevention, amelioration, or treatment of bacterial infections of leoidin, derivatives thereof, or a pharmaceutically acceptable salt thereof.

In addition, the present invention provides a method for inhibiting bacterial toxicity or pathogenicity, comprising the step of administering to a subject a leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

The present invention also provides a cosmetic composition for preventing or improving bacterial infection comprising leoidin, a derivative thereof, or a cosmetically acceptable salt thereof.

The present invention also provides a health functional food composition for preventing or ameliorating a bacterial infection comprising leoidin or a derivative thereof.

The present invention also provides an animal feed comprising Leoidin or a derivative thereof.

Leiodin or a derivative thereof according to the present invention can inhibit erythropoiesis caused by bacteria without affecting the growth of bacteria and inhibit the expression of sae and sarA regulatory factors, Expression can be suppressed. It may also inhibit bacterial internalization through inhibition of bacterial adhesion to host cells and / or invasion. Furthermore, since Leoidin or a derivative thereof does not cause any toxicity to a host cell, production of pharmaceuticals, cosmetic composition, health food, animal feed, food or feed additive, etc. for prevention, improvement or treatment of bacterial infection And it is expected that it can be usefully used for cleaning medical containers and further for antibiotic resistance or for inhibiting bacteria which are toxic when antibiotics are treated.

Fig. 1 shows the structure of a leoidin compound screened with a compound having a strong toxicity-inhibiting activity from a low-molecular-weight compound library derived from a natural product.
Fig. 2 shows the structure of a gangaleoidin compound screened with a compound having a strong toxicity-inhibiting activity from a low molecular compound library derived from a natural product.
FIG. 3 shows the results of confirming the antioxidant effect against USA300 when various concentrations of the reoidin (1, 2, 4 and 8 μM) were treated.
FIG. 4 shows the results of confirming the antioxidant effect against USA 300 when treating various concentrations of strong galoisidine (1, 2, 5, 10, 15, 20 and 25 μM).
FIG. 5 shows the results of confirming the erythrocyte hemolysis inhibitory effect of USA 300 when treating various concentrations of the reoidin (1, 2, 4 and 8 μM).
FIG. 6 shows the results of confirming the erythrocyte hemolytic inhibitory effect of USA 300 when treating galangioides (1, 2, 4, 8, 16 and 32 μM) at various concentrations.
FIG. 7 shows the results of confirming the effect of inhibiting the expression of transcriptional regulatory factors by leiadin.
FIG. 8 shows the results of confirming the inhibitory effect of the toxin gene on the expression of the gene regulated by the sae regulatory factor by leiadin.
FIG. 9 shows the results of confirming the effect of suppressing the expression of a toxin gene regulated by the sarA regulator by leiadin.
FIG. 10 shows the results of confirming the effect of inhibiting the expression of other toxic genes by leiadin.
Fig. 11 shows the inhibition effect of USA300 on Hela epithelial cells induced by leiadin.
FIG. 12 shows the results obtained when the cells were cultured with USA300 (A), USA300 (USA), and USA300 (B) in order to examine the cell protection effect from the cell damage by S. aureus (C) in the case of treatment with leiodine (Le), and (D) in case of treatment with 8 uM of leoidin.
FIG. 13 shows the effect of the combination of leucine and oxacillin in combination with (A) oxacillin alone, (B) combination with 4 uM of leucine, And (C) the result of confirming the antitoxic effect.
FIG. 14 is a graph showing the synergistic effect of combination of leodin and norfloxacin in the case of (A) when Norfloxacin is singly administered, (B) when combined with 4 uM of a leuidin, (C) in the case of the combination.
Fig. 15 is a graph showing the synergistic effect of combination of leiodine and methicillin in the case of (A) when methicillin was singly administered, (B) when combined with 4 uM of leuidine, And (C) the result of confirming the antitoxic effect.
FIG. 16 is a graph showing the effect of combining vancomycin alone (A), 4 uM concentration of leion (B) and 8 uM of leion (FIG. 16) C). The results are shown in Fig.
Fig. 17 shows the hemolysis inhibitory effect of 26 pathogenic strains of rheidin.

As a result of screening for substances capable of inhibiting toxicity and / or pathogenicity without affecting the growth of bacteria from a low molecular compound library derived from natural products, the present inventors have found that a novel compound of Leoidin as an antitoxic and / And the present invention was completed on the basis thereof.

Hereinafter, the present invention will be described in detail.

The present invention provides a pharmaceutical composition for preventing or treating a bacterial infection comprising leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

As used herein, the term " prophylactic " means any act that inhibits or slows the onset of a bacterial infectious disease by administration of the composition of the present invention.

As used herein, the term " treatment " means any action that improves or alleviates symptoms due to a bacterial infectious disease caused by administration of the composition of the present invention.

In the present invention, leoidin can be obtained by a natural process or artificially synthesized process, and it can be represented by the following general formula (1) whether or not it is produced by any raw material, manufacturing method or the like.

[Chemical Formula 1]

In the present invention, " derivative of Leoidin " refers to a compound having the same activity as Leoidin and having an effect of inhibiting toxicity and / or pathogenicity without affecting the growth of bacteria, May be a compound represented by the following general formula (2) or (3), but is not limited thereto.

(2)

In Formula 2,

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl or C 1 to C 7 hydroxyalkyl, ,

R ₃ is selected from the group consisting of hydrogen, hydroxy, aldehyde, halide, CN, OR _a , NR _b , SR _c Or COOR _d ,

R ₄ is selected from the group consisting of 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.

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

[Chemical Formula 4]

(3)

In Formula 3,

R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl or C 1 to 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 selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl, C 1 to C 7 hydroxyalkyl, a 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 the general formula (3) can be prepared from the compound represented by the general formula (2) through the following general reaction.

Leoidin represented by the formula (1) or Leoidin derivative represented by the formula (2) or (3), which is included in the composition according to the present invention as an active ingredient, Lt; / RTI > and / or anti-pathogenic activity. More specifically, the compound of the present invention, Leoidin or a derivative thereof, inhibits erythrocyte hemolysis by bacteria and inhibits the expression of transcription factors and toxic genes, thereby exhibiting antitoxic and / or antinuclear activity Lt; / RTI > The bacteria may be selected from the group consisting of Staphylococcus aureus, Streptococcus ferus, Serratia marcescens, Vibrio parahaemolyticus, Streptococcus pneumoniae (Streptococcus aureus, Streptococcus spp. Staphylococcus pneumonia, Staphylococcus saprophyticus, Campylobacter jejuni, Helicobacter pylori, Pseudomonas aeruginosa, Bacillus cereus, For example, Enterococcus fecalis, Bacillus licheniformis, Staphylococcus epidermidis, Corynebacterium diphtheriae, Klebsiella pneumoniae, Listreia innocua, Burkholderia cepacia (Burkholderia cepacia) ), Streptococcus parasanguinis, Salmonella typhimurium, Streptococcus sobrinus, Streptococcus sanguinis, Streptococcus iniae, Streptococcus spp., Streptococcus spp. Streptococcus pyogen, Streptococcus mitis, Listeria Ivanovii subsp ivanovii, Listeria monocytogenes, Streptococcus suis, Clostridium purpurei, Streptococcus spp., Streptococcus spp., Streptococcus spp. Clostridium perfringens, Yersinia enterocolitica, Shigella boydii, Shigella flexneri, Shigella sonnei, Salmonella choleraeusis, (Salmonella choleraesuis subsp), Salmonella enteritidis, Mycobacterium tuberculosis, Salmonella bongori, Salmonella enterica, Mycobacterium tuberculosis, Mycobacterium leprae, Clostridium botulinum, Bacillus anthracis Bacillus anthracis, Yersinia pestis, Chlamydia pneumonia, Borrelia burgdorferi, Coxiella burnetii, Mycobacterium avium, avium, Escherichia coli, Borrelia sp., Bartonella sp., Chlamydia trachomatis, and Mycoplasma pneumonia. But are not limited thereto.

According to one embodiment of the present invention, it was confirmed that the compound of the present invention, Leoidin, significantly inhibited haemolysis of S. aureus (see Example 3), and the transcriptional regulatory factor sae And sarA, as well as the expression of toxic genes and other toxic genes, which are mainly regulated in them, (see Examples 4 and 5).

In addition, the compound of the present invention, Leoidin or a derivative thereof, has antitoxic and / or anti-pathogenic activity through its action of inhibiting bacterial internalization due to inhibition of bacterial adhesion and / or invasion to host cells Lt; / RTI >

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

Meanwhile, the composition according to the present invention may be formulated together with conventional antibiotics or may be used in combination with antibiotics, such as methicillin, oxacillin, norfloxacin, vancomycin, Amikacin, Gentamicin, Kanamycin, Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin, Specification The compounds of the present invention may be used in combination with other drugs such as Spectinomycin, Geldanamycin, Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem, Imipenem / Cilastatin, Meropenem, Cefadroxil, Cefazolin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, < RTI ID = 0.0 > Cefuroxime, Cefixime, Cefdinir, Cefditoren, Cefoperazone, Cefotaxime, Cefpodoxime, Ceftazidime, ), Ceftibuten, Ceftizoxime, Ceftriaxone, Cefepime, Ceftaroline fosamil, Ceftobiprole, Teicoplasma, Such as Teicoplanin, Telavancin, Dalbavancin, Oritavancin, Clindamycin, Lincomycin, Daptomycin, Azithromycin, , Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, Troleandomycin, Telithromycin, Spiramycin, Tryptophan, Aztreonam, Furazolidone, Nitrofurantoin, Nitrofurantoin, Linezolid, Posizolid, Radezolid, Torezolid, Amoxicillin, Ampicillin, Azlocillin, , Carbenicillin, Cloxacillin, Dicloxacillin, Flucloxacillin, Mezlocillin, Nafcillin, Penicillin G, , Penicillin V, Piperacillin, Temocillin, Ticarcillin, Amoxicillin / clavulanate, Ampicillin / sulbactam, (Piperacillin / tazobactam), ticarcillin / clavulanate, bacitracin, colistin, polymyxin B, ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, levofloxacin, (Levofloxacin), Lomefloxacin, Moxifloxacin, Nalidixic acid, Ofloxacin, Trovafloxacin, Grepafloxacin, Spas The compounds of the present invention may be selected from the group consisting of Sparfloxacin, Temafloxacin, Mafenide, Sulfacetamide, Sulfadiazine, Silver sulfadiazine, Sulfadimethoxine, Sulfamethiazole, Sulfamethoxazole, Sulfanilide, Sulfasalazine, Sulfisoxazole, Trimethoprim-Sulfamethoxazole (Co-trimoxazole), Sulfamethoxazole, TMP-SMX), Sulfonamido chrysoidine, Demeclocycline, Doxycycline, Minocycline, Oxytetracycline, Tetracycline, Clozapine, Clofazimine, Dapsone, Capreomycin, Cycloserine, Ethambutol, Ethionamide, Isoniazid, Pyrazinamide, and rifampicin. Rifampicin, Rifabutin, Rifapentine, Arsphenamine, Chloramphenicol, Fosfomycin, Fusidic acid, Metronidazole, Consisting of Mupirocin, Platensimycin, Quinupristin / Dalfopristin, Thiamphenicol, Tigecycline, Tinidazole, and Trimethoprim. , And more preferably selected from the group consisting of methicillin, oxacillin, norfloxacin, and vancomycin. But, not limited to this.

According to another embodiment of the present invention, when a compound of the present invention, Leoidin, is combined with existing antibiotics methicillin, oxacillin, norfloxacin, and vancomycin to treat antibiotic resistant bacteria, (See Example 9).

The leoidin or derivative thereof represented by Formula 1 of the present invention may include not only pharmaceutically acceptable salts but also all salts, hydrates and solvates which can be prepared by a conventional method. When used in the form of a pharmaceutically acceptable salt, the acid addition salt formed by a pharmaceutically acceptable free acid is useful as a salt. Acid addition salts include those derived from 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, hydroxyalkanoates, Dioleate, aromatic acid, aliphatic and aromatic sulfonic acids. Such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, Butyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, succinate, maleic anhydride, maleic anhydride, , Sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chlorobenzene sulfide Propyl sulphonate, naphthalene-1-yne, xylenesulfonate, phenylsulfate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, Sulfonate, naphthalene-2-sulfonate or mandelate.

The acid addition salt according to the invention can be prepared by a conventional method, for example by dissolving leoidin in an excess of an aqueous acid solution and treating the salt with a water-miscible organic solvent such as methanol, ethanol, acetone or acetonitrile To precipitate it. By heating the same amount of leoidin and an acid or alcohol in water, then evaporating the mixture and drying, or by suction filtration of the precipitated salt.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding silver salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable silver salt (e.g., silver nitrate).

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

Examples of the formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules and elixirs. These formulations may contain, in addition to the active ingredient, a diluent (e.g., lactose, dextrose, (E.g., silica, talc, stearic acid and magnesium or calcium salts thereof and / or polyethylene glycols), such as, for example, water, rosin, sucrose, mannitol, sorbitol, cellulose and / or glycine. The tablets may also contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain additives such as starch, agar, alginic acid or its sodium salt A disintegrating or boiling mixture and / or an absorbent, a colorant, a flavoring agent, and a sweetening agent.

The pharmaceutical composition comprising Leoidin or a derivative thereof as an active ingredient can be administered parenterally, and parenteral administration can be carried out by subcutaneous injection, intravenous injection, intramuscular injection, intrathoracic injection or transdermal administration And may be applied by a topical application method, preferably by application.

In order to formulate the composition for parenteral administration, leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof is mixed with water or a stabilizer or a buffer to prepare a solution or suspension, which is then mixed with an ampule or vial unit May be prepared in dosage forms. The composition may be sterilized or may contain other therapeutically useful substances such as preservatives, stabilizers, wettable or emulsifying accelerators, salts for controlling osmotic pressure and / or buffers, and other therapeutically useful substances, 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 will depend on the type of disease, severity, , Sensitivity to the drug, time of administration, route of administration and rate of release, duration of treatment, factors including co-administered drugs, and other factors well known in the medical arts. The pharmaceutical composition according to the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agents, and may be administered sequentially or simultaneously with conventional therapeutic agents, and may be administered singly or in multiple doses. It is important to take into account all of the above factors and to administer the amount in which the maximum effect can be obtained in a minimal amount without side effects, which can be easily determined by those skilled in the art.

Specifically, the effective amount of the pharmaceutical composition according to the present invention may vary depending on the patient's age, sex, condition, body weight, absorbency of the active ingredient, inactivation rate and excretion rate, type of disease,

In another aspect of the present invention, the present invention provides a method for preventing or treating a bacterial infection comprising administering to a subject a 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 a bacterium comprising the step of administering to a subject a leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.

The term " individual " as used herein refers to a subject in need of treatment for a disease, and more specifically refers to a human or non-human primate, mouse, rat, dog, cat, It means mammals.

In another aspect of the present invention, there is provided a cosmetic composition for prevention or improvement of bacterial infection comprising leoidin, a derivative thereof, or a cosmetically acceptable salt thereof.

The cosmetic composition of the present invention can be prepared into any of the formulations conventionally produced in the art and can be used as a solution, a suspension, an emulsion, a paste, a gel, a cream, a lotion, a powder, a soap, , Oil, powdered foundation, emulsion foundation, wax foundation and spray, but is not limited thereto. More specifically, it can be manufactured in the form of a soft lotion, a nutritional lotion, a nutritional cream, a massage cream, an essence, an eye cream, a cleansing cream, a cleansing foam, a cleansing water, a pack, a spray or a powder.

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

When the formulation of the present invention is a powder or a spray, lactose, talc, silica, aluminum hydroxide, calcium silicate or polyamide powder may be used as a carrier component. In the case of a spray, in particular, / Propane or dimethyl ether.

When the formulation of the present invention is a solution or an emulsion, a solvent, a dissolving agent or an emulsifying agent is used as a carrier component, and examples thereof include water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, , 3-butyl glycol oil, glycerol aliphatic ester, polyethylene glycol or sorbitan fatty acid esters.

In the case where the formulation of the present invention is a suspension, a carrier such as water, a liquid diluent such as ethanol or propylene glycol, a suspending agent such as ethoxylated isostearyl alcohol, polyoxyethylene sorbitol ester and polyoxyethylene sorbitan ester, Cellulose, aluminum metahydroxide, bentonite, agar or tracant, etc. may be used.

When the formulation of the present invention is an interfacial active agent-containing cleansing, the carrier component may include aliphatic alcohol sulfate, aliphatic alcohol ether sulfate, sulfosuccinic acid monoester, isethionate, imidazolinium derivative, methyltaurate, sarcosinate, fatty acid amide Ether sulfates, alkylamidobetaines, aliphatic alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable oils, lanolin derivatives or ethoxylated glycerol fatty acid esters.

The ingredients contained in the cosmetic composition of the present invention include, in addition to the active ingredient and the carrier ingredient, ingredients conventionally used in cosmetic compositions and include conventional additives such as antioxidants, stabilizers, solubilizers, vitamins, . ≪ / RTI >

In another aspect of the present invention, there is provided a health functional food composition for preventing or ameliorating a bacterial infection comprising leoidin or a derivative thereof. In the present invention, Leoidin or a derivative thereof can be easily used for the production of a health functional food having an antitoxic and / or antinociceptive effect, for example, a raw material, an additive, a food additive, a functional food or a beverage .

In the present invention, the term " health functional food " refers to a food group imparted with added value to function or express the function of the food by physical, biochemical, biotechnological techniques or the like, Means a food prepared by sufficiently designing the body to control the function of the body in terms of disease prevention and recovery, etc. It may further include a food-acceptable food-aid additive, and may contain a suitable carrier, It may further comprise a diluent.

In addition, the health functional food composition of the present invention can be used as a nutritional supplement, a vitamin, a mineral (electrolytic), a flavor such as a synthetic flavor and a natural flavor, a coloring agent and a filler (cheese, chocolate etc.), a pectic acid and its salt, And a salt thereof, an organic acid, a protective colloid thickener, a pH adjusting agent, a stabilizer, a preservative, a glycerin, an alcohol, a carbonating agent used in a carbonated drink, and the like. These components may be used independently or in combination.

The amount of the leiodin or a derivative thereof may be 0.001 to 90% by weight, preferably 0.1 to 40% by weight, of the total weight of the health functional food, , The effective amount may be used in an amount of more than the above range because there is no problem in terms of safety and therefore it is not limited to the above range.

In another aspect of the present invention, the present invention provides an animal feed comprising leoidin or a derivative thereof. The animal feed can be in any suitable form, such as a dry, semi-wet or wet form, which can be a chilled or long-preserved 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 invention. The animal feed can be prepared using conventional manufacturing methods well known in the art, such as extrusion cooking, baking and other suitable processing methods. When animal feed is extruded, it can be provided in the form of a kibble. In the case of wet food or wet pet food, it may be provided in the form of a meat imitation product. Other methods for the manufacture of chunk type products can also be used, for example, in cooking in a steam oven. Alternatively, a loaf type product may be prepared by emulsifying a suitable meat material to produce a meat emulsion, adding a suitable gelling agent, heating the meat emulsion and placing it in a can or other container.

Hereinafter, preferred embodiments of the present invention will be described in order to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.

[Example]

Example 1. Experimental preparation and analysis method

1-1. Culture of strains and production of reporter system

Staphylococcus aureus strain (USA300) with multidrug resistance was cultured in a tryptic soy broth (TSB) medium at 37 ° C in a rotary shaker.

Meanwhile, the virulence reporter strain was prepared by introducing hla promoter fused with green fluorescent protein (GFP) into USA300. For selection of reporter strains, 5 [mu] g / ml chloramphenicol (Sigma-Aldrich, USA) was added to the culture medium. The viable cell count was determined by smearing the diluted culture with TSA (tryptic soy agar).

1-2. Candidate compound screening

A library containing approximately 800 native compound-derived compounds was purchased from Microsource discovery systems, Inc., USA. All compounds had a 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 antimicrobial and antitoxic activity of the library compound. That is, Colonies were collected from TSA plates and suspended in tubes with fresh TSB medium to 1 at OD ₆₀₀ . Thereafter, the cells are cultured on an rotary shaker at 180 rpm and 37 ° C until the exponential phase, and the cell density is increased to ~ 2 × 10 ⁷ CFU ml ^{-1 in} the early exponential phase. And diluted in fresh medium. The diluted culture 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, the absorbance at 600 nm and the fluorescence at 480/520 nm were measured. At this time, the compound was reported to be active when reducing GFP production without reducing bacterial growth compared to the vehicle (untreated control).

1-3. Determination of effective concentration of compound

The reporter strain prepared in Example 1-1 was cultivated overnight in TSB, diluted 1: 100 in fresh TSB medium, and cultured to the initial exponential phase. Then, 100 μl of the culture (containing 2 × 10 ⁷ bacteria) Was added to a 48-well plate of sterile polystyrene material with serial dilutions and vehicle (untreated control). The plate was incubated at 37 ° C for 6 hours, and fluorescence was measured. The effective concentration of the compound was calculated by measuring IC ₅₀ and IC ₉₀ as compared to the vehicle (control).

1-4. Analysis of anti-virulent activity

USA300 was cultivated overnight in TSB, diluted 1: 100 in fresh TSB medium and grown to the initial exponential phase. 500 μl of the culture without or with various concentrations of leoidin or its derivatives were added to sterilized polystyrene Well plate. The culture was grown in a rotary shaker at 37 ° C for 6 hours in a rotary shaker at 200 rpm, and the absorbance was measured at 595 nm for leodine and at 600 nm for derivatives thereof.

1-5. Hemolytic activity analysis

The anti-hemolytic activity of leoidin or its derivatives was measured using human-derived red blood cells. USA300 was cultured overnight, diluted with 20 ml of fresh TSB medium to OD ₆₀₀ = 0.1, and then incubated at 37 ° C for 3 hours to have OD ₆₀₀ = 0.6. Cells were collected by centrifugation at 10,000 xg for 10 min at 4 ° C and resuspended in 20 ml of PBS (phosphate buffer saline). 2% erythrocytes were obtained by centrifuging 1 ml of fresh tear fibrinogen blood and resuspended in 1 ml of sterile PBS. Then, it was repeatedly washed with PBS, resuspended in 0.75 ml of PBS, and a 2% erythrocyte suspension was prepared for analysis. 100 μl of culture medium with or without added various concentrations of leiodine was mixed with 900 μl of 2% red blood cells and cultured at 37 ° C. for 3 hours. The aliquot was 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 leoidin were grown to the basal exponential phase. Total RNA was isolated and purified using Qiagen RNA Protect Bacteria Reagent and RNeasy Mini Kit (Qiagen) and subjected to mechanical and enzymatic milling. RNA was purified using a silica column and DNase was treated to remove DNA contaminants. CDNA was obtained from RNA using Eco dry premix random hexamers (Clontech Laboratories, Inc.) and thermocycler (Applied biosystem), where the reaction was set at 42 ° C for 60 min according to the manufacturer's instructions, It was stopped for a minute. Quantitative PCR was performed using iTaq universal SYBR green supermix (Bio Rad) and BioRad Real-Time PCR system, with the following reaction conditions: denaturation at 95 ° C for 5 seconds, binding at 60 ° C for 15 seconds annealing), over 30 cycles. The reaction was carried out three times, and the primer information used at this time is shown in Table 1 below. The results, on the other hand, indicate how many times the transcription increased relative to 16S and ProC.

division Sequence information FP (forward primer) 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 Gt;
(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 Gt;
(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. Leoidin (the same concentration as IC ₅₀ and IC ₉₀ ) was treated and incubated for 1 hour and then added to a cover glass placed on a 12-well micro-titre plate. All experiments were repeated 3 times. The overnight cultured USA300 culture was centrifuged at 4000 rpm for 10 min at 4 < 0 > C. Cells were washed three times with DMEM medium and set to OD = 1 (containing approximately 10 < ⁹ > cfu / ml). 2 x 10 < ⁷ > cfu / ml USA300 was dispensed into wells and cultured for 6 hours. Cells were stained with FDA (fluorescein diacetate) and PI (propidium iodide), and stained cells were identified using confocal laser scanning microscopy.

1-8. Cell proliferation assay

Cell proliferation assay was performed using EZ-Cytox cell viability assay (Daeil lab services Co., Seoul, Korea) according to the manufacturer's guide. That is, Hela cells were cultured in DMEM supplemented with 10% FBS (fetal bovine serum, Invitrogen) in a 5% CO ₂ chamber. Cells were inoculated into 96-well plates (1 × 10 ⁵ cells per well) and incubated for 24 h. Twenty microliters of EZ-Cytox reagent was added to each well after addition of 10 μM leoidin at 2 μM to each well and incubation for 72 h. Then, the cells were cultured in a CO ₂ humidifying incubator at 37 ° C for 3 hours. After incubation, the absorbance was measured at 450 nm using a microplate absorber reader (Tecan infinite m200, Switzerland) and all experiments were repeated three times.

1-9. Cell internalization analysis

Internalization analysis following S. aureus-based cell infiltration was performed using gentamycin protection assays. That is, Hela cells were cultured in DMEM medium containing 10% FBS (fetal bovine serum, Invitrogen) in a 5% CO ₂ chamber. When confluency reached 70%, 5x10 ⁵ cells per well were applied to a 24-well plate containing glass cover slips and incubated for 48 hours. USA300 was cultured overnight in TSB, centrifuged (4000 rpm, 10 minutes), the bacterial cells were suspended in DMEM and adjusted to OD ₆₀₀ = 1 corresponding to 10 ⁹ cfu / ml. One hour before bacterial treatment, IC ₅₀ and IC ₉₀ concentrations of leoidin were added to each well. Approximately 1 × 10 ⁷ cells were treated with Hela cells and incubated for 90 minutes at 37 ° C. under CO ₂ , resulting in a multiplicity of infection (MOI) of 100. After incubation, cells were washed and gentamicin (10 μg / mL) was added for 60 min to dissolve extracellular or adherent staphylococci. The cells were then washed with PBS, plated on a TSA plate, incubated for 24 hours, and the colonies formed counted.

1-10. Antibiotic and combination 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 was calculated. USA300 was cultivated in TSB overnight with constant shaking at 37 ° C at 180 rpm and diluted 1: 100 in fresh TSB medium with varying concentrations of antibiotics ranging from 0.1-10 μg / ml. The IC ₅₀ of the four antibiotic drugs was then treated alone, or in combination with 4 μM or 8 μM of leoidin.

The FIC (Fractional Inhibitory Concentration) of the antibiotics was determined using the following equation.

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 the Graph Pad prism program version 6.0 (Graph Pad Software Inc., San Diego, Calif.). The minimum level of significance was P ≤ 0.001. All analyzes were performed three times and statistical analysis was done.

Example 2. Verification of Anti-Virulent Activity Effect

Among the 800 compounds tested in screening through the method described in Example 1-2, leoidin and gangaleoidin having potent toxicity inhibitory activity were identified (see FIGS. 1 and 2) Treatment of various concentrations of leiodine (1, 2, 4 and 8 μM) or galangioidins (1, 2, 5, 10, 15, 20 and 25 μM) via the method described in Examples 1-4 The effect of the antioxidant activity was confirmed.

As a result, as shown in Figure 3, reohyi Dean (Leoidin) was able to confirm that, while maintaining the bacterial growth at least 95% inhibition of Green Fluorescent Protein (GFP) produced less than 50%, particularly, 4 μM (IC ₅₀ ) And 8 μM (IC ₉₀ ) at 50% and 90% reduction in green fluorescent protein (GFP) production.

In addition, as shown in FIG. 4, it was confirmed that Gangaleoidin suppressed the production of green fluorescent protein (GFP) to less than 50% while maintaining the bacterial growth of 95% or more, ₉₀ ), the production of green fluorescent protein (GFP) was reduced by 90%.

From these results, it can be seen that Leoidin and Gangaleoidin can be used as an antiviral agent.

Example 3: Hemolysis inhibitory effect against S. aureus

In order to confirm whether leoidin or gangaleoidin has an activity of inhibiting haemolysis of S. aureus, various concentrations of the reoidin (1, 2, 4 and 8 μM) or galangioidins (1, 2, 4, 8, 16 and 32 μM), respectively.

As a result, as shown in FIG. 5, it was confirmed that leoidin significantly inhibited red blood cell hemolysis by S. aureus. More specifically, when 4 [mu] M of leiodine was added, hemolytic activity was inhibited up to 50%, and no measurable hemolytic activity was found at 8 [mu] M.

In addition, as shown in FIG. 6, it was confirmed that Gangaleoidin significantly inhibited red blood cell hemolysis by S. aureus. More specifically, when 2 [mu] M of leiodine was added, the hemolytic activity was suppressed to 30%, and no measurable hemolytic activity was found at 8 [mu] M.

From these results, it can be seen that Leoidin and Gangaleoidin are effective inhibitors of hemolytic α-hemolysin.

Example 4. Verification of the inhibitory effect of leiodin on the transcription factor

In previous studies, production of α-hemolysin, one of the most essential exotoxins secreted by S. aureus, has been reported to be regulated by sae (staphylococcal accessory effector). It has also been reported that the expression of hla is affected by sar (staphylococcal accessory regulator) and agr (accessory gene regulator). Therefore, it was confirmed by the method described in Examples 1-6 that the expression of such transcription regulatory factors can be suppressed by Leoidin treatment.

As a result, as shown in Fig. 7, the levels of saeS and sarA expression decreased to 74% and 50%, respectively, in the culture medium treated with Leoidin, as compared with the control group not treated with Leoidin I could confirm. On the other hand, other major regulators such as agrA showed no inhibitory effect. From these results, it can be seen that Leoidin inhibits the expression of α-hemolysin as well as inhibits various toxic genes through the sae and sarA regulatory factors, so that anti-toxicity It can be applied as a therapeutic agent.

Example  5. Leoidin  Verification of toxic gene expression inhibitory effect

Whether or not the toxic gene expression of S. aureus (USA300) could be inhibited by treatment with Leoidin was confirmed by the method described in Examples 1-6.

As a result, as shown in Fig. 8, in the case of treating leoidin as compared with the control group not treated with leoidin, hla, eap, nuc, lukS, isdH and various It was confirmed that the expression of hemolysin (hlgA, hlgB and hlgC) was markedly suppressed. In particular, expression level of hla decreased to 82%. Similarly, when leoidin is treated, the expression of cap8, clumping factors (clfA and clfB) and fibronectin binding proteins (fnbA and fnbB) whose transcription is regulated by sarA is markedly suppressed as shown in Fig. 9 I could confirm. In addition, in the case of plc, phenol-soluble modulins, geh (lipases), proteases (sspA, sspB), and sak (staphylokinases) as shown in FIG. 10, expression in the case of treatment with leoidin (Fig. 10A). In addition, the expression of CHIPS (chemotaxis inhibiting protein) was decreased by about 2-fold, and expression of aureolysin, which inhibits bacterial phagocytosis by neutrophils, and sdrE (serine-aspartate repeat protein) % And 38%, respectively (Fig. 10B). On the other hand, it did not affect the transfer of enterotoxin, SigB, cap5 (capsular polysaccharide) and coa (coagulase).

Example 6. Inhibition of Internalization of S. aureus by Leoidin

Adherence and invasion of S. aureus in cell epithelial cells is a fundamental and essential step in the pathogenesis of various infections. Therefore, a gentamycin protection assay was performed to determine whether the internalization of S. aureus could be inhibited by leoidin treatment in host cells. That is, in the presence of Leoidin, Hela cells were treated with USA300 to induce cell internalization, and non-internalized extracellular bacteria were eliminated using gentamicin. The host cells were then lysed and the internalized USA300 counted.

As a result, as shown in Fig. 11, treatment of 1 x 10 < ⁷ > cells of USA300 cells with ⁵ x 10 < ⁵ > Hela cells for 90 minutes decreased internalization when treated with Leoidin, / ml of Leoidin significantly reduced the internalization by USA300. From the above results, it was found that the invasion of bacteria can be suppressed by inhibiting the expression of surface binding proteins necessary for adhesion and internalization of leoidin.

Example 7. Cytotoxicity assay of leoidin

After confirming the efficacy of Leoidin in the internalization analysis according to Example 6, the toxicity of Heloid cells to Hela cells was analyzed. As a result, the addition of Leoidin to Hela cells showed no toxic effect at the concentration of 8 μM, and the viability of Hela cells after 72 hours of treatment was almost the same as that of the control group. From the above results, it was found that Leoidin could weaken S. aureus infection without causing side effects in epithelial cells.

Example 8: Protective effect of leoidin on cell protection from S. aureus

From Example 3 to Example 5, it was confirmed that Leoidin can inhibit hemolysis and various toxic gene expression, so that Leoidin protects host cells from host cell damage due to bacterial infection Was confirmed by the method described in Example 1-7.

As a result, as shown in Fig. 12, when control cells without infection with USA300 maintained green fluorescence (Fig. 12A), when cultured with USA300 without treatment of leoidin, It was confirmed that it was stained with red (Fig. 12B). However, when treated with 4 μM leoidin, 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 leiodine almost completely protects cells from USA300 infection (Fig. 12D). From the above results, it can be seen that Leoidin protects cells from cell damage caused by bacterial infection in a concentration-dependent manner.

Example 9. Synergistic Effect of Leiodin and Antibiotic Combination

The rise in antibiotic effect by the combination of four antibiotics known as S. aureus antibiotics, methicillin, oxacillin, norfloxacin, and vancomycin and leoidin The effect was confirmed by the method described in Examples 1-10. In the case of the USA300, which is resistant to the antibiotics used in this experiment, the concentration (IC ₅₀ ) of reducing the growth of bacteria by more than 50% was determined for each antibiotic (1 μg / ml methicillin, 1 μg / ml oxacillin, 1 μg / ml norfloxacin or 5 μg / ml vancomycin). After this, 4 μM, 8 μM of leiodine and IC ₅₀ antibiotics were combined with each other, and the degree of inhibition of the growth of the bacteria was observed.

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

Example 10: Hemolytic inhibitory effect of other pathogenic bacteria of leoidin

In addition to S. aureus, leoidin was also found to inhibit hemolysis against a variety of other bacteria, and the bacterial species 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 Helicobacter pylori KCTC12083 Pseudomonas aureginosa KCTC1637 Bacillus cereus KCTC13153 Enterococcus fecalis KCTC3511 Bacillus licheniformis KCTC1918 Staphylococcus epidermidis KCTC1917 Cornebactreium diptheria KCTC3075 Klepsella pneumoniae Samsung hospital infection medical department 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 infection medical department

As a result, as shown in Fig. 17, Streptococcus pneumonia and Streptococcus sobrinus, among the 26 pathogenic bacteria that tested hemolytic activity after treatment with 8 [mu] M of reovirus, , Hemolytic activity was inhibited by 80% or more, and hemolytic activity of Streptococcus ferus and Listreia innocua were reduced by 77.65% and 76.73%, respectively. A decrease of more than 50% was also found in Klebsiella pneumoniae and Pseudomonas aeruginosa (Fig. 17A). In addition, when cultured with 8 [mu] M leiodine, Campylobacter jejuni, Helicobacter pylori, Enterococcus fecalis, as well as significantly inhibiting the hemolytic function of several bacterial species, Corynebacterium diphtheriae, S. parasanguinis, S. sanguinis, S. pyogene, S. suis, and the like. ) Was also found to have antibacterial activity (Fig. 17B).

It will be understood by those skilled in the art that the foregoing description of the present invention is for illustrative purposes only and that those of ordinary skill in the art can readily understand that various changes and modifications may be made without departing from the spirit or essential characteristics of the present invention. will be. It is therefore to be understood that the above-described embodiments are illustrative in all aspects and not restrictive.

<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> 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 gtagggaaa 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)

A pharmaceutical composition for preventing or treating bacterial infection, which comprises, as an active ingredient, leoidin, a derivative thereof, or a pharmaceutically acceptable salt thereof.
2. The composition according to claim 1, wherein the leodine is a compound represented by the following formula (1).
[Chemical Formula 1]

2. The composition according to claim 1, wherein the derivative of the leodine is a compound represented by the following formula (2).
(2)

(In the formula (2)
R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl or C 1 to C 7 hydroxyalkyl, ,
R ₃ is hydrogen, hydroxy, aldehyde, halide, CN, OR _a , NR _b , SR _c or COOR _d ,
R ₄ is selected from the group consisting of 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, C 1 -C 7 thioalkyl, C 1 -C 7 aminoalkyl or C 1 -C 7 hydroxyalkyl.
The composition according to claim 3, wherein the derivative of the leodine is a compound represented by the following formula (4).
[Chemical Formula 4]

The composition according to claim 1, wherein the derivative of the leodine is a compound represented by the following formula (3).
(3)

(3)
R ₁ and R ₂ are each independently selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl or C 1 to 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 selected from the group consisting of hydrogen, C 1 to C 7 alkyl, C 1 to C 7 thioalkyl, C 1 to C 7 aminoalkyl, C 1 to C 7 hydroxyalkyl, a halide, CN, oR _a, NR _b or SR _c,
R _a , R _b , R _c And R _d each independently represent hydrogen, hydroxy, C 1 -C 7 thioalkyl, C 1 -C 7 aminoalkyl or C 1 -C 7 hydroxyalkyl.
2. The composition of claim 1, wherein the composition has an anti-toxic or anti-pathogenic activity against bacteria.
The composition of claim 1, wherein the composition inhibits red blood cell hemolysis by bacteria.
2. The composition of claim 1, wherein the composition inhibits expression of a staphylococcal accessory effector (sar) or sar (staphylococcal accessory regulator) gene.
2. The composition of claim 1, wherein the composition inhibits internalization of the bacteria.
2. The composition of claim 1, wherein said composition protects host cells from host cell damage by bacterial infection.
The method of claim 1, wherein the bacteria are selected from the group consisting of Staphylococcus aureus, Streptococcus ferus, Serratia marcescens, Vibrio parahaemolyticus, For example, Streptococcus pneumonia, Staphylococcus saprophyticus, Campylobacter jejuni, Helicobactor pylori, Pseudomonas aeruginosa, Bacillus cereus Bacillus cereus, Enterococcus fecalis, Bacillus licheniformis, Staphylococcus epidermidis, Corynebacterium diphtheriae, Klebsiella pneumoniae, Klebsiella pneumoniae, Listreia innocua, Burkholderia sephacia, Such as Burkholderia cepacia, Streptococcus parasanguinis, Salmonella typhimurium, Streptococcus sobrinus, Streptococcus sanguinis, Streptococcus spp., Streptococcus spp. iniae, Streptococcus pyogene, Streptococcus mitis, Listeria Ivanovii subsp ivanovii, Listeria monocytogenes, Streptococcus suis, Clostridium perfringens, Yersinia enterocolitica, Shigella boydii, Shigella flexneri, Shigella sonnei, Salmonella cholerae, Salmonella choleraesuis subsp, Salmonella enteritidis Salmonella bongori, Salmonella enterica, Mycobacterium tuberculosis, Mycobacterium leprae, Clostridium botulinum, Mycobacterium tuberculum, Mycobacterium tuberculosis, Bacillus anthracis, Yersinia pestis, Chlamydia pneumonia, Borrelia burgdorferi, Coxiella burnetii, Mycobacterium sp., Bacillus anthracis, Mycobacterium avium, Escherichia coli, Borrelia sp., Bartonella sp., Chlamydia trachomatis, and Mycoplasma pneumoniae &Lt; / RTI &gt; Mycoplasma pneumonia.
The composition of claim 1, wherein the composition is formulated with or in combination with an antibiotic.
12. The method of claim 11, wherein the antibiotic is selected from the group consisting of methicillin, oxacillin, norfloxacin, vancomycin, amikacin, gentamicin, kanamycin, , Neomycin, Netilmicin, Tobramycin, Paromomycin, Streptomycin, Spectinomycin, Geldanamycin, Herbimycin, Herbimycin, Rifaximin, Loracarbef, Ertapenem, Doripenem, Imipenem / Cilastatin, Meropenem, Cefadroxil, , Cefazolin, Cefalothin, Cefalexin, Cefaclor, Cefamandole, Cefoxitin, Cefprozil, Sephroxime, Cefuroxime), Cefixime, Cefdinir, Cefditoren, (Cefoperoxone), Cefotaxime, Cefpodoxime, Ceftazidime, Ceftibuten, Ceftizoxime, Ceftriaxone, Cephipimine, Cefepime, Ceftaroline fosamil, Ceftobiprole, Teicoplanin, Telavancin, Dalbavancin, Oritavancin, Clindamycin, Clindamycin, Lincomycin, Daptomycin, Azithromycin, Clarithromycin, Dirithromycin, Erythromycin, Roxithromycin, (Roxithromycin), Troleandomycin, Telithromycin, Spiramycin, Aztreonam, Furazolidone, Nitrofurantoin, Linezolid ), Posizolid, Radezolid, Torezolid, Amoxicillin, Ampicillin, Azlocillin, Carbenicillin, Cloxacillin, Dicloxacillin, PluClock Facts, Muclocillin, Nafcillin, Penicillin G, Penicillin V, Piperacillin, Temocillin, Ticarcillin, Ticarcillin, Amoxicillin / clavulanate, Ampicillin / sulbactam, Piperacillin / tazobactam, Ticarcillin / clavulanate, Bacitracin / clavulanate, Bacitracin, Colistin, Polymyxin B, Ciprofloxacin, Enoxacin, Gatifloxacin, Gemifloxacin, Levofloxacin, Lomefloxacin, Moxifloxacin, Nal idxic acid, Ofloxacin, Trovafloxacin, Grepafloxacin, Sparfloxacin, Temafloxacin, Mafenide, Sulfaacetamma, The compounds of the present invention may be selected from the group consisting of 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, Cycloserine, ine, ethambutol, ethionamide, isoniazid, pyrazinamide, rifampicin, rifabutin, rifapentine, arsphenamine, , Chloramphenicol, Fosfomycin, Fusidic acid, Metronidazole, Mupirocin, Platensimycin, Quinupristin / Dalfopristin, Wherein the composition is selected from the group consisting of Thiamphenicol, Tigecycline, Tinidazole, and Trimethoprim.
A cosmetic composition for preventing or improving a bacterial infection comprising Leoidin, a derivative thereof, or a cosmetically acceptable salt thereof.
A food composition for preventing or improving a bacterial infection comprising Leoidin or a derivative thereof.
Animal feed comprising leoidin or a derivative thereof.

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