WO2023113396A1 - Utilisation d'une protéine antibactérienne recombinante permettant de tuer efficacement des bactéries clostridium difficile - Google Patents

Utilisation d'une protéine antibactérienne recombinante permettant de tuer efficacement des bactéries clostridium difficile Download PDF

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WO2023113396A1
WO2023113396A1 PCT/KR2022/020105 KR2022020105W WO2023113396A1 WO 2023113396 A1 WO2023113396 A1 WO 2023113396A1 KR 2022020105 W KR2022020105 W KR 2022020105W WO 2023113396 A1 WO2023113396 A1 WO 2023113396A1
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lyssap26
chap
clostridium difficile
bacteria
protein
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English (en)
Korean (ko)
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김정민
김석호
최윤정
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경북대학교 산학협력단
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    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
    • A01N63/50—Isolated enzymes; Isolated proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23K—FODDER
    • A23K20/00—Accessory food factors for animal feeding-stuffs
    • A23K20/10—Organic substances
    • A23K20/142—Amino acids; Derivatives thereof
    • A23K20/147—Polymeric derivatives, e.g. peptides or proteins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/34—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals
    • A23L3/3454—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by treatment with chemicals in the form of liquids or solids
    • A23L3/3463—Organic compounds; Microorganisms; Enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents

Definitions

  • the present invention relates to the use of a recombinant antibacterial protein that effectively kills Clostridium difficile bacteria, and in detail, the amino acid sequence at positions 162 to 251 of the C-terminal region of LysSAP26, an endolysin having antibacterial activity, is deleted. It relates to the use of a recombinant protein (CHAP-161 LysSAP26 ).
  • Bacteriophage is a bacterial virus, which infects the host bacterium according to its biological life cycle, reproduces a large amount of phage, and makes proteins that break through or decompose the cell wall of the bacterium in the process of being killed by a large number of phages in the cell of the host bacterium.
  • the proteins break down the cell wall made of peptidoglycan, disintegrating the cell wall and killing the bacteria.
  • Clostridium difficile is an anaerobic bacillus that forms spores as a Gram-positive bacterium. When the intestinal flora is destroyed by the use of antibiotics or drugs, it is colonized by Clostridium difficile and progresses to inflammation by secreted toxin A or B. The more secreted toxin (enterotoxin), the more severe enteritis. In the case of the United States, the incidence of intestinal diseases caused by Clostridium difficile is on the rise, and in particular, the incidence and mortality rates of the elderly over 65 years of age are rapidly increasing.
  • An object of the present invention is to provide a pharmaceutical composition for preventing or treating Clostridium difficile infectious diseases comprising CHAP-161 LysSAP26 recombinant protein as an active ingredient.
  • Another object of the present invention is to provide an antibiotic for killing Clostridium difficile containing CHAP-161 LysSAP26 recombinant protein as an active ingredient.
  • the present invention comprises a CHAP-161 LysSAP26 recombinant protein consisting of the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient Clostridium difficile ( Clostridium difficile )
  • a pharmaceutical composition for preventing or treating infectious diseases provides
  • the present invention provides an antibiotic for killing Clostridium difficile comprising the CHAP-161 LysSAP26 recombinant protein consisting of the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
  • the present invention relates to the use of a recombinant antibacterial protein that effectively kills Clostridium difficile bacteria, and in detail, the amino acid sequence at positions 162 to 251 of the C-terminal region of LysSAP26, an endolysin having antibacterial activity, is deleted. It relates to the use of a recombinant protein (CHAP-161 LysSAP26 ).
  • CHAP-161 LysSAP26 recombinant protein of the present invention exhibits the ability to kill Clostridium difficile and can prevent or treat infectious diseases caused by this bacterium.
  • CHAP-161 LysSAP26 uses peptidoglycan, a component of the cell wall of bacteria, as a substrate to show the ability to kill bacteria by decomposing peptidoglycan, and peptidoglycan exists only in bacteria and does not exist in humans or animals
  • CHAP-161 LysSAP26 of the present invention is safe because it does not affect humans and animals.
  • Figure 1 is an SDS-PAGE analysis photograph (A) after purification of LysSAP26 and CHAP-139 LysSAP26 proteins, including CHAP-161 LysSAP26 , and Western analysis using specific antibodies recognizing the C-terminal 6 histidine amino acid sequences of each protein. to confirm CHAP-161 LysSAP26 , LysSAP26, and CHAP-139 LysSAP26 (B).
  • Figure 2 is CHAP-161 LysSAP26 , LysSAP26, and CHAP-139 LysSAP26 of Acinetobacter baumanii ATCC 17978 (A) and Staphylococcus aureus ATCC 25923 (B) for 20 hours antibacterial activity was determined by measuring the absorbance.
  • Figure 3 is a photograph of the protein precipitate in the aqueous solution after 15 days of each protein purification in relation to the protein stability of CHAP-161 LysSAP26 and LysSAP26.
  • Figure 4 is the minimum inhibitory concentration (MIC) and minimum killing concentration for 1 week and 3 weeks (PO3654, PO3780, PO3783) of Clostridium difficile standard strain (ATCC 9689) by CHAP-161 LysSAP26 and clinical isolates (Minimum bactericidal concentration, MBC) was confirmed as an experimental result.
  • FIG. 5 shows a schematic diagram of an in vivo experiment for the treatment effect of CHAP-161 LysSAP26 on an animal model infected with Clostridium difficile.
  • Figure 6 shows the results of the 14-day survival rate change for the Clostridium difficile ATCC 9689 infection test group (groups 4-6).
  • Figure 7 shows the results of changes in survival rate for 14 days and 14 days for Clostridium difficile CD-M-5 infection test groups (groups 7-9).
  • Figure 8 shows the results of the 14-day survival rate change for the Clostridium difficile CD-H-7 infection test group (groups 10-12).
  • Figure 9 shows the results of changes in the body weight of mice for 14 days for Clostridium difficile ATCC 9689 infection test groups (groups 4-6).
  • Figure 10 shows the results of changes in the body weight of mice for 14 days for Clostridium difficile CD-M-5 infection test groups (groups 7-9).
  • Figure 11 shows the results of changes in the body weight of mice for 14 days for the test group infected with Clostridium difficile CD-H-7 (groups 10-12).
  • the inventors of the present invention made a CHAP-161 LysSAP26 expression vector by preparing a deletion mutant based on DNA encoding endolysin LysSAP26, and transformed it into E. coli to express the protein.
  • the protein showed the ability to kill Clostridium difficile, in particular, has higher protein productivity than wild type LysSAP26, has a small molecular weight and is stable, and has a better antibacterial effect against Clostridium difficile bacteria, thereby confirming the present invention. completed.
  • the present invention provides a pharmaceutical composition for the prevention or treatment of Clostridium difficile infectious diseases comprising the CHAP-161 LysSAP26 recombinant protein consisting of the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
  • the LysSAP26 protein may be derived from bacteriophage SAP26 (KCTC 11665BP) of Siphoviridae, but is not limited thereto.
  • the present inventors induced and isolated a novel bacteriophage from a clinical isolate of Staphylococcus aureus, and deposited the isolated bacteriophage in the gene bank of the Korea Research Institute of Bioscience and Biotechnology on March 11, 2010 (accession number KCTC 11665BP).
  • the gene encoding the CHAP-161 LysSAP26 recombinant protein may consist of the nucleotide sequence represented by SEQ ID NO: 2, but is not limited thereto.
  • Clostridium difficile infectious disease may be endocarditis, diarrhea, enteritis, inflammatory bowel disease (IBD), pseudomembranous colitis, toxic megacolon, gastrointestinal perforation or sepsis, It is not limited thereto.
  • the CHAP-161 LysSAP26 recombinant protein of the present invention uses peptidoglycan, a bacterial cell wall component, as a substrate to decompose and disintegrate the cell wall to kill bacteria. Since the peptidoglycan exists only in bacteria and not in humans or animals, the CHAP-161 LysSAP26 recombinant protein of the present invention does not affect humans and animals, so it is safe and can be applied to the pharmaceutical industry, food industry, and biotechnology. In addition to being possible, there is an advantage in that bacteria can be effectively killed at the target site or target substance without problems with multi-drug antimicrobial resistance.
  • treatment refers to the prevention, suppression and alleviation of infectious diseases caused by Clostridium difficile .
  • composition of the present invention when it is a pharmaceutical composition, it may contain a pharmaceutically acceptable carrier, excipient or diluent in addition to the above-described active ingredients for administration.
  • the carriers, excipients and diluents include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil.
  • the pharmaceutical composition of the present invention can be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, external preparations, suppositories or sterile injection solutions according to conventional methods. . Specifically, when formulated, it may be prepared using diluents or excipients such as commonly used fillers, weighting agents, binders, wetting agents, disintegrants, and surfactants. Solid preparations for oral administration include, but are not limited to, tablets, pills, powders, granules, capsules, and the like.
  • Such a solid preparation may be prepared by mixing at least one or more excipients, for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc., in addition to the active ingredient.
  • excipients for example, starch, calcium carbonate, sucrose, lactose, gelatin, etc.
  • lubricants such as magnesium stearate and talc may also be used.
  • It may be prepared by adding various excipients, for example, wetting agents, sweeteners, aromatics, and preservatives, in addition to liquids and liquid paraffin for oral use.
  • Formulations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized formulations and tablets.
  • Propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used as non-aqueous solvents and suspending agents.
  • As a base for suppositories Witepsol, Macrosol, Tween 61, cacao butter, laurin paper, glycerogelatin, and the like may be used.
  • a suitable dose of the pharmaceutical composition of the present invention varies depending on the condition and weight of the patient, the severity of the disease, the drug type, and the time, but can be appropriately selected by a person skilled in the art, and the daily dose of the composition is preferably It is 0.001 mg/kg to 50 mg/kg, and it can be divided and administered once a day to several times as needed.
  • the present invention provides an antibiotic for killing Clostridium difficile comprising the CHAP-161 LysSAP26 recombinant protein consisting of the amino acid sequence represented by SEQ ID NO: 1 as an active ingredient.
  • antibiotic is a generic term for preservatives, bactericides and antibacterial agents for medical use.
  • the CHAP-161 LysSAP26 recombinant protein of the present invention has excellent selective bacterial killing ability compared to conventional antibacterial agents.
  • the protein when used as an antimicrobial agent, unlike conventional antibacterial agents, it has the advantage of not inducing resistance or resistance of bacteria, so it is possible to provide an antibiotic material with a longer life cycle than conventional antibiotic agents. While most antibiotics have a decreasing range of use as they face increased resistance, the antimicrobial agent containing the protein of the present invention as an active ingredient can fundamentally solve the problem of antimicrobial resistance, thereby increasing the product lifespan as an antimicrobial agent. can
  • the antibiotic containing the CHAP-161 LysSAP26 recombinant protein of the present invention having a specific killing activity for Clostridium difficile as an active ingredient is useful as an antibiotic with excellent antibacterial, bactericidal and antiseptic effects can be used
  • Example 1 LysSAP26 Endolysin and LysSAP26 C-terminal deletion mutant recombinant protein CHAP-139 LysSAP26 , CHAP-161 LysSAP26 production and purification of
  • Plasmid vectors pLysSAP26 (6.12 Kbp), pCHAP139 (5.78 Kbp), and pCHAP161 (5.89 Kbp) expressing LysSAP26 endolysin and LysSAP26 C-terminal deletion mutant recombinant proteins CHAP-139 LysSAP26 and CHAP-161 LysSAP26 are prepared as follows.
  • the genome was extracted from the SAP26 phage and subjected to polymerase chain reaction (PCR) using this as a template, and the primers used at this time are shown in Table 1 below.
  • PCR polymerase chain reaction
  • PCR fragments produced using the primers mentioned in Table 1 were obtained by performing electrophoresis on an agarose gel and then eluting the band.
  • the PCR fragments were digested with restriction enzymes NdeI and XhoI, respectively, and then ligated with the expression vector (pET21a) digested with the same enzymes.
  • pET21a restriction enzymes
  • IPTG isopropyl ⁇ -D-1-thiogalactopyranoside
  • the bacteria were disrupted using a lysis buffer [50 mM Tris-Cl (pH 8.0), 200 mM NaCl] and an ultrasonicator. The supernatant was collected by centrifugation of the disrupted bacterial lysate, injected into a Ni-NTA column, and C using an elution buffer [500 mM imidazole, 50 mM Tris-Cl (pH 8.0), 200 mM NaCl].
  • -LysSAP26, CHAP-139 LysSAP26 , and CHAP-161 LysSAP26 proteins tagged with six histidines at the end were purified.
  • FIG. 1A M is a protein size marker
  • the number of each gel picture is the number of each protein purification fraction
  • FIG. 1B is a Western test result using an anti-6 ⁇ His monoclonal antibody against RKR protein.
  • the amino acid sequence and number of CHAP-161 LysSAP26 is composed of 169 amino acids (SEQ ID NO: 1) including a histidine tag, and the theoretical protein size is 18.6 kDa.
  • the gene coding sequence excluding the histidine tag is 483 bp (SEQ ID NO: 2).
  • Example 2 LysSAP26 Endolysin and LysSAP26 C-terminal deletion mutant recombinant protein CHAP-139 LysSAP26 , CHAP-161 LysSAP26 Antibacterial activity comparison test of
  • LysSAP26 CHAP-139 LysSAP26 , CHAP-161
  • Acinetobacter baumani ATCC 17978 and Staphylococcus aureus ATCC 25923 were used as target strains and the antibacterial activity was measured as follows. Each bacteria was cultured on a Blood Agar Plate medium and cultured at 37° C. for 18 hours, and then diluted to about 10 4 CFU/mL using a sterilized Mueller Hinton Broth medium.
  • CHAP-161 LysSAP26 almost completely killed Acinetobacter baumani bacteria (95% or more antibacterial rate) like LysSAP26 at 25 ⁇ g/mL and higher concentrations, and at concentrations of 5 and 12.5 ⁇ g/mL, CHAP-161 LysSAP26 161 LysSAP26 (about 80, 82% antibacterial rate) showed better antibacterial activity than LysSAP26 (about 15, 42% antibacterial rate).
  • CHAP-139 LysSAP26 showed lower antimicrobial rates than CHAP-161 LysSAP26 at all concentrations tested (about 45, 50, 55, and 65% antibacterial rates at 5, 12.5, 25, and 50 ⁇ g/mL, respectively) (FIG. 2A).
  • CHAP-161 LysSAP26 (65%, 95%, and 95% or more) in the concentration range of 25, 50, and 75 ⁇ g/mL, respectively, LysSAP26 (55%, 95%, and 95% or more, respectively) and CHAP-139 had higher antibacterial rates than LysSAP26 (35% and 45%, respectively) (Fig. 2B).
  • CHAP-139 LysSAP26 could not be tested at a concentration of 75 ⁇ g/mL due to protein yield problems.
  • CHAP-161 LysSAP26 was found to be the most excellent. In terms of protein stability, after 15 days of protein purification, LysSAP26 precipitated in an aqueous solution and lost its activity, whereas CHAP-161 LysSAP26 was slightly precipitated compared to LysSAP26, which was excellent in terms of protein stability (FIG. 3).
  • Protein purification yield (protein yield showing antimicrobial activity from 1 Liter culture, mg/Liter) LysSAP26 CHAP-139 LysSAP26 CHAP-161 LysSAP26 2.672 2.032 17.320
  • Each bacterium was prepared to a bacterial count of 5 ⁇ 104CFU/well using Mueller Hinton Broth (MHB), and purified CHAP-161 LysSAP26 was added thereto to 5, 10, 25, 50, and 75 ⁇ g/mL, respectively, to anaerobically After reacting at 37 ° C. for 16 hours under the condition, the degree of bacterial growth was confirmed with the naked eye. As a result, bacterial growth was observed in all control groups (-CHAP-161 LysSAP26 ) in the well plate, whereas in the test group (+CHAP-161 LysSAP26 ), Clostridium difficile ATCC 9689 and Clostridium difficile PO3645 had a protein amount of 25 ⁇ g/mL or more. The growth of bacteria was not observed, and the growth of two other clinical strains was not confirmed at 50 ⁇ g/mL or more.
  • the minimum bactericidal concentration (MBC) of CHAP-161 LysSAP26 against Clostridium difficile bacteria was measured as follows (FIG. 4B). After inoculating 20 ⁇ L of the mixed solution of each well confirmed in the MIC experiment on a Mueller Hinton Agar (MHA) plate under anaerobic conditions, it was incubated at 37 ° C for 18 to 24 hours and the growth of bacteria was confirmed. As a result, CHAP-161 LysSAP26 Clostridium difficile ATCC 9689 and Clostridium difficile PO3645 were killed at 25 ⁇ g/mL and higher concentrations, and two other clinical strains were killed at CHAP-161 LysSAP26 at 50 ⁇ g/mL and higher concentrations (Fig. 4B). Based on the results of MIC and MBC experiments, CHAP-161 LysSAP26 It was proved that the MIC and MBC values had the same bactericidal effect.
  • LysSAP26 showed 50% or less antibacterial activity compared to CHAP-161 LysSAP26 according to the MIC and MBC measurements for Clostrididium difficile.
  • Immunodeficiency injections of 5-week-old C57BL/6 mice were administered twice and kanamycin (kanamycin 0.4 mg/mL, Nacalai Tesque), gentamicin (gentamicin 0.035 mg/mL, Nacalai Tesque), and colistin (850 U) were administered in drinking water. /mL, Sigma-Aldrich), metronidazole (0.215 mg/mL, Nacalai), and vancomycin (0.045 mg/mL) were prepared, and mice were then fed the antibiotic cocktail for 5 days, followed by 2 days. fed with sterile water. One day before bacterial infection, a single dose of clindamycin (20 mg/kg) was injected intraperitoneally.
  • Clostridium difficile ATCC 9689, clinical isolates CD-M-5 and CD-H-7 were orally injected (10 9 CFU/mouse) to induce infection, and after 24 hours, CHAP-161 (150 ⁇ g, 300 ⁇ g) ), PBS (negative control) was followed up for 14 days after each injection (Fig. 5).
  • the mouse experimental groups are as follows.
  • Negative control group injected with 100 ⁇ L of PBS on days 0 and 7
  • the survival rate and weight change were recorded every day, and the experiment was terminated after confirmation for a total of 14 days.
  • groups 1-3 showed a 100% survival rate for 14 days
  • group 4 showed a 50% survival rate on the 6th day and a 25% survival rate after the 8th day
  • CHAP-161 was injected with 100 ⁇ g or 150 ⁇ g
  • One group, 5 and 6, had a survival rate of 100%.
  • Group 10 showed a survival rate of 66% on the 6th day and 33% after the 9th day, but Groups 11 and 12 injected with 100 ⁇ g and 150 ⁇ g of CHAP-161 showed a 100% survival rate. looked Group 7 did not die during the test day, unlike groups 4 and 10, which were control groups infected with Clostridium difficile.
  • group 7 showed a significant weight loss from the 4th day of infection and continued until the 14th day, whereas the treatment groups of groups 8 and 9 injected with 100 ⁇ g and 150 ⁇ g of CHAP-161 showed a steady increase in body weight, similar to normal mouse controls.
  • a powder is prepared by mixing the above ingredients and filling them in an airtight bag.
  • tablets are prepared by tableting according to a conventional tablet manufacturing method.
  • Capsules are prepared by mixing the above ingredients and filling them into gelatin capsules according to a conventional capsule preparation method.

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Abstract

La présente invention concerne l'utilisation d'une protéine antibactérienne recombinante permettant de tuer efficacement des bactéries Clostridium difficile et, plus particulièrement, l'utilisation d'une protéine recombinante (CHAP-161LysSAP26) dans laquelle les séquences d'acides aminés de SEQ ID no : 162-251 de la région C-terminale de l'endolysine LysSAP26 possédant une activité antibactérienne sont délétées. La protéine recombinante CHAP-161LysSAP26 de la présente invention présente une capacité à tuer Clostridium difficile, et peut ainsi prévenir ou traiter des maladies inflammatoires causées par la bactérie. En particulier, CHAP-161LysSAP26 utilise un peptidoglycane, qui est un constituant des parois cellulaires bactériennes, comme substrat afin de présenter une capacité à tuer des bactéries par une décomposition du peptidoglycane et, dans la mesure où le peptidoglycane est présent uniquement chez les bactéries et non chez les êtres humains ou les animaux, CHAP-161LysSAP26 de la présente invention n'affecte pas les êtres humains et les animaux, et est ainsi sans danger.
PCT/KR2022/020105 2021-12-14 2022-12-12 Utilisation d'une protéine antibactérienne recombinante permettant de tuer efficacement des bactéries clostridium difficile WO2023113396A1 (fr)

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KR102131692B1 (ko) * 2018-09-11 2020-07-08 경북대학교 산학협력단 병원성 세균을 효과적으로 사멸시키는 재조합 항균 효소 LysSAP26의 용도

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Publication number Priority date Publication date Assignee Title
US9134312B2 (en) * 2009-02-06 2015-09-15 Tecnifar—Industria Tecnica Farmaceutica, S.A. Antibacterial phage, phage peptides and methods of use thereof
KR20110130285A (ko) * 2010-05-27 2011-12-05 경북대학교 산학협력단 황색포도상구균을 사멸시키는 박테리오파지
KR20140078633A (ko) * 2011-08-22 2014-06-25 캔진코포레이션 클로스트리듐 디피실리균 항체
KR20150035573A (ko) * 2012-05-07 2015-04-06 마이크레오스 휴먼 헬스 비.브이. 항균 활성을 갖는 폴리펩티드 혼합물
KR102131692B1 (ko) * 2018-09-11 2020-07-08 경북대학교 산학협력단 병원성 세균을 효과적으로 사멸시키는 재조합 항균 효소 LysSAP26의 용도

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