WO2022154287A1 - Protéine antibactérienne efl200 possédant une activité lytique contre enterococcus faecium - Google Patents

Protéine antibactérienne efl200 possédant une activité lytique contre enterococcus faecium Download PDF

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WO2022154287A1
WO2022154287A1 PCT/KR2021/019368 KR2021019368W WO2022154287A1 WO 2022154287 A1 WO2022154287 A1 WO 2022154287A1 KR 2021019368 W KR2021019368 W KR 2021019368W WO 2022154287 A1 WO2022154287 A1 WO 2022154287A1
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efl200
enterococcus
antibacterial protein
fasium
infection
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PCT/KR2021/019368
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English (en)
Korean (ko)
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윤성준
손지수
김인황
오은경
전수연
강상현
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주식회사 인트론바이오테크놀로지
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Publication of WO2022154287A1 publication Critical patent/WO2022154287A1/fr

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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
    • A01N63/20—Bacteria; Substances produced thereby or obtained therefrom
    • 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
    • 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
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
    • C12N15/09—Recombinant DNA-technology
    • C12N15/63—Introduction of foreign genetic material using vectors; Vectors; Use of hosts therefor; Regulation of expression
    • C12N15/70—Vectors or expression systems specially adapted for E. coli

Definitions

  • the present invention relates to Enterococcus fasium faecium ) relates to an antibacterial protein EFL200 having lytic activity against bacteria, and more particularly, has the ability to specifically lyse Enterococcus fasium bacteria, which can cause diseases by infecting animals, including humans, SEQ ID NO: By Enterococcus fasium bacteria containing the Enterococcus fasium species-specific antibacterial protein EFL200, and the Enterococcus fasium bacteria-specific antibacterial protein EFL200 as an active ingredient, comprising the amino acid sequence represented by 1. It relates to a pharmaceutical composition for treating induced infections and diseases, and a method for producing the antibacterial protein EFL200.
  • Enterococcus ( Enterococci ) is a facultative anaerobic Gram-positive coli that resides in the gastrointestinal tract and urogenital system.
  • Enterococcus faecalis Enterococcus faecalis
  • Enterococcus fasium Enterococcus faecium
  • Enterococcus Durans Enterococcus Durans
  • Enterococcus casseliflavus including about 19 species (Species) have been reported, and among them, the major bacterial species that actually cause infection are Enterococcus faecalis and Enterococcus fasium. can present
  • infection by Enterococcus faecalis was very common, but recently, infection by Enterococcus faecium has been relatively increasing.
  • Enterococcus is relatively weak and does not cause disease in normal people, but it causes various opportunistic infections such as urinary tract infections, wound infections, bacteremia, and endocarditis in the elderly, immunocompromised patients, chronic underlying diseases, or hospitalized patients.
  • enterococci may induce infectious diseases by acquiring virus factors through gene hybridization from the outside. Among the infections caused by enterococci, urinary tract infection is the most frequent, followed by wound infection. Other major infections caused by enterococci may suggest endocarditis, and 5-20% of bacterial endocarditis is caused by enterococci.
  • Enterococci are known to acquire new DNA (plasmid, transposons) or to acquire antibiotic resistance by using mutations.
  • Enterococci which have acquired resistance to aminoglycosides, cause endocarditis or severe infections, it is difficult to succeed in treatment because they cannot be sterilized.
  • VRE Vancomycin-Resistance Enterococci
  • Vancomycin-resistant VRE was first reported in France in 1986, and VRE was first isolated in Korea in 1992. In the United States, since VRE was first isolated in 1988, according to NNIS (National Nosocomial Infection Surveillance) data, 1-15% of Enterococcus isolated between 1990-1997 were VRE, and 25% in 1999 and 2003 It is increasing at 28.5% per year. Recently, the appearance of VRE is increasing worldwide, not only in Europe and the United States, but also in Asia and Oceania including Korea. Accordingly, it is necessary to develop a drug that can be used to prevent or treat antibiotic-resistant enterococcal infection. In particular, it is very urgent to develop a pharmaceutical formulation that can provide a rapid therapeutic effect.
  • NNIS National Nosocomial Infection Surveillance
  • the present inventors provide an antibacterial protein capable of specifically lysing Enterococcus fasium bacteria, and further It contains as an active ingredient and provides a pharmaceutical composition that can be used to treat Enterococcus fasium infection, and further effectively treats Enterococcus fasium infection or disease using the pharmaceutical composition
  • a pharmaceutical composition that can be used to treat Enterococcus fasium infection, and further effectively treats Enterococcus fasium infection or disease using the pharmaceutical composition
  • an antibacterial protein EFL200 having an activity capable of specifically lysing Enterococcus fasium and comprising the amino acid sequence represented by SEQ ID NO: 1.
  • Another object of the present invention is to provide a method for efficiently producing the antibacterial protein EFL200 having the activity to specifically lyse the Enterococcus fasium bacteria and comprising the amino acid sequence represented by SEQ ID NO: 1.
  • Another object of the present invention is to provide a pharmaceutical composition for the treatment of Enterococcus fasium infection comprising the antibacterial protein EFL200 capable of specifically lysing the Enterococcus fasium bacteria as an active ingredient.
  • Another object of the present invention is to provide a method for treating Enterococcus fasium infection or disease using a pharmaceutical composition comprising the antibacterial protein EFL200 as an active ingredient.
  • Another object of the present invention is to provide a food composition comprising the antibacterial protein EFL200 as an active ingredient and a method for improving infection or disease of Enterococcus fasium using the same.
  • the inventors of the present invention prepared various antibacterial protein candidates in the form of recombinant proteins by utilizing various antibacterial protein information known to have antibacterial activity against various bacterial species, and their lysis against Enterococcus fasium bacteria. Antibacterial proteins with excellent lytic activity were selected by examining their activity, and a method for efficiently manufacturing them was developed. The present invention was completed by developing a composition.
  • the present invention provides an amino acid sequence of the antibacterial protein EFL200 capable of specifically lysing Enterococcus fasium bacteria.
  • EFL200 an antibacterial protein capable of specifically lysing Enterococcus fasium, is composed of 284 amino acid residues and has a molecular weight of about 30.7 kDa.
  • amino acid sequence of SEQ ID NO: 1 may be partially modified by those skilled in the art using known techniques. Such modifications include partial substitutions of amino acid sequences, partial additions of amino acid sequences, and partial deletions of amino acid sequences. However, it is most preferable to apply the amino acid sequence of SEQ ID NO: 1 disclosed in the present invention mutatis mutandis.
  • the present invention provides a strain TOP10-EFL200 that can be used for the production of the antibacterial protein EFL200 having the amino acid sequence of SEQ ID NO: 1.
  • the strain TOP10-EFL200 is a strain prepared to produce the antibacterial protein EFL200 by transforming E. coli using a plasmid containing the gene sequence of SEQ ID NO: 2 prepared by the present inventors.
  • This E. coli TOP10-EFL200 was deposited at the Korea Research Institute of Bioscience and Biotechnology Biological Resources Center on November 10, 2020 by the present inventors (accession number KCTC 14364BP).
  • the term "gene” has a meaning comprehensively including DNA (gDNA and cDNA) and RNA molecules, and nucleotides, which are the basic building blocks of genes, are natural nucleotides as well as modified sugars or base sites. Also includes analogs ( Chemical Reviews 90:543-584, 1990).
  • the present invention is Enterococcus fasium bacteria characterized by the amino acid sequence of SEQ ID NO: 1 and comprising the antibacterial protein EFL200 having a specific lytic ability against Enterococcus fasium bacteria as an active ingredient.
  • a pharmaceutical composition that can be effectively used for treatment of infection or disease.
  • the antibacterial protein EFL200 having a specific lytic ability against Enterococcus fasium, characterized by the amino acid sequence of SEQ ID NO: 1 according to the present invention, contained in the pharmaceutical composition of the present invention is Enterococcus fasium as described above. Because it specifically lyses, it shows an effect in the treatment of various diseases caused by Enterococcus fasium bacteria. Therefore, the pharmaceutical composition of the present invention can be utilized for the treatment of diseases caused by Enterococcus fasium bacteria. In addition, the pharmaceutical composition of the present invention is implemented as an antibiotic, disinfectant, bactericide, therapeutic agent, etc., can be utilized for the treatment of various diseases caused by Enterococcus fasium bacteria.
  • the present invention provides an antibacterial protein EFL200 specific to Enterococcus fasium, characterized in that it has the amino acid sequence represented by SEQ ID NO: 1, and various types caused by Enterococcus fasium.
  • an antibacterial protein EFL200 specific to Enterococcus fasium characterized in that it has the amino acid sequence represented by SEQ ID NO: 1, and various types caused by Enterococcus fasium.
  • a method of treating various diseases caused by Enterococcus fasium by administering to a subject having a disease.
  • disease caused by Enterococcus fasium refers to a disease caused by Enterococcus fasium infection, including urinary tract infection, wound infection, bacteremia, endocarditis, and the like, but is not limited thereto. does not
  • Enterococcus fasium bacteria is not sensitive to existing antibiotics or resistant bacteria with resistance to existing antibiotics. That is, it does not matter whether resistance to existing antibiotics is acquired.
  • prevention refers to (i) prevention of Enterococcus fasium infection; and (ii) inhibiting the development of a disease caused by Enterococcus fasium infection.
  • treatment refers to any action that reduces the pathological condition of an infection or disease caused by Enterococcus faecium, and a disease caused by Enterococcus fasium. it means.
  • antibacterial substances capable of providing antibacterial activity against other bacterial species may be added to the pharmaceutical composition of the present invention.
  • Pharmaceutically acceptable carriers included in the pharmaceutical composition of the present invention are commonly used in formulation, and include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, water, syrup, methyl cellulose, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate and mineral oil, and the like.
  • the pharmaceutical composition of the present invention may further include a lubricant, a wetting agent, a sweetening agent, a flavoring agent, an emulsifying agent, a suspending agent, a preservative, and the like, in addition to the above components.
  • the pharmaceutical composition of the present invention may be administered through oral administration or parenteral administration, and in the case of parenteral administration, it may be administered using intravenous administration, intraperitoneal administration, intramuscular administration, subcutaneous administration or local administration, It may also be used as a method of application or spraying outside the diseased area, but is not limited thereto.
  • the pharmaceutical composition of the present invention is prepared in unit dosage form by being formulated using a pharmaceutically acceptable carrier and/or excipient according to a method that can be easily carried out by a person of ordinary skill in the art to which the present invention pertains. Alternatively, it may be prepared by placing it in a multi-dose container.
  • the formulation may be in the form of a solution, suspension, or emulsion in oil or an aqueous medium, or may be in the form of an extract, powder, granule, tablet or capsule, and may additionally include a dispersant or stabilizer.
  • suitable application, spraying and dosage of the pharmaceutical composition depend on factors such as formulation method, administration method, age, weight, sex, degree of disease symptoms, food, administration time, administration route, excretion rate, and reaction sensitivity. , and an ordinarily skilled physician or veterinarian can readily determine and prescribe an effective dosage for the desired treatment.
  • the pharmaceutical composition of the present invention may be embodied as an antibiotic, an antiseptic, a bactericide, a therapeutic agent, and the like.
  • the term 'antibiotic' refers to a preservative, a disinfectant, and an antibacterial agent.
  • the pharmaceutical composition of the present invention may be implemented in the form of a food composition.
  • Enterococcus fasium infection and disease treatment method using a pharmaceutical composition comprising the antibacterial protein EFL200 having the amino acid sequence represented by SEQ ID NO: 1 according to the present invention as an active ingredient, as well as general Enterococcus fasium bacteria, as well as existing antibiotics It can also effectively act on Enterococcus fasium bacteria, which have acquired resistance to bacteria and antibacterial substances.
  • the Enterococcus fasium-specific antibacterial protein EFL200 of the present invention does not affect the normal flora in the body other than Enterococcus fasium. can be minimized.
  • Existing antibiotics have a disadvantage of causing adverse effects on beneficial bacteria in the body, causing various side effects.
  • Lanes 1 to 3 are chromatography flow-throughs during purification, and lanes 4 to 10 are purification fractions.
  • FIG. 2 is a result showing the antibacterial activity (lytic activity) of the antibacterial protein EFL200 against Enterococcus fasium (VRE indicated at the bottom), and the transparent part is generated by the antibacterial activity (lytic activity) of the antibacterial protein EFL200.
  • a control Buffer control
  • a buffer solution not containing the antibacterial protein EFL200 was used, and the presence or absence of the lysis ring indicates the antibacterial activity of the antibacterial protein EFL200.
  • Figure 3 is a result showing the experimental results of the turbidity reduction assay (Turbidity reduction assay) performed on Enterococcus fasium bacteria of the antibacterial protein EFL200.
  • the negative control group used the buffer itself without antibacterial protein EFL200.
  • the horizontal axis is time (minutes) and the vertical axis is absorbance at 600 nm.
  • Lane M is a protein size marker, and lanes 1 to 7 are samples obtained every 10 minutes.
  • EFL200 Enterococcus fasium-specific antibacterial protein EFL200
  • an expression plasmid having the gene sequence of SEQ ID NO: 2 was prepared through a conventional molecular biological method, and transformed by introducing it into E. coli Strain TOP10-EFL200 (Accession No. KCTC 14364BP) was prepared.
  • culture was carried out at 37°C.
  • anhydrotetracycline was added so that the final concentration was 0.2 ⁇ g/ml to induce the expression of the antibacterial protein EFL200 of the amino acid sequence shown in SEQ ID NO: 1. did.
  • culture was further performed for 3 hours.
  • the cell culture solution was taken and centrifuged at 7,000 rpm at 4° C. for 15 minutes to recover cell precipitates, and the recovered cell precipitates were suspended in 30 ml of buffer (50 mM K 3 PO 4 , pH 7.0).
  • the cell suspension thus prepared was disrupted by sonication, and the sonication method was repeated in an ice bath for a total of 5 minutes under the condition that ultrasonic waves were applied for 3 seconds to break the cells and stopped for 3 seconds.
  • the supernatant obtained by centrifuging the cell disruption solution at 7,000 rpm for 15 minutes at 4° C. was purified through a conventional cation-exchange chromatography purification process.
  • fractions containing the antimicrobial protein EFL200 at a high concentration were collected, and a buffer (50 mM K 3 PO 4 , pH 7.0) was subjected to dialysis to perform medium exchange. Through this, it was possible to secure an antibacterial protein EFL200 solution having a purity of 90% or more.
  • the present inventors investigated the antibacterial activity of the antibacterial protein EFL200 through a conventional spot-on-lawn assay.
  • Enterococcus faecium 5 weeks Enterococcus faecium ( Enterococcus ) faecalis ) 2 weeks, Staphylococcus aureus ) 2 weeks, Salmonella 2 weeks, and Escherichia coli 2 weeks were the subjects.
  • the bacteria were purchased from an external institution such as The American Type Culture Collection (ATCC) in the United States, or those isolated and identified by the present inventors.
  • ATCC American Type Culture Collection
  • the antibacterial protein EFL200 had antibacterial activity (dissolution power) only against Enterococcus fasium bacteria, and had no antibacterial activity against other bacterial species. Antibacterial activity against Enterococcus fasium was confirmed for all 5 strains of Enterococcus fasium that were the subject of the experiment. The results of the antimicrobial activity of the antibacterial protein EFL200 against Enterococcus fasium bacteria are presented in FIG. 2 .
  • the antibacterial protein EFL200 can provide excellent bactericidal power (antibacterial power) against Enterococcus faecium, and can also be effectively used for preventing or treating infectious diseases caused by Enterococcus faecium. there was.
  • Example 3 Investigation of antibacterial activity of antibacterial protein EFL200 through turbidity reduction investigation method
  • the antibacterial activity of the antibacterial protein EFL200 was investigated through a turbidity reduction assay for 5 Enterococcus fasium strains tested in Example 2.
  • the experimental method of the turbidity reduction investigation method is as follows. After suspending the test bacteria in physiological saline so that the absorbance at 600 nm becomes about 0.7, 0.1 ml of antibacterial protein EFL200 solution is added to 0.9 ml of this suspension (final concentration: 10 ⁇ g/ml), and the absorbance at 600 nm is measured. It was carried out in a manner of measuring for 30 minutes. As a negative control, a buffer solution (50 mM K 3 PO 4 , pH 7.0) not containing the antimicrobial protein EFL200 was used instead of the antimicrobial protein EFL200 solution.
  • the Enterococcus fasium-specific antibacterial protein EFL200 of the present invention could eventually be killed by lysing the Enterococcus fasium bacteria.
  • a pharmaceutical composition containing the Enterococcus fasium-specific antibacterial protein EFL200 can be utilized for the purpose of killing Enterococcus fasium during Enterococcus fasium infection, and also Enterococcus fasium It shows that it can be used in the same way as conventional antibiotics for the purpose of treating infections.
  • the stability of the antibacterial protein EFL200 to the digestive enzymes was investigated by conducting a digestion test by digestive enzymes.
  • the experimental method was as follows.
  • a SIF-P solution was prepared by dissolving 0.05 g of Pancreatin (Sigma-Aldrich, Cat. No. P1625) in 5 ml of Simulated Intestinal Fluids (SIF, 50 mM KH 2 PO 4 , 0.015 N NaOH, pH 6.8) solution. .
  • SIF Simulated Intestinal Fluids
  • the negative control group used a buffer solution (50 mM K 3 PO 4 , pH 7.0) not containing the antibacterial protein EFL200 instead of the antibacterial protein EFL200 solution, and the positive control group added the antibacterial protein EFL200 solution to the SIF solution and reacted for 60 minutes. liquid was used.
  • Example 5 Enterococcus fasium fungal specific antibacterial protein EFL200's Enterococcus Investigation of the therapeutic effect on Pasium infection
  • mice Five-week-old ICR mice [specific pathogen-free (SPF) grade] weighing about 20 g were used as experimental animals. After dividing a total of 20 animals into 2 groups (10 mice per group), 1 ⁇ 10 8 cfu of Enterococcus fasium (ie, 1 ⁇ 10 8 cfu/mouse) was administered to each mouse by intravenous administration to prevent infection. induced. For one group (treatment group), 0.2 ml of antimicrobial protein EFL200 solution (10 mg/ml) was intravenously administered at 30 minutes, 12 hours, and 24 hours after forced bacterial infection. For another group (control group), only buffer (50 mM K 3 PO 4 , pH 7.0) was intravenously administered in the same volume.
  • buffer 50 mM K 3 PO 4 , pH 7.0
  • Buffer administration was performed at 30 minutes, 12 hours, and 24 hours after forced bacterial infection in the same manner as the administration of the antimicrobial protein EFL200 solution.
  • the number of deaths was investigated every day for 5 days after the forced bacterial infection, and the results are presented in Table 1.
  • the observation of unusual phenomena was also investigated twice a day, in the morning and in the afternoon.
  • the antibacterial protein EFL200 of the present invention was effective in treating Enterococcus fasium infection.
  • the pharmaceutical composition containing the antibacterial protein EFL200 of the present invention as an active ingredient can be used for the purpose of treating Enterococcus fasium infection, and also a common antibiotic for the purpose of treating Enterococcus fasium infection. It shows that it can be utilized in the same way.
  • this specific technique is only a preferred embodiment, and thus It is clear that the scope is not limited. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.

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Abstract

La présente invention concerne une protéine antibactérienne EFL200 présentant une activité antibactérienne spécifique contre Enterococcus faecium et, plus particulièrement, une protéine antibactérienne EFL200, un procédé de production de celle-ci et une composition pharmaceutique pour le traitement d'infections ou de maladies provoquées par Enterococcus faecium, comprenant, en tant que principe actif, la protéine antibactérienne CEL200 spécifique à Enterococcus faecium, la protéine antibactérienne EFL200 spécifique à Enterococcus faecium ayant la capacité de lyser spécifiquement Enterococcus faecium et comprenant une séquence d'acides aminés représentée par SEQ ID NO : 1.
PCT/KR2021/019368 2021-01-15 2021-12-20 Protéine antibactérienne efl200 possédant une activité lytique contre enterococcus faecium WO2022154287A1 (fr)

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KR20210005635 2021-01-15
KR10-2021-0005635 2021-01-15
KR1020210180284A KR20220103619A (ko) 2021-01-15 2021-12-16 엔테로코쿠스 패슘(Enterococcus faecium) 균에 대하여 용균활성을 갖는 항균단백질 EFL200
KR10-2021-0180284 2021-12-16

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US20070025978A1 (en) * 2005-06-30 2007-02-01 Pauline Yoong Bactiophage lysins for Enterococcus faecalis, Enterococcus faecium and other bacteria
KR100988771B1 (ko) * 2008-09-29 2010-10-20 주식회사 인트론바이오테크놀로지 엔테로코쿠스 및 스트렙토코쿠스 특이적 사멸능을 갖는 신규한 리신 단백질
US20190330608A1 (en) * 2016-10-20 2019-10-31 Lysando Ag New antimicrobial agents against enterococcus bacteria
KR101957266B1 (ko) * 2017-02-22 2019-03-13 주식회사 인트론바이오테크놀로지 엔테로코쿠스 패슘에 대하여 용균력을 가지는 신규한 항균단백질 efal-2

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Title
ANONYMOUS: "Intron Biotechnology, VRE Infection Treatment EFL200 Proved the Efficacy of Patient-Derived Clinical Isolates", 2 November 2021 (2021-11-02), XP055950693, Retrieved from the Internet <URL:www.healthinnews.co.kr/news/articlePrint.html?idxno=26085> *
DATABASE PROTEIN 20 September 2021 (2021-09-20), ANONYMOUS : "NlpC/P60 family protein [Enterococcus faecium] ", XP055950692, retrieved from NCBI Database accession no. WP_123838437 *

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