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WO2018121499A1 - Médicament résistant à mycobacterium tuberculosis et à une infection par mycobacterium tuberculosis et application de celui-ci - Google Patents

Médicament résistant à mycobacterium tuberculosis et à une infection par mycobacterium tuberculosis et application de celui-ci Download PDF

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WO2018121499A1
WO2018121499A1 PCT/CN2017/118497 CN2017118497W WO2018121499A1 WO 2018121499 A1 WO2018121499 A1 WO 2018121499A1 CN 2017118497 W CN2017118497 W CN 2017118497W WO 2018121499 A1 WO2018121499 A1 WO 2018121499A1
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recombinant polypeptide
drug
tuberculosis
polypeptide
molecule
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PCT/CN2017/118497
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Chinese (zh)
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丘小庆
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畿晋庆三联（北京）生物技术有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1267—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria
    • C07K16/1289—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-positive bacteria from Mycobacteriaceae (F)
    • 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
    • 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
    • A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0008—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'non-active' part of the composition delivered, e.g. wherein such 'non-active' part is not delivered simultaneously with the 'active' part of the composition
    • 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
    • A61P31/06—Antibacterial agents for tuberculosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
    • C07K14/245—Escherichia (G)
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K19/00—Hybrid peptides, i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
    • 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
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/62—DNA sequences coding for fusion proteins
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/567—Framework region [FR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/33—Fusion polypeptide fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/70—Fusion polypeptide containing domain for protein-protein interaction
    • C07K2319/74—Fusion polypeptide containing domain for protein-protein interaction containing a fusion for binding to a cell surface receptor

Definitions

  • the invention relates to the field of biomedicine, in particular to a medicament for preventing Mycobacterium tuberculosis and infection thereof and application thereof
  • Tuberculosis is a chronic infectious disease caused by the Mycobacterium tuberculosis complex (Mycobacterium tuberculosis complex, M. tuberculosis or tuberculosis), which can affect the whole body multi-organ system.
  • Mycobacterium tuberculosis complex M. tuberculosis or tuberculosis
  • the most common diseased part is the lung, which accounts for tuberculosis in various organs. 80-90% of the total. It can also involve organs such as liver, kidney, brain, and lymph nodes.
  • the main routes of transmission are the respiratory tract, the digestive tract, the skin and the uterus, but mainly through the respiratory tract. After the sputum of the sterilized tuberculosis patient is dried, the bacteria fly with the dust and are inhaled by others to cause infection.
  • the human body inhales the droplets containing M. tuberculosis is mainly caused by the amount of inhaled tuberculosis
  • the existing drugs for treating tuberculosis include isoniazid, rifampicin, pyrazinamide, ethambutol, and streptomycin, rifapentine, etc., which have side effects on liver and kidney damage, for the lungs.
  • the treatment of external tuberculosis such as bone tuberculosis and tuberculous meningitis is usually treated with chemotherapy or surgery, and the condition is repeated and even amputation treatment is required to bring physical and mental pain to the patient.
  • a large number of drug-resistant/drug-resistant tuberculosis strains have been produced.
  • the drug-resistant Mycobacterium tuberculosis has strong killing activity and no damage to the animal body of the infected bacteria. Based on this and subsequent extensive experimental research, the following technical solutions are provided:
  • Mycobacterium tuberculosis antibody mimetic, characterized in that an immunoglobulin V H CDR1, V H FR2 and V L CDR3 region NV H CDR1-V H FR2- L CDR3-C V connected in a manner that the amino acid sequence as shown in Seq ID No.2.
  • the acting molecule is a chemical molecule or a polypeptide molecule
  • the chemical molecule comprises a label, a bacterial cytotoxic agent, a growth inhibitor; the polypeptide molecule comprises an enzymatic active toxin, a bacteriocin;
  • the bacteriocin is selected from the group consisting of coenzyme E1, Ia, Ib, A, B, N, an aqueous channel domain polypeptide thereof, and pyocyanin.
  • the acting molecule is a polypeptide molecule and the ligation is by a protein coupling agent or recombinant expression.
  • a recombinant polypeptide of Mycobacterium tuberculosis wherein the recombinant polypeptide is linked to a peptide chain of the above antibody mimetic by a carboxy terminus of a peptide chain of a polypeptide-acting molecule.
  • the amino terminal linkage is composed; the polypeptide-acting molecule is selected from the group consisting of colicin E1, Ia, Ib, A, B, N or an aqueous channel domain polypeptide thereof, and pyocyanin.
  • the colicin is Ia.
  • the recombinant polypeptide has an amino acid sequence such as Seq ID No. 6.
  • the recombinant polypeptide of any of the above or the agent comprising the recombinant polypeptide is used as the entire pharmaceutically active ingredient or a part of the pharmaceutically active ingredient of the anti-tuberculosis drug.
  • the reagent comprising the recombinant polypeptide refers to a protein recombinant expression product that has been purified initially or multiple times, wherein the recombinant polypeptide has a purity of 30-99.5%.
  • the preparation method further comprises a recombinant expression step and a purification step of the recombinant polypeptide, wherein the recombinant expression vector for expressing any of the recombinant polypeptides is transformed into an expression cell to induce expression of the recombinant polypeptide. And purification.
  • any of the above recombinant polypeptides as anti-tuberculosis drugs, characterized in that the recombinant polypeptide or an agent comprising the recombinant polypeptide is used as the total drug activity of the anti-tuberculosis drug Ingredients or parts of pharmaceutically active ingredients.
  • an anti-tuberculosis bacterium or an agent thereof wherein all or a pharmaceutically active ingredient thereof is a recombinant polypeptide of any of the above or an agent comprising the recombinant polypeptide.
  • the reagent comprising the recombinant polypeptide refers to a protein recombinant expression product that has been purified initially or multiple times, wherein the recombinant polypeptide has a purity of 30-99.5%.
  • the medicament further comprises a pharmaceutically acceptable ingredient, which is formulated to:
  • Enteral administration agents such as powders, tablets, granules, capsules, solutions, emulsions, suspensions;
  • Injectable agents such as intravenous, intramuscular, subcutaneous, intradermal, and intraluminal; or
  • Respiratory agents such as sprays, aerosols, powders.
  • the present disclosure provides a recombinant expression vector for the preparation of a drug against Mycobacterium tuberculosis or an infection thereof, which is loaded with an open reading frame expressing any of the above recombinant polypeptides.
  • the coding gene sequence in the open reading frame is as shown in Seq ID No. 5.
  • the invention provides a method of treating a Mycobacterium tuberculosis infection, characterized in that any one of the above agents is provided to an infected individual.
  • Antibody mimics of the present disclosure for identifying Mycobacterium tuberculosis which was originally based on specific V H CDR1 antibody anti Meningococcal porin A, V H FR2 and V L CDR3 designed to retain the original The recognition, binding or affinity activity of an antibody.
  • a recombinant polypeptide linked to a bacteriocin, such as colicin in addition to recognizing the killing of meningococcus, also against vancomycin-resistant intestinal Cocci, anti-methicillin-resistant Staphylococcus aureus or anti-multi-drug resistant Pseudomonas aeruginosa have recognition and sterilizing activity.
  • bacteriocins such as colicin have only the ability to recognize E. coli, and they do not have the ability to specifically recognize other bacteria. Therefore, it is clear that the recombinant polypeptide is resistant to Van Gogh.
  • the antibody mimetic recognizes the colicin and directs it to the cell membrane of the identified target. Attack.
  • the inventors have found that the recombinant polypeptide obtained by linking the antibody mimetic to bacteriocin has superior killing activity against hundreds of strains of currently resistant strains of Mycobacterium tuberculosis. However, antibody simulation or colicin was co-cultured with these strains alone, and no antibacterial activity was found.
  • the above antibody mimetic can be used as a targeting molecule targeting a cell of Mycobacterium tuberculosis, and some of the acting molecules are linked at one end thereof to form a coupling molecule, which can be guided to the cell membrane of Mycobacterium tuberculosis cells.
  • the acting molecule includes, but is not limited to, the aforementioned bacteriocin such as colicin or a well-known fragment of the aqueous channel region thereof.
  • cytotoxic chemical reagent such as a radioisotope (for example, a typical radioactive element comprising At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and cesium radioisotopes), growth inhibition Agent, toxin (eg, a protein toxin, an enzymatically active toxin of a bacterial, fungal, plant or animal source or a fragment thereof).
  • a radioisotope for example, a typical radioactive element comprising At211, I131, I125, Y90, Re186, Re188, Sm153, Bi212, P32, Pb212 and cesium radioisotopes
  • growth inhibition Agent eg, toxin (eg, a protein toxin, an enzymatically active toxin of a bacterial, fungal, plant or animal source or a fragment thereof).
  • toxin eg, a protein toxin, an enzymatically active to
  • Methods of making recombinant polypeptides of the present disclosure are also optional. It is not limited to the description in the examples.
  • a specific aspect of the present disclosure is to claim the use of the above antibody mimetic in the preparation of a drug against Mycobacterium tuberculosis or an infection, the use of which mainly comprises the imitation of the antibody and the bacteriocin, selected from the large intestine a group consisting of an amino acid domain polypeptide, a pyocyanin, a recombinant polypeptide, and a recombinant polypeptide obtained as a whole or a part of a pharmaceutical active ingredient to prepare and produce antituberculosis Bacillus or its infected drugs.
  • the peptide chain of the antibody mimetic is linked to the carboxy terminus of the peptide chain of Ia, and the amino acid sequence of the antibody mimetic
  • the antibody mimetic peptide chain is ligated at the carboxy terminus of Ia, and the antibody mimetic peptide chain is: the carboxy terminus of the first complementarity determining region of the heavy chain variable region is linked to the amino terminus of the second backbone region of the heavy chain, and the light chain variable region The peptide-terminal carboxy-terminal amino acid of the third complementarity determining region is linked to the carboxy-terminal amino acid of the second backbone region of the heavy chain, as shown by Seq ID No. 4.
  • T and R are two signal recognition domains at the amino terminus of colicin Ia; channel-forming is the formation of an ion channel domain at the carboxy terminus of coenzyme Ia; AM is an antibody mimetic.
  • Figure 7 Results of blood biochemical tests in a model of cynomolgus tuberculosis infection.
  • the picture on the left is 40x magnification, and the image on the right is 200x magnification.
  • the untreated group of monkeys (A) showed typical miliary tuberculosis lesions in the lungs;
  • Isoniazid/rifampicin treatment group monkeys showed typical tuberculous granulomatous lesions in the lungs;
  • Example 1 The active molecule was selected from colistin Ia to prepare a recombinant polypeptide.
  • the mutation program was performed according to the Strategene QuickChange SiteDirected Mutagenesis Kit (catalog #200518) kit manual, ie:
  • PMC-AM1 and PMC-AM2 can be obtained, respectively, and the amino acid sequences thereof are as shown in Seq ID No. 6, Seq ID No. 8.
  • PMC-AM1 is the first complementarity determining region of the heavy chain variable region, the second heavy chain region of the heavy chain, and the third complementarity determining region of the light chain variable region, and the three regions are sequentially linked to the amino terminus of the next region by the carboxy terminus.
  • the amino acid sequence is shown as Seq ID No. 2;
  • PMC-AM2 is the carboxy-terminal linked heavy chain second framework region of the first complementarity determining region of the heavy chain variable region, and the third complementarity determining region of the light chain variable region
  • the carboxy terminal amino acid of the peptide chain is linked to the carboxy terminal amino acid of the second backbone region of the heavy chain, and the amino acid sequence is shown as Seq ID No. 4.
  • PMC-AM2 was used as a control for PMC-AM1 to verify the function of antibiotics produced in the different linkages between the amino acid stretches of the antibody mimics designed in the present invention.
  • oligonucleotide primer sequences designed in the above preparation plasmids are as follows:
  • Mtb Erdman is sensitive to current anti-tuberculosis drugs, SUNY Upstate Medical University, State University of New York
  • Drug-resistant strain is a Beijing genotype strain, resistant to isoniazid and rifampicin, with a classic isoniazid resistance to katG315 gene mutation and rifampicin rpoB531, 526 gene mutation, PUMC-94789
  • the virulence is strong, and the survival time of LD50 mice is 7 days (the survival rate of tuberculosis standard strain H37Rv is 14 days).
  • Peking Union Medical College Peking Union Medical College.
  • MDR-TB multidrug-resistant tuberculosis
  • strains are well-known strains, and the applicant's laboratory also has a preservation.
  • the appropriate amount can be provided to the public within 20 years from the date of application for verification of this application.
  • the genomicin PMC-AM1 was prepared in Example 1;
  • Isoniazid and other commonly used anti-tuberculosis drugs are commercially available.
  • 7H9-S medium containing 0.47% 7H9 (purchased from BD Company, USA, Cat. No. 271310), 0.2% glycerol, 0.05% Tween-80, 0.085% sodium chloride, 0.5% calf serum component V (Roche, Cat. No. 10735094001), 0.2% glucose, 0.003% catalase (Sigma-Aldrich, Cat. No. C9322-1G).
  • the final concentration gradient of each drug was: 80, 40, 20, 10, 5, 2.5, 1.25, 0.62, 0.31, 0.16, 0.08 ⁇ g/ml, and other anti-tuberculosis drugs were 256, 128, 64, 32, 16, 8 , 4, 2, 1, 0.5 ⁇ g/ml
  • the final concentration of tuberculosis in each well was adjusted to 5x10 5 CFU/ml.
  • the microplate was cultured for 10 days (35 to 37 ° C).
  • the minimum concentration that inhibits the growth of tuberculosis visible to the naked eye is the minimum inhibitory concentration of the drug.
  • the MIC 50 and MIC 90 of anti-tuberculosis drugs are in the range of hundreds to hundreds of thousands of nM. That is, the bactericidal effect of the pheromone on the hundreds of MDR-TB tested is hundreds to hundreds of thousands times greater than the bactericidal efficacy of the 11 existing anti-tuberculosis drugs.
  • mice Female BLAB/c mice were vaccinated with 6.8x10 2 CFU Mtb Erdman tuberculosis;
  • Each group of 6 was divided into five groups: early control group, late control group, isoniazid group, low dose pheromone group, high dose pheromone group;
  • each group of rats was treated as follows:
  • the early control group and the late control group were intraperitoneally injected with physiological saline;
  • the low-dose pheromone group and the high-dose pheromone group were intraperitoneally injected with 0.286 or 0.572 ⁇ mol/kg/d (ie 20 or 40 mg/kg/d) pheromone.
  • 300CFU multidrug-resistant tuberculosis PUMC-94789 was inoculated into the right lower lung by bronchoscopy.
  • the pulmonary tuberculosis test and lung CT examination confirmed that the lung infection was successful, treated with each drug for more than 150 days, and after stopping the drug for more than 180 days, the test totaled 52 weeks (about one year).
  • the therapeutic doses were as follows: Group 1. No treatment; Group 2. Isoniazid/rifampicin 21.8/3.65 ⁇ mol/kg/d (3/3 mg/kg/d), intraperitoneal injection; Group 3. Informationin 43nM/kg/d (3mg/kg/d), intraperitoneal injection.
  • the remaining 3 monkeys did not find any recurrence of the disease during the 180-month follow-up observation of the drug withdrawal; and the appetite and behavior were good during the observation period of withdrawal, and the body weight gradually increased. Therefore, after 150 days of informationin treatment, 60% (3/5) of the tuberculosis infection in the monkey was effectively controlled, and there was no recurrence in the 180-day withdrawal observation period, which should be clinically cured.
  • Serum enzymes such as alanine aminotransferase ALT, serum pancreatic amylase AMY, alkaline phosphatase ALP and other indicators and serum, globular protein levels such as total protein TP, serum albumin ALB, globulin Glob no significant difference;
  • the serum glucose Glu and triglyceride TG of untreated monkeys were significantly lower than that of the informationin treatment group, which should be due to the aggravation of tuberculosis, poor eating and malnutrition in the untreated group;
  • the 150-day pheromone treatment did not cause toxicity to the liver, kidney, and metabolic functions of the experimental monkeys.
  • the untreated group of monkeys (A) showed typical miliary tuberculosis lesions in the lungs, isoniazid/rifampicin treatment group, and monkeys (B) showed typical tuberculous granulomatous lesions in the lungs.
  • monkeys (B) showed typical tuberculous granulomatous lesions in the lungs.
  • the pheromone treatment group only the interstitial pneumonia was present in the lungs of the monkey (C), and no TB lesions were observed. (40x magnification on the left and 200x magnification on the right)

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Abstract

L'invention concerne un médicament résistant à Mycobacterium tuberculosis et à une infection par Mycobacterium tuberculosis, ainsi qu'une application de celui-ci. La présente invention se rapporte au domaine des produits pharmaceutiques. Tout ou une partie des principes actifs du médicament sont un polypeptide recombinant constitué de bactériocines, telles que des colicines E1, Ia, Ib, A, B et N, ou un polypeptide mimétique d'anticorps ayant son domaine de pores aqueux et l'extrémité carboxyle de la chaîne peptidique liée. Selon l'invention, le médicament a un puissant effet bactéricide contre Mycobacterium tuberculosis résistant aux médicaments multiples, et peut guérir un macaque infecté de manière fatale avec une souche de Mycobacterium tuberculosis résistante aux médicaments.
PCT/CN2017/118497 2016-12-26 2017-12-26 Médicament résistant à mycobacterium tuberculosis et à une infection par mycobacterium tuberculosis et application de celui-ci WO2018121499A1 (fr)

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Citations (3)

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CN102643346A (zh) * 2009-09-02 2012-08-22 畿晋庆堂国际生物技术有限公司 一种含抗体模拟物的新型抗生素及其制备方法与应用
EP2789632A1 (fr) * 2011-12-08 2014-10-15 Protein Design Lab, Ltd. Nouveau procédé de préparation d'antibiotique et système de plate-forme utilisant ce procédé
US9073989B2 (en) * 2011-01-25 2015-07-07 Protein Design Lab, Ltd Antibiotic comprising an antibody mimetic, its preparation methods and uses thereof

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