CN102871996A - Antibiotic composition and application thereof - Google Patents
Antibiotic composition and application thereof Download PDFInfo
- Publication number
- CN102871996A CN102871996A CN2012103336941A CN201210333694A CN102871996A CN 102871996 A CN102871996 A CN 102871996A CN 2012103336941 A CN2012103336941 A CN 2012103336941A CN 201210333694 A CN201210333694 A CN 201210333694A CN 102871996 A CN102871996 A CN 102871996A
- Authority
- CN
- China
- Prior art keywords
- aminoacid
- antibacterial
- antibiotic
- ser
- combination
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides a novel antibiotic composition and an application thereof. The antibiotic composition consists of two components: D-amino acid and an antibiotic activity drug and/or derivative of the antibiotic activity drug. The D-amino acid is composited with the available antibiotics for the first time, and used to interfere with physiologic metabolism of bacteria to improve the antibiotic activity of the antibiotics, thereby providing a brand-new approach to dealing with the problem of increasingly severe bacterial drug resistance. Compared with the traditional new drug research and development, the antibiotic composition and a method of combined administration have the advantages of high efficiency, quickness, low cost, multiple optional compositions and the like, and show the favorable antibiotic activity in in-vitro and in-vivo anti-infection researches.
Description
Technical field
The invention belongs to pharmaceutical field, specifically, relate to a kind of antibacterial combination and application thereof.
Background technology
Infectious disease is the common frdquently encountered disease that threatens human life's health, also is one of the important complication of many organ diseases and cause of the death.The application of anti-infectives greatly reduces the death of infectious disease.Anti-infectives commonly used comprises beta-lactam antibiotic, quinolone antibiotic, aminoglycoside antibiotics etc.Its mechanism of action comprises the anti-bacteria Cell wall synthesis, suppresses some function of cell membrane, and Profilin matter is synthetic, suppresses nucleic acid synthetic, and inhibition folic acid is synthetic etc.
D-aminoacid is natural to be present in many biologies, and the performance specific function is the important component of bacteria cell wall such as D-alanine and D-Glu, and D-Ser is the mankind's neurotransmitter etc.But under the usual condition, these relatively rare aminoacid concentration in thalline is very low.And the various D-aminoacid that in the recent period report discovery antibacterial produces when steady state period can be accumulated mM level that reaches, and prompting D-aminoacid is relevant with the physiological status of antibacterial.
Biofilm be by bacterial adhesion in contact surface, secretion polysaccharide matrix, fibrin, lipid protein etc., a large amount of antibacterials that himself embedding is wherein formed assemble film sample things.Various bacteria can form biofilm (such as Pseudomonas aeruginosa, staphylococcus aureus, staphylococcus epidermidis, escherichia coli etc.).It is to cause some chronic infection repeatedly to show effect to be difficult to cure the major reason that produces with bacterial drug resistance that bacterial biofilm forms, and its mechanism mainly comprises: antibiotic permeability is reduced; Absorption antibiotic inactivator, the deactivation antibiotic; Bacterial metabolism slows down, and is " inferior hibernation-like state ", to antibiotic Reduced susceptibility (antibacterial that forms biofilm is low more than 1000 times to the antibacterial of the sensitivity specific ionization state of medicine); Escape the scavenging action of body immune system etc.And recently research is found, the D-ispol of nanomole level can make the bacterial strains such as bacillus subtilis that form biofilm return free state, thereby recover the sensitivity of strains, and can produce the amino acid whose fact of D-based on many bacterial strains, infer that D-aminoacid may be the universal signal that biofilm dissociates.
Owing to having drawback on the pesticide application strategy of traditional anti-infectives treatment, add that the drug dependence problem is serious, have a strong impact on thereby microecological balance produced.Under antibiotic selective pressure, occur such as the MRSA(methicillin-resistant staphylococcus aureus), the VRE(vancomycin-resistant enterococcus), the PRSP(penicillin resistance pneumococcus) etc. Gram-positive fastbacteria and multidrug resistance gram negative bacteria such as Acinetobacter bauamnnii, klebsiella pneumoniae, escherichia coli, bacillus pyocyaneus etc., and the fastbacteria treatment is very thorny, the infection mortality rate is sharply risen, health to the whole mankind has consisted of serious threat (Clin Microbiol Rev, 22 (4): 582-610,2009).
The situation is tense for China's bacterial resistance, and multidrug resistance G-bacterium infection problems is serious, Pseudomonas aeruginosa, the Acinetobacter bauamnnii of carbapenem antibiotic drug resistance is widely current clinically, and the treatment difficulty, even past medical help.Become the primary cause of death of infectious disease at U.S. MRSA, superbacteria NDM-1 breaks out with popular the whole world, more causes showing great attention to of the whole world.And bacterial resistance gene also often is positioned on the displaceable element, thereby accelerated the propagation of drug resistant gene between different strains.Therefore in the urgent need to strengthening the research and development to drug-resistance bacteria medicine.
Many drug resistant genes derive from the non-pathogenic bacteria in the environment, and the powerful drug resistance system that non-pathogenic bacteria carries comprises natural, semi-synthetic and complete synthesis antibiotic drug resistance element, and the generation of drug resistance is seemingly inevitable.Seldom there is in recent decades the antibiotic of newtype to come out, and provides new approaches with the antibiotic adjuvant of antibiotic and other biological bioactive molecule and existing Antibiotic combination medication for the exploitation of novel drug-resistance bacteria medicine.
Summary of the invention
The purpose of this invention is to provide the application of D-aminoacid in the antibacterial activity that strengthens antibacterials.
Another object of the present invention provides a kind of novel antibacterial pharmaceutical composition and application thereof.
A further object of the present invention provides D-aminoacid and the application of antibacterials drug combination aspect the infectious disease treatment.
In order to realize the object of the invention, a kind of antibacterial combination of the present invention is made of two kinds of components, and a kind of is D-aminoacid, and another kind is antibacterial activity medicine and/or its derivant; Wherein, described D-aminoacid is one or more in D-alanine, D-Ser, D-methionine, D-Thr, D-phenylalanine, D-Glu, D-Gln, D-PROLINE, D-Arg, D-Lys, D-Cys, D-Val, D-Leu, D-Ile, D-trp, D-Tyrosine, D-Asp, D-His, D-Asn and the glycine that does not possess D L typing; Described antibacterial activity medicine and/or its derivant are one or more in beta-lactam antibiotic, aminoglycoside antibiotics, quinolone antibiotic, macrolide antibiotics, chloromycetin series antibiotics, glycopeptide antibiotics or the fosfomycin etc.
The amino acid whose concentration range of D-is 0.001mM ~ 10M in the aforesaid antibacterial combination.The selection of the amino acid whose kind of D-and concentration in the compositions, the bacterial strain of using according to work done in the manner of a certain author, antibiotic kind and difference are preferably on obvious one or more D-aminoacid drug combinations of (the MIC value is lower) of the anti-specific bacterial strain impact of this antibiotic.Final purpose is to obtain a series of D-aminoacid antibacterial combinations that can effectively resist respectively specific strain infection.
The preparation method of aforementioned antibacterial combination comprises two kinds, the first is: at first two kinds of component D-aminoacid, antibacterial activity medicine and/or its derivant difference water or suitable solvent (according to D-aminoacid, antibacterial activity medicament selection) are mixed with mother solution, then and required D-amino acid concentration active according to antibacterials is mixed with both drug combination liquid.The second is: be mixed in proportion D-aminoacid, antibacterial activity medicine and/or its derivant, then add entry or suitable solvent (according to D-aminoacid, antibacterial activity medicament selection) and directly be mixed with both drug combination liquid.Such as, the solvent that is used for dissolving D-Leu, imipenum, erythromycin, chloromycetin is respectively 1M hydrochloric acid solution, 0.01M phosphate buffer (pH7.2), 95% ethanol or glacial acetic acid, 95% ethanol.
The present invention also provides the application of described antibacterial combination in the preparation anti-infectives.
The antimicrobial spectrum of this anti-infectives is Gram-positive and/or gram negative bacteria and their fastbacteria.Preferably, described gram-positive bacterium is: one or more in staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis, enterococcus faecalis, streptococcus pneumoniae, the streptococcus pyogenes etc.
Described gram negative bacteria is: one or more in Acinetobacter bauamnnii, klebsiella pneumoniae, escherichia coli, bacillus pyocyaneus, serratia marcescens, proteus mirabilis, proteus vulgaris, Mo Genmo Salmonella, special-shaped citrobacter, enterobacter cloacae, clostridium perfringen, the thunder Ji Shi Pu Lufeideng bacillus etc.The present invention further provides the application aspect the infectious disease treatment of D-aminoacid and antibacterials drug combination, comprising: 1) D-aminoacid and antibacterials are made the compound formulation drug combination; Or 2) successively medication of D-aminoacid and antibacterials namely gives first D-aminoacid, after give antibacterials; Or give first antibacterials, after give D-aminoacid.
The present invention carries out science, reasonably combination with D-aminoacid and existing antibacterials first, disturb the antibacterial activity that is used for strengthening antibacterials of Bacterial Physiological metabolism by D-aminoacid, for the day by day serious bacterial drug resistance problem of reply provides a brand-new approach.The advantages such as the method for antibacterial combination provided by the invention and drug combination has for traditional new drug development efficiently, quick, cheap, the optional combination of expense is many, and demonstrate good antibacterial activity in the in vivo and in vitro infection research.
The specific embodiment
Following examples are used for explanation the present invention, but are not used for limiting the scope of the invention.If do not specialize, the conventional means that used technological means is well known to those skilled in the art among the embodiment, the raw materials used commercial goods that is.
The preparation of embodiment 1 D-Ser and meropenem drug combination liquid
1. take by weighing D-Ser powder (molecular weight 105.09, purity 98%) 0.429g, be settled to 10ml with sterilized water, aseptic filtration gets the 0.4M mother solution.
2. get 0.4M D-Ser mother solution 0.25ml, be settled to 10ml with sterilized water, get 10mMD-serine mother solution.
3. get 10mM D-Ser mother solution 0.1ml, be settled to 10ml with sterilized water, get 0.1mM D-Ser mother solution.
4. take by weighing meropenem powder (purity 99.1%; Moisture 12.4%) 57.6mg is settled to 10ml with sterilized water, and aseptic filtration gets the 5mg/mL mother solution.
5. 0.4M D-Ser mother solution 0.25ml and 5mg/ml meropenem mother solution 0.512ml are mixed, be settled to 10ml with sterilized water, namely get the drug combination liquid of 10mM D-Ser and 256 μ g/ml meropenems.
6. 10mM D-Ser mother solution 0.1ml and 5mg/ml meropenem mother solution 0.512ml are mixed, be settled to 10ml with sterilized water, namely get the drug combination liquid of 0.1mM D-Ser and 256 μ g/ml meropenems.
7. 0.1mM D-Ser mother solution 0.1ml and 5mg/ml meropenem mother solution 0.512ml are mixed, be settled to 10ml with sterilized water, namely get the drug combination liquid of 0.001mM D-Ser and 256 μ g/ml meropenems.
The preparation of embodiment 2 D-Sers and meropenem drug combination liquid
1. take by weighing D-Ser powder (molecular weight 105.09, purity 98%) 3.43g.
2. take by weighing meropenem powder (purity 99.1%; Moisture 12.4%) 115.2g.
3. both are mixed, be settled to 10ml with sterilized water, namely get the drug combination liquid of 3.2M D-Ser and 10mg/ml meropenem.
The preparation of the antibacterial combination that is comprised of other D-aminoacid and antibacterial activity medicine and/or its derivant is carried out according to the description among embodiment 1 or the embodiment 2.
Methicillin-resistant resistant Staphylococcus aureus (MRSA) activity research of embodiment 3 D-Sers and meropenem drug combination
1. get D-Ser (available from Sigma company), be mixed with the 0.4M mother solution with sterilized water, filter for subsequent use.Merrem (available from Hebei Zhongrun Pharmaceutical Co.ltd., Shiyao Group) is formulated as the 5mg/mL mother solution with sterilized water.
2. meropenem is carried out two times of Concentraton gradient dilutions with the MH broth bouillon that contains 0mM, 0.2mM, 2mM and 20mM D-Ser respectively, concentration range is 64 μ g/mL-0.03 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes added in aseptic 96 orifice plates.Establish simultaneously the strain growth contrast that does not contain meropenem.
3. with MRSA reference culture ATCC 33591, ATCC 43300, N315, and Beijing area clinical separation strain 06-3,06-16,06-23,06-37,08-6,08-26,08-32,08-36,08-44,08-45,08-48,08-50 are inoculated in respectively in the 1mL MH broth bouillon 37 ° of C overnight incubation.
4. the bacterium liquid of incubated overnight is transferred to 0.5 Maxwell turbidity and (be about 1.0 * 10
8CFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 * 10
5CFU/mL.
5. 96 well culture plates are suitably wrapped up, prevent the liquid excessive vaporization, place 37 ° of C to cultivate 16-18h.
6. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (Minimal Inhibitory Concentration, MIC).The result is as shown in table 1.
Table 1D-serine is on the result that affects of the anti-MRSA activity of meropenem
As can be seen from Table 1,20mM D-Ser and meropenem drug combination can improve the antibacterial activity of meropenem, and compare without D-Ser, and MIC has descended more than 32 times.The strain growth contrast of each concentration D-Ser is compared without significant difference with the growth control that does not contain D-Ser.
The activity research of the anti-klebsiella pneumoniae of embodiment 4D-methionine and meropenem drug combination, escherichia coli, bacillus pyocyaneus
1. get D-methionine (available from Sigma company), be mixed with the 0.25M mother solution with sterilized water, filter for subsequent use.Merrem (available from Hebei Zhongrun Pharmaceutical Co.ltd., Shiyao Group) is formulated as the 5mg/mL mother solution with sterilized water.
2. meropenem is carried out two times of Concentraton gradient dilutions with the MH broth bouillon that contains 0mM, 0.2mM, 2mM and 20mM D-methionine respectively, concentration range is 8 μ g/mL-0.004 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes added in aseptic 96 orifice plates.Establish simultaneously the strain growth contrast that does not contain meropenem.
3. with tested reference culture klebsiella pneumoniae ATCC 700603, escherichia coli ATCC25922, bacillus pyocyaneus ATCC 27853, bacillus pyocyaneus PAO1, and clinical isolates strain lung in Beijing area restrains bacillus 7, escherichia coli 1515 are inoculated in respectively in the 1mL MH broth bouillon 37 ° of C overnight incubation.
4. the bacterium liquid of incubated overnight is transferred to 0.5 Maxwell turbidity and (be about 1.0 * 10
8CFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 * 10
5CFU/mL.
5. 96 well culture plates are suitably wrapped up, prevent the liquid excessive vaporization, place 37 ° of C to cultivate 16-18h.
6. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (MIC).The result is as shown in table 2.
Table 2D-methionine is on the impact of the anti-klebsiella pneumoniae of meropenem, escherichia coli and bacillus pyocyaneus activity
As can be seen from Table 2,20mM D-methionine and meropenem drug combination can improve the antibacterial activity of meropenem, and compare without the D-methionine, and MIC has descended 4-8 doubly.The strain growth contrast of each concentration D-methionine is compared without significant difference with the growth control that does not contain the D-methionine.
The anti-Staphylococcus aureus activity research of embodiment 5D-methionine and ampicillin, D-Ser and ampicillin and D-Thr and ampicillin drug combination
1. get D-methionine, D-Ser and D-Thr (available from Sigma company), be mixed with respectively 0.25M, 0.4M and 0.4M mother solution with sterilized water, filter for subsequent use.Ampicillin standard substance (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute) are formulated as the 5mg/mL mother solution with sterilized water.
2. two times of Concentraton gradient dilutions are carried out with the MH broth bouillon that contains 0mM, 0.1mM, 10mM D-methionine, D-Ser or D-Thr respectively in the ampicillin, concentration range is 512 μ g/mL-0.125 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes added in aseptic 96 orifice plates.Establish simultaneously the strain growth contrast that does not contain the ampicillin.
3. tested reference culture staphylococcus aureus ATCC 43300, staphylococcus aureus N315, staphylococcus aureus Mu50 are inoculated in respectively in the 1mL MH broth bouillon 37 ° of C overnight incubation.
4. the bacterium liquid of incubated overnight is transferred to 0.5 Maxwell turbidity and (be about 1.0 * 10
8CFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 * 10
5CFU/mL.
5. 96 well culture plates are suitably wrapped up, prevent the liquid excessive vaporization, place 37 ° of C to cultivate 16-18h.
6. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (MIC).The result is as shown in table 3.
Table 3D-methionine, D-Ser and D-Thr are on the impact of ampicillin anti-Staphylococcus aureus activity
As can be seen from Table 3,10mM D-methionine and ampicillin drug combination can improve the antibacterial activity 2-4 of ampicillin doubly; 10mM D-Ser and ampicillin drug combination can improve the antibacterial activity 2-4 of ampicillin doubly; 10mM D-Thr and ampicillin drug combination can improve the antibacterial activity 1-2 of ampicillin doubly.The contrast of the amino acid whose strain growth of each concentration D-with do not contain the amino acid whose growth control of D-and compare without significant difference.
Anti-enterococcus faecalis, the enterococcus faecalis activity research of embodiment 6 D-methionine, D-Ser, three kinds of D-aminoacid of D-Thr and meropenem drug combination
1. get D-methionine, D-Ser, D-Thr (available from Sigma company), be mixed with respectively 0.25M, 0.4M, 0.4M mother solution with sterilized water, filter for subsequent use.Merrem (available from Hebei Zhongrun Pharmaceutical Co.ltd., Shiyao Group) is formulated as the 5mg/mL mother solution with sterilized water.
2. prepare respectively the brain heart infusion broth bouillon (Brain heart infusion, BHI) of the three kinds of D-aminoacid (D-methionine, D-Ser, D-Thr) that contain 0.2mM, 2mM and 20mM.
3. meropenem is carried out two times of Concentraton gradient dilutions with three kinds of amino acid whose BHI of D-that contain 0mM, 0.2mM, 2mM and 20mM respectively, concentration range is 256 μ g/mL-0.125 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes added in aseptic 96 orifice plates.Establish simultaneously the strain growth contrast that does not contain meropenem.
4. with tested reference culture enterococcus faecalis ATCC 51299, enterococcus faecalis ATCC29212, enterococcus faecalis ATCC 700802, enterococcus faecalis ATCC 51575 and enterococcus faecalis ATCC 700221, clinical isolates strain enterococcus faecalis HH22 and enterococcus faecalis EFL4041 are inoculated in respectively in the 1mL brain-heart broth culture medium, 37 ° of C overnight incubation.
5. the bacterium liquid of incubated overnight is transferred to 0.5 Maxwell turbidity and (be about 1.0 * 10
8CFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 * 10
5CFU/mL.
6. 96 well culture plates are suitably wrapped up, prevent the liquid excessive vaporization, place 37 ° of C to cultivate 16-18h.
7. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (MIC).The result is as shown in table 4.
Anti-enterococcus faecalis, the enterococcus faecalis of table 4D-methionine, D-Ser, three kinds of D-aminoacid of D-Thr and meropenem drug combination are active
As can be seen from Table 4, the D-methionine of 20mM, D-Ser, three kinds of D-aminoacid of D-Thr and meropenem drug combination can improve the antibacterial activity of meropenem.With compare without D-aminoacid, MIC has descended 8-32 doubly.The amino acid whose strain growth contrast of each concentration D-is compared with not containing the amino acid whose growth control of D-, and except three kinds of amino acid whose culture medium of D-that contain 20mM have the minimal effect enterococcus faecalis ATCC 51299, other are without significant difference.
Anti-enterococcus faecalis, the enterococcus faecalis activity research of embodiment 7 D-methionine, D-Ser, three kinds of D-aminoacid of D-Thr and vancomycin drug combination
1. get D-methionine, D-Ser, D-Thr (available from Sigma company), be mixed with respectively 0.25M, 0.4M, 0.4M mother solution with sterilized water, filter for subsequent use.Vancomycin standard substance (available from Nat'l Pharmaceutical ﹠ Biological Products Control Institute) are formulated as the 10mg/mL mother solution with sterilized water.
2. prepare respectively the BHI of the three kinds of D-aminoacid (D-methionine, D-Ser, D-Thr) that contain 0.2mM, 2mM and 20mM.
3. vancomycin is carried out two times of Concentraton gradient dilutions with three kinds of amino acid whose BHI of D-that contain 0mM, 0.2mM, 2mM and 20mM respectively, concentration range is 256 μ g/mL-0.125 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes added in aseptic 96 orifice plates.Establish simultaneously the strain growth contrast that does not contain vancomycin.
4. strain subject enterococcus faecalis ATCC 51299, enterococcus faecalis HH22, enterococcus faecalis ATCC 29212, enterococcus faecalis ATCC 700802, enterococcus faecalis ATCC 51575, enterococcus faecalis EFL4041 and enterococcus faecalis ATCC 700221 are inoculated in respectively in the 1mL brain-heart broth culture medium 37 ° of C overnight incubation.
5. the bacterium liquid of incubated overnight is transferred to 0.5 Maxwell turbidity and (be about 1.0 * 10
8CFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 * 10
5CFU/mL.
6. 96 well culture plates are suitably wrapped up, prevent the liquid excessive vaporization, place 37 ° of C to cultivate 16-18h.
7. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (MIC).The result is as shown in table 5.
Anti-enterococcus faecalis, the enterococcus faecalis of table 5D-methionine, D-Ser, three kinds of D-aminoacid of D-Thr and vancomycin drug combination are active
As can be seen from Table 5, the D-methionine of 20mM, D-Ser, three kinds of D-aminoacid of D-Thr and vancomycin drug combination, can improve the activity of the anti-vancocin drug resistance enterococcus (enterococcus faecalis ATCC 51299, enterococcus faecalis ATCC 700802, enterococcus faecalis ATCC51575, enterococcus faecalis EFL4041 and enterococcus faecalis ATCC 700221) of vancomycin, with compare without D-aminoacid, MIC has descended 8-16 doubly.And to the activity influence not obvious (MIC is constant or descend 2 times) of the anti-non-Vancomycin-resistant Enterococcus (enterococcus faecalis HH22 and enterococcus faecalis ATCC 29212) of vancomycin.The amino acid whose strain growth contrast of each concentration D-is compared with not containing the amino acid whose growth control of D-, and except three kinds of amino acid whose culture medium of D-that contain 20mM have the minimal effect enterococcus faecalis ATCC 51299, other are without significant difference.
Embodiment 8 D-Sers are studied the clinical protective effect that separates Mrsa In Rabbits (MRSA) 08-50 infecting mouse with the meropenem drug combination
1. Beijing area clinical separation MRSA bacterial strain 08-50 is inoculated in 10mL and increases in the bacterial context soup (0.5%MH+2.5% yeast extract, autoclaving), transferring behind 37 ° of C cultivation 6h increases in the bacterial context soup in 10mL is fresh, continues overnight incubation (16-18h).
2. after the bacterium liquid of overnight incubation being carried out 100,1000,10000 times of dilutions, sterilised yeast suspension (w/v with 5%, use behind the autoclaving, yeast is available from sugar refinery, Dongguan, Guangdong Province yeast subsidiary factory) be mixed with to infect by the volume ratio of 1:9 and use bacterium liquid, carry out respectively 1000,10000,100000 times of dilutions.
3. choose 100 ICR mices (available from Beijing Vital River Experimental Animals Technology Co., Ltd.), male and female half and half, body weight 18-21g, be divided at random 20 groups, every group 5 (2 female 3 heros or 2 heros 3 are female), 0.5mL a bacterium liquid/abdominal cavity infection mice is wherein all established contrast by the infectious bacteria liquid after 1000,10000,100000 times of dilutions, remains 12 groups and gives different pharmaceutical after dying with the bacterium liquid inductance after 10000 times of dilutions.
4. get D-Ser (available from Sigma company) and Merrem (available from Hebei Zhongrun Pharmaceutical Co.ltd., Shiyao Group), be mixed with respectively the drug combination liquid that contains variable concentrations D-Ser and meropenem with normal saline, as shown in table 6:
The pharmaceutical formulation of table 6D-serine and meropenem drug combination
5. 1h and 6h are administered once respectively behind the Murine Model of Intraperitoneal Infection, and each 0.2mL/ only observes animals survived number in 7 days.Analyze the curative effect of D-Ser and meropenem drug combination.The result is as shown in table 7,
Table 7D-serine and meropenem drug combination are to the therapeutical effect result (survival rate) of mouse infection MRSA bacterial strain 08-50
When as can be seen from Table 7, D-Ser uses separately to zoogenetic infection MRSA bacterial strain 08-50 without therapeutical effect; When meropenem uses separately; the animal dis motility rate is up to 40%; and during the two drug combination 〉=200mM D-Ser+10mg/mL meropenem or 400mMD-serine+〉=the 2.5mg/mL meropenem all can make the survival rate of animal reach 100%, show that D-Ser and meropenem drug combination have good protective effect to Murine Model of Intraperitoneal Infection Mrsa In Rabbits 08-50.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (10)
1.D-the application of aminoacid in the antibacterial activity that strengthens antibacterials.
2. an antibacterial combination is characterized in that, is made of two kinds of components, and a kind of is D-aminoacid, and another kind is antibacterial activity medicine and/or its derivant.
3. antibacterial combination according to claim 2, it is characterized in that, described D-aminoacid is one or more in D-alanine, D-Ser, D-methionine, D-Thr, D-phenylalanine, D-Glu, D-Gln, D-PROLINE, D-Arg, D-Lys, D-Cys, D-Val, D-Leu, D-Ile, D-trp, D-Tyrosine, D-Asp, D-His, D-Asn and the glycine that does not possess D L typing;
Described antibacterial activity medicine and/or its derivant are one or more in beta-lactam antibiotic, aminoglycoside antibiotics, quinolone antibiotic, macrolide antibiotics, chloromycetin series antibiotics, glycopeptide antibiotics or the fosfomycin.
4. according to claim 2 or 3 described antibacterial combinations, it is characterized in that, the amino acid whose concentration range of D-is 0.001mM ~ 10M in the described compositions.
5. the preparation method of each described antibacterial combination of claim 2-4, described method is: at first two kinds of component D-aminoacid, antibacterial activity medicine and/or its derivants are mixed with respectively mother solution, then and required D-amino acid concentration active according to antibacterials is mixed with both drug combination liquid.
6. the preparation method of each described antibacterial combination of claim 2-4, described method is: be mixed in proportion D-aminoacid, antibacterial activity medicine and/or its derivant, then be mixed with both drug combination liquid.
7. the application of each described antibacterial combination of claim 2-4 in the preparation anti-infectives.
8. application according to claim 7 is characterized in that, the antimicrobial spectrum of described anti-infectives is Gram-positive and/or gram negative bacteria and their fastbacteria.
9. application according to claim 8 is characterized in that, described gram-positive bacterium is: one or more in staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis, enterococcus faecalis, streptococcus pneumoniae, the streptococcus pyogenes.
10. application according to claim 8, it is characterized in that, described gram negative bacteria is: one or more in Acinetobacter bauamnnii, klebsiella pneumoniae, escherichia coli, bacillus pyocyaneus, serratia marcescens, proteus mirabilis, proteus vulgaris, Mo Genmo Salmonella, special-shaped citrobacter, enterobacter cloacae, clostridium perfringen, the thunder Ji Shi Pu Lufeideng bacillus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210333694.1A CN102871996B (en) | 2012-09-10 | 2012-09-10 | Antibiotic composition and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210333694.1A CN102871996B (en) | 2012-09-10 | 2012-09-10 | Antibiotic composition and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102871996A true CN102871996A (en) | 2013-01-16 |
| CN102871996B CN102871996B (en) | 2014-12-24 |
Family
ID=47473670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210333694.1A Active CN102871996B (en) | 2012-09-10 | 2012-09-10 | Antibiotic composition and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102871996B (en) |
Cited By (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103931614A (en) * | 2014-04-01 | 2014-07-23 | 重庆大学 | Plant pathogenic bacteria bactericide/bacteriostatic agent and application thereof |
| CN104586869A (en) * | 2014-12-31 | 2015-05-06 | 中山大学 | Small molecule metabolite for improving effect of antibiotic to eliminate pathogenic bacteria |
| CN104721176A (en) * | 2015-02-02 | 2015-06-24 | 中山大学 | Application of alpha-ketoglutaric acid to improvement on sensitivity to antibiotics of bacteria |
| WO2016106712A1 (en) * | 2014-12-31 | 2016-07-07 | 中山大学 | Small molecule metabolite for improving antibiotic clearance of pathogenic bacteria |
| CN104546856B (en) * | 2013-10-18 | 2016-11-23 | 北京北科德源生物医药科技有限公司 | A kind of antibacterial application of beta-lactam |
| CN106667984A (en) * | 2017-01-22 | 2017-05-17 | 河南师范大学 | Small-molecule substance capable of enhancing antibacterial drug effects of florfenicol |
| CN106860466A (en) * | 2017-01-22 | 2017-06-20 | 河南师范大学 | A kind of synergist for improving neomycinsulphate antibacterial drug effect |
| CN106860467A (en) * | 2017-01-22 | 2017-06-20 | 河南师范大学 | Aspartic acid as neomycinsulphate synergist application |
| CN106974909A (en) * | 2017-05-26 | 2017-07-25 | 蔡挺 | Application of the D tryptophans in pseudomonas aeruginosa production elastoser is suppressed |
| CN107050018A (en) * | 2017-05-26 | 2017-08-18 | 蔡挺 | D tryptophans are suppressing the application during pseudomonas aeruginosa biofilm is formed |
| CN107308453A (en) * | 2017-06-30 | 2017-11-03 | 河南科技大学 | The application of cystine or cysteine, bacteriostatic agent |
| CN107412225A (en) * | 2017-05-26 | 2017-12-01 | 蔡挺 | Application of the D tryptophans in pseudomonas aeruginosa production pyo is suppressed |
| CN107737338A (en) * | 2017-11-30 | 2018-02-27 | 厦门显德生物科技有限公司 | A kind of preparation for improving sensibility of bacteria on antibiotic |
| CN107889939A (en) * | 2017-11-30 | 2018-04-10 | 福建九为生物技术有限公司 | A kind of glycine glucose exocellular polysaccharide compound feed additive |
| CN107998118A (en) * | 2017-11-30 | 2018-05-08 | 厦门显德生物科技有限公司 | A kind of glycine and preparation associated with tetracycline antibiotics |
| CN107998138A (en) * | 2017-11-30 | 2018-05-08 | 福建九为生物技术有限公司 | A kind of glycine and preparation associated with kanamycins |
| CN108125952A (en) * | 2017-11-30 | 2018-06-08 | 厦门显德生物科技有限公司 | A kind of glycine and preparation associated with Amoxicillin |
| CN109464435A (en) * | 2018-11-30 | 2019-03-15 | 河南师范大学 | It is a kind of for preventing and treating the pharmaceutical composition of fish liver inflammation |
| CN109464448A (en) * | 2018-11-30 | 2019-03-15 | 河南师范大学 | A kind of antibacterials compound preparation and its application containing small molecule metabolites |
| CN109464449A (en) * | 2018-11-30 | 2019-03-15 | 河南师范大学 | A kind of aquatic products antibacterial combination and its application |
| CN110064075A (en) * | 2019-04-23 | 2019-07-30 | 北京科技大学 | One kind being based on nano silver/D-Cys self assembly antimicrobial coating and preparation method |
| CN111714495A (en) * | 2019-03-18 | 2020-09-29 | 深圳罗兹曼国际转化医学研究院 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN111714482A (en) * | 2019-03-18 | 2020-09-29 | 深圳罗兹曼国际转化医学研究院 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN111714481A (en) * | 2019-03-18 | 2020-09-29 | 深圳市益米诺医药科技有限公司 | Application of valine in improving staphylococcus aureus removing capability of host and application in preparing medicine for resisting staphylococcus aureus infection |
| CN111714496A (en) * | 2019-03-18 | 2020-09-29 | 深圳市益米诺医药科技有限公司 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN111773206A (en) * | 2020-06-29 | 2020-10-16 | 广东利泰制药股份有限公司 | Application of glutamine in preparation of medicine for inhibiting gene mutation generated by escherichia coli |
| CN113045498A (en) * | 2021-03-24 | 2021-06-29 | 江苏食品药品职业技术学院 | 1, 5-diaryl pyrazole derivative, synthesis method and application |
| CN113876952A (en) * | 2020-07-03 | 2022-01-04 | 厦门大学 | Use of nitrogen source for inhibiting bacterial type III secretion system |
| CN113999282A (en) * | 2021-01-21 | 2022-02-01 | 扬州大学 | Antibacterial peptide LI7, repeated polypeptides LI14 and LI21 thereof, and derivatives and application thereof |
| WO2022028243A1 (en) * | 2020-08-06 | 2022-02-10 | 中山大学 | Use of compound amino acids in preparation of drugs enhancing sensitivity of bacteria to antibiotics |
| CN116063390A (en) * | 2022-09-07 | 2023-05-05 | 东北农业大学 | Antibacterial peptide VCK-17 and application of antibacterial peptide VCK-17 and citronellal combined as antibacterial drug |
| CN117298076A (en) * | 2023-08-17 | 2023-12-29 | 遵义医科大学珠海校区 | Application of bletilla striata biphenanthrene B in preparation of antibacterial products |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20190000789A1 (en) * | 2015-12-24 | 2019-01-03 | Universiteit Leiden | Composition and method for treating infections caused by vancomycin-resistant infectious agents in a subject |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1441668A (en) * | 2000-06-21 | 2003-09-10 | 卡比斯特制药公司 | Compositions and methods to improve oral absorption of antimicrobial agents |
| US20100003276A1 (en) * | 2004-12-07 | 2010-01-07 | Hermes Jeffery D | Methods for treating anthrax and inhibiting lethal factor |
| CN101933921A (en) * | 2009-07-01 | 2011-01-05 | 江苏正大天晴药业股份有限公司 | Composition of Doripenem and amino acid |
| CN102579430A (en) * | 2011-01-10 | 2012-07-18 | 王乐 | Composition of meropenem and L-arginine |
-
2012
- 2012-09-10 CN CN201210333694.1A patent/CN102871996B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1441668A (en) * | 2000-06-21 | 2003-09-10 | 卡比斯特制药公司 | Compositions and methods to improve oral absorption of antimicrobial agents |
| US20100003276A1 (en) * | 2004-12-07 | 2010-01-07 | Hermes Jeffery D | Methods for treating anthrax and inhibiting lethal factor |
| CN101933921A (en) * | 2009-07-01 | 2011-01-05 | 江苏正大天晴药业股份有限公司 | Composition of Doripenem and amino acid |
| CN102579430A (en) * | 2011-01-10 | 2012-07-18 | 王乐 | Composition of meropenem and L-arginine |
Cited By (43)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546856B (en) * | 2013-10-18 | 2016-11-23 | 北京北科德源生物医药科技有限公司 | A kind of antibacterial application of beta-lactam |
| CN103931614B (en) * | 2014-04-01 | 2015-08-26 | 重庆大学 | A kind of plant pathogenetic bacteria kills/bacteriostatic agent and application thereof |
| CN103931614A (en) * | 2014-04-01 | 2014-07-23 | 重庆大学 | Plant pathogenic bacteria bactericide/bacteriostatic agent and application thereof |
| CN104586869A (en) * | 2014-12-31 | 2015-05-06 | 中山大学 | Small molecule metabolite for improving effect of antibiotic to eliminate pathogenic bacteria |
| WO2016106712A1 (en) * | 2014-12-31 | 2016-07-07 | 中山大学 | Small molecule metabolite for improving antibiotic clearance of pathogenic bacteria |
| CN104586869B (en) * | 2014-12-31 | 2019-01-11 | 中山大学 | A kind of small molecule metabolites for improving antibiotic and removing pathogen |
| CN104721176B (en) * | 2015-02-02 | 2018-07-10 | 中山大学 | Application of the α-ketoglutaric acid in terms of sensibility of bacteria on antibiotic is improved |
| CN104721176A (en) * | 2015-02-02 | 2015-06-24 | 中山大学 | Application of alpha-ketoglutaric acid to improvement on sensitivity to antibiotics of bacteria |
| CN106667984A (en) * | 2017-01-22 | 2017-05-17 | 河南师范大学 | Small-molecule substance capable of enhancing antibacterial drug effects of florfenicol |
| CN106860466A (en) * | 2017-01-22 | 2017-06-20 | 河南师范大学 | A kind of synergist for improving neomycinsulphate antibacterial drug effect |
| CN106860467A (en) * | 2017-01-22 | 2017-06-20 | 河南师范大学 | Aspartic acid as neomycinsulphate synergist application |
| CN107050018A (en) * | 2017-05-26 | 2017-08-18 | 蔡挺 | D tryptophans are suppressing the application during pseudomonas aeruginosa biofilm is formed |
| CN107412225A (en) * | 2017-05-26 | 2017-12-01 | 蔡挺 | Application of the D tryptophans in pseudomonas aeruginosa production pyo is suppressed |
| CN106974909A (en) * | 2017-05-26 | 2017-07-25 | 蔡挺 | Application of the D tryptophans in pseudomonas aeruginosa production elastoser is suppressed |
| CN107308453A (en) * | 2017-06-30 | 2017-11-03 | 河南科技大学 | The application of cystine or cysteine, bacteriostatic agent |
| CN107308453B (en) * | 2017-06-30 | 2020-04-14 | 河南科技大学 | Application of cystine or cysteine and bacteriostatic agent |
| CN107737338A (en) * | 2017-11-30 | 2018-02-27 | 厦门显德生物科技有限公司 | A kind of preparation for improving sensibility of bacteria on antibiotic |
| CN107889939A (en) * | 2017-11-30 | 2018-04-10 | 福建九为生物技术有限公司 | A kind of glycine glucose exocellular polysaccharide compound feed additive |
| CN107998118A (en) * | 2017-11-30 | 2018-05-08 | 厦门显德生物科技有限公司 | A kind of glycine and preparation associated with tetracycline antibiotics |
| CN107998138A (en) * | 2017-11-30 | 2018-05-08 | 福建九为生物技术有限公司 | A kind of glycine and preparation associated with kanamycins |
| CN108125952A (en) * | 2017-11-30 | 2018-06-08 | 厦门显德生物科技有限公司 | A kind of glycine and preparation associated with Amoxicillin |
| CN107889939B (en) * | 2017-11-30 | 2020-12-25 | 福建九为生物技术有限公司 | Glycine glucose extracellular polysaccharide compound feed additive |
| CN107998118B (en) * | 2017-11-30 | 2020-09-25 | 厦门显德生物科技有限公司 | Preparation combining glycine and tetracycline antibiotics |
| CN109464435A (en) * | 2018-11-30 | 2019-03-15 | 河南师范大学 | It is a kind of for preventing and treating the pharmaceutical composition of fish liver inflammation |
| CN109464448A (en) * | 2018-11-30 | 2019-03-15 | 河南师范大学 | A kind of antibacterials compound preparation and its application containing small molecule metabolites |
| CN109464449A (en) * | 2018-11-30 | 2019-03-15 | 河南师范大学 | A kind of aquatic products antibacterial combination and its application |
| CN109464435B (en) * | 2018-11-30 | 2021-06-29 | 河南师范大学 | Pharmaceutical composition for preventing and treating fish liver inflammation |
| CN111714481A (en) * | 2019-03-18 | 2020-09-29 | 深圳市益米诺医药科技有限公司 | Application of valine in improving staphylococcus aureus removing capability of host and application in preparing medicine for resisting staphylococcus aureus infection |
| CN111714495A (en) * | 2019-03-18 | 2020-09-29 | 深圳罗兹曼国际转化医学研究院 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN111714496A (en) * | 2019-03-18 | 2020-09-29 | 深圳市益米诺医药科技有限公司 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN111714482A (en) * | 2019-03-18 | 2020-09-29 | 深圳罗兹曼国际转化医学研究院 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN110064075B (en) * | 2019-04-23 | 2020-10-13 | 北京科技大学 | Self-assembled antibacterial coating based on nano silver/D-cysteine and preparation method thereof |
| CN110064075A (en) * | 2019-04-23 | 2019-07-30 | 北京科技大学 | One kind being based on nano silver/D-Cys self assembly antimicrobial coating and preparation method |
| CN111773206A (en) * | 2020-06-29 | 2020-10-16 | 广东利泰制药股份有限公司 | Application of glutamine in preparation of medicine for inhibiting gene mutation generated by escherichia coli |
| CN113876952A (en) * | 2020-07-03 | 2022-01-04 | 厦门大学 | Use of nitrogen source for inhibiting bacterial type III secretion system |
| WO2022028243A1 (en) * | 2020-08-06 | 2022-02-10 | 中山大学 | Use of compound amino acids in preparation of drugs enhancing sensitivity of bacteria to antibiotics |
| CN113999282A (en) * | 2021-01-21 | 2022-02-01 | 扬州大学 | Antibacterial peptide LI7, repeated polypeptides LI14 and LI21 thereof, and derivatives and application thereof |
| CN113999282B (en) * | 2021-01-21 | 2023-08-22 | 扬州大学 | Antibacterial peptide LI7, repeated polypeptides LI14 and LI21 thereof, derivatives and application thereof |
| CN113045498A (en) * | 2021-03-24 | 2021-06-29 | 江苏食品药品职业技术学院 | 1, 5-diaryl pyrazole derivative, synthesis method and application |
| CN113045498B (en) * | 2021-03-24 | 2023-01-24 | 江苏食品药品职业技术学院 | 1, 5-diaryl pyrazole derivative, synthesis method and application |
| CN116063390A (en) * | 2022-09-07 | 2023-05-05 | 东北农业大学 | Antibacterial peptide VCK-17 and application of antibacterial peptide VCK-17 and citronellal combined as antibacterial drug |
| CN116063390B (en) * | 2022-09-07 | 2023-11-24 | 东北农业大学 | Antibacterial peptide VCK-17 and application of antibacterial peptide VCK-17 and citronellal combined as antibacterial drug |
| CN117298076A (en) * | 2023-08-17 | 2023-12-29 | 遵义医科大学珠海校区 | Application of bletilla striata biphenanthrene B in preparation of antibacterial products |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102871996B (en) | 2014-12-24 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102871996B (en) | Antibiotic composition and application thereof | |
| CN103732232B (en) | Comprise the compositions of antibiotic and dispersant or caking inhibiter | |
| Ghazi et al. | Humanized exposures of cefiderocol, a siderophore cephalosporin, display sustained in vivo activity against siderophore-resistant Pseudomonas aeruginosa | |
| Eliopoulos et al. | Susceptibility of enterococci and Listeria monocytogenes to N-formimidoyl thienamycin alone and in combination with an aminoglycoside | |
| Grosserode et al. | The continuing importance of staphylococci as major hospital pathogens | |
| JP2961182B2 (en) | Pharmaceutical composition for prevention and treatment of Clostridium difficile diarrhea and pseudomembranous colitis | |
| WO2020056359A1 (en) | Bacteriotherapy against proprionibacterium acnes for the treatment of acne | |
| CN103920137B (en) | A kind of pharmaceutical composition with the effect of anti-drug resistance gram-positive bacteria | |
| JPH05271096A (en) | Antimicrobial composition and pharmaceutical preparation containing the same as active ingredient | |
| Xu et al. | Enterococci facilitate polymicrobial infections | |
| CN102911257B (en) | Cyclic lipopeptide antibiotic and preparation and application thereof | |
| Moghadam et al. | Comparison of the effects of Lactobacillus plantarum versus imipenem on infected burn wound healing | |
| CN102558307B (en) | Octapeptin as well as preparation and application thereof | |
| CN114149483B (en) | Antibacterial peptide composition and application thereof | |
| CN107794232B (en) | Streptococcus antagonizing growth of propionibacterium acnes and gram-positive bacteria and metabolites thereof | |
| CN103865839B (en) | A kind of probiotics applied to aquaculture | |
| Liang et al. | Structure–activity relationships of bivalent aminoglycosides and evaluation of their microbiological activities | |
| CN113318149A (en) | Jasminum extract and preparation method and application thereof | |
| CN101816669B (en) | Composition containing gentamicin and borneol and use thereof | |
| Zbar et al. | Synergistic effect of partially purified bacteriocin from Cronobacter sakazakii and antibiotics against staphylococcus aureus | |
| RU2792679C1 (en) | Bactericidal pharmaceutical composition for parenteral use in the form of lyophilizate with endolysin | |
| CN106673989A (en) | Pharmaceutical composition as well as preparation method and application thereof | |
| CN110478486B (en) | Bactericidal pharmaceutical composition and application thereof in preparation of antifungal biomembrane medicines | |
| CN104971342A (en) | Pharmaceutical composition for resisting methicillin-resistant staphylococcus aureus (mrsa) | |
| Мokrozub et al. | Antistaphylococcal action of lacto-and bifidobacteria and interleukin-2 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |