CN1352567A - A means for the prophylactic and therapeutic treamtent of streptococcal infections - Google Patents
A means for the prophylactic and therapeutic treamtent of streptococcal infections Download PDFInfo
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- CN1352567A CN1352567A CN 99816592 CN99816592A CN1352567A CN 1352567 A CN1352567 A CN 1352567A CN 99816592 CN99816592 CN 99816592 CN 99816592 A CN99816592 A CN 99816592A CN 1352567 A CN1352567 A CN 1352567A
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Abstract
The present ivnention relates to compositions containing Group C streptococcal phage associated lysin enzyme for the prophylactic and therepeutic treatment of Streptococcal infections, including the infection commonly known as strep throat. Methods for therapeutically and prophylactically treating such infection also are described.
Description
Background of invention
1, invention field
The present invention relates to contain the compositions of C group B streptococcus phage dependency Lysin enzyme and carrier, wherein said carrier is used for this C group B streptococcus phage dependency Lysin enzyme is released into mammiferous mouth, larynx or nasal cavity.Described compositions is specially adapted to preventative and therapeutic treatment streptococcal infection comprises the infection that is referred to as streptococcal sore throat usually.
2, description of the Prior Art
Known for asymptomatic individuality or suffer from slight sore throat, tonsillitis or impetiginous band symptom individuality, the A group B streptococcus has been shown as the important pathogen that can exist with carrier state.If do not treated, these streptococcal infections can cause glomerulonephritis, rheumatic fever and the nonvolatil rheumatic heart disease of possibility.Along with the particularly appearance of Penicillin antibiotics of antibiotic, according to suitable antibiotic therapy prescribed regimen, causal organism is eliminated easily.
Because infected individuality (being generally child and youngster) can pass to other people to the A group B streptococcus, particularly in nursery school and school, therefore must be after antimicrobial therapy begins known infected individuality be separated from these environment in 24-72 hour at least.Show in comparative study: early diagnosis and suitable treatment can make the global cycle of tedious pathogen infect reduction, and can reduce or reduce the sequela (joint heat or nephritis) that category-A infects.
U.S. Pat 5,604,109 (Fischetti etc.) instruction: carry out diagnostic analysis by using C group B streptococcus phage dependency Lysin enzyme, can carry out fast and Sensitive Detection to A group B streptococcus antigen.This detection can help to identify infected individuality rapidly, makes the infected individual conventional antibiotic therapy of accepting then.
Yet, have also a problem is exactly whether to be highly resistant to streptococcal infection.The patient who suffers from the streptococcus pharyngitis has hyperinfection, and can be passed to the Close contacts to pathogen, thereby causes septic sore throat popular.The school and the army of contact seem particularly outstanding to this problem closely the bigger person to person of crowd density.And, need prevent the prevention method of streptococcal infection, this is because owing to many-sided reason, it is inappropriate that common antibiotic prophylaxis is used.
Summary of the invention
(it quotes U.S. Pat 5 in the present invention, 604, content in 109 is as a reference) provide the compositions that contains C group B streptococcus phage dependency Lysin enzyme and carrier, described carrier to be used for that this C group B streptococcus is had a liking for thalline dependency Lysin enzyme to be released into animal for example people's mouth, larynx or nasal cavity.Such compositions can be used as especially: prophylactic treatment is infected to prevent after contacting infected individuals, perhaps infected patient is carried out the therapeutic treatment that streptococcus A larynx infects, thereby alleviates infection.
Owing to have Lysin in oral cavity or the nasal cavity, therefore when streptococcus during from infected individual the introducing, the streptococcus of at least some intrusions is killed, so reaches preventive effect by protecting from infection.Be transmitted to other individual mode by reducing to infect and promote to reduce streptococcus, this activity quick and the anti-existing streptococcal infection of specificity (lethal) of Lysin enzyme has therapeutic effect.
In a scheme of the present invention, the form of medication of Lysin enzyme is: confection, chewing gum, lozenge, lozenge, tablet, powder, aerosol, liquid (for example gargarism) or liquid spray.In another embodiment of the invention, the Lysin enzyme is with the nasal spray administration.
The method that treatment streptococcus A infects comprises: the pharmaceutically acceptable amount C group B streptococcus of effective dose is had a liking for mammiferous oral cavity or the nasal cavity that thalline dependency Lysin enzyme is applied to the needs treatment, thereby allow Lysin enzyme contact opening transmucosal and necessary a period of time of stop make its saturated oral mucosa; This Lysin enzyme of using other dosage then in the same way when treatment is finished till.According to the difference of the carrier that contains the Lysin enzyme, described enzyme can be administered to the mucosal wall (mucosal lining) of larynx or nose.
Except can resisting the infection of A group B streptococcus effectively, described compositions can also be used to resist the C group B streptococcus in a similar manner and infect.And described enzyme can also be resisted the E group B streptococcus in a similar manner.
Detailed Description Of The Invention
It is found that Lysin stay for some time and can kill the streptococcus of intrusion when streptococcus during from infected individual the intrusion in the oral cavity, thus prevention infection and provide prophylactic treatment to prevent streptococcal infection.In infected individuality, be transmitted to other individual mode by reducing to infect and reduce streptococcus, this activity quick and that specificity (lethal) streptococcus infects of Lysin enzyme also produces therapeutic effect.
After specific phage (claiming C1) infection, C group B streptococcus organism produces amidase muralytic (Lysin) enzyme, and with its separation and collection, these methods are recorded in the 5th, 604, in No. 109 United States Patent (USP)s.Perhaps, by any other known method, also can separate and collect this C group B streptococcus enzyme (being also referred to as the Lysin enzyme), this kind of enzyme has unique specificity to the cell wall of A, C and E group B streptococcus.
Being used for preventative and compositions therapeutic treatment streptococcal infection contains: Lysin enzyme and application tool (for example carrier system or oral administration pattern) are to be released to oral cavity or nasal membrane wall.
During in this kind of enzyme being joined carrier system or oral administration pattern or before, preferably place this enzyme stable buffer environment to be used to keep the pH scope at about 4.0-about 8.0, more preferably from about 5.5 to about 7.5 and most preferably from about 6.1.
Described stable buffer agent should make the Lysin enzyme show optimum activity.This buffer agent can be a for example dithiothreitol, DTT of Reducing agent.It maybe can be for example disodium EDTA of metal-chelator that described stable buffer agent can also contain, and perhaps it also can contain phosphate or citrate acid phosphoric acid salt buffer agent.
In order to prevent to go bad, described stable buffer agent also can contain antibacterial or antibacterial as antiseptic, and for example it can contain a small amount of sodium benzoate.
Application mode includes but not limited to directly, indirectly, the combination of carrier and particular form or any-mode.It is nasal spray, nasal drop, nose ointment, nasal douche, nose injection, nose implant or by ointment directly being applied to the combination in any of nostril, nose bridge or face or aforesaid way, perhaps by similar application process or other known nose vector administration that the Lysin enzyme directly is applied to mode that nasal mucosa can pass through.Be applied to mode that oral cavity or throat can pass through for using larynx lozenge or by using collutory, gargarism, solution, spray, confection and glue etc.Therefore, form that can the dosed cells lysin includes but not limited to lozenge, lozenge, confection, injection, chewing gum agent, tablet, powder, spray, liquid preparation, ointment and aerosol.
Lozenge, tablet or the glue that is added with the Lysin enzyme can contain sugar, Semen Maydis pulp, various dyestuff, non-sugar sweetener, correctives, the combination of binding agent or these materials arbitrarily.Similarly, any gum base product can contain the combination of arabic gum, Brazil wax, citric acid, corn starch, food color, correctives, non-sugar sweetener, gelatin, glucose, glycerol, gum base, lac, saccharin sodium, sugar, water, white beeswax, cellulose, other binding agent and above-mentioned substance.
Lozenge can also contain the combination of sugar, corn starch, arabic gum, Tragacanth, anethole, Semen Lini, oleo-resins, mineral oil and cellulose, other binding agent and these materials.In another embodiment of the present invention, use sugared substituent and replace glucose, sucrose or other sugar.
Can also place nasal spray to this enzyme, wherein nasal spray is a carrier.Described nasal spray can be the spray or the temporary transient spray that discharges of long term, and can prepare by mode well known in the art.
All these carriers that are used for the Lysin enzyme all can prepare by conventional methods, but preferred any collutory or similar products do not contain ethanol to prevent enzyme denaturation.Similarly, during preparation process, when the Lysin enzyme being placed cough drop, glue, confection or lozenge, should can avoid enzyme denaturation like this before lozenge or the confection sclerosis but after cough drop or confection cool off a little, the Lysin enzyme is placed.
Can join described enzyme in the material of these liquid forms or lyophilised state, can be dissolved when therefore described enzyme runs into liquid.Described enzyme also can be for example micelle or liposome form, perhaps other encapsulated form, perhaps with prodrug forms or slow release form administration so that the storage life and/or the releasing effect of prolongation are provided.
The effective dose or the content of the Lysin enzyme that treatment is infected will depend in part on following factor: this Lysin enzyme be used to prevent or treat, medication person contacts the streptococcic persistent period and/or character, body volume and the weight etc. of infection.Suitable dose standardize solution is really easily determined by those skilled in the art.The application persistent period of containing the compositions of this enzyme is also depended on following factor: whether described application is used to prevent purpose, and described application can be every day or weekly for example when being used to prevent purpose, continues time of determining for example 1 week, January or longer; Whether perhaps described application is used for the treatment of purpose, when being used for the treatment of purpose, may using the scheme of more strengthening and for example use 2,3,4,5,6,7,10 or 14 days or longer.Therefore, therapeutic treatment may be across a couple of days or several weeks, can be based on the sky, and a plurality of intervals may be arranged during one day.
In order to be effective, described enzyme should exist with the enzyme unit that effective number is provided with q.s and comes contact opening, larynx or nasal cavity.If the enzyme unit of contact opening, larynx or nasal cavity very little, even Long contact time can not produce the beneficial effect that needs yet.Therefore, the dosage form of all application should provide approximately minimum unit of quantity in a period of time, and described like this dosage form will provide enzyme to mouth, larynx or nasal cavity.In nasal cavity or oral environment, being considered to the scope of effective content or dosage active unit enzyme concentration is provided is about 100 units to about 100,000 units.It is believed that from the relative broad range of about 100 units to about 10,000 units are acceptables.Such unit may reside in the small size carrier 1ml for example or the carrier for example (for example lozenge) in liquid or the saliva of small size more, perhaps also may reside in large volume for example in some milliliters of gargarism.Therefore, the volume of carrier is big more usually, and it is big more to reach the required unit sum of organized enzyme valid density.Therefore, in nose or oral cavity, acceptable concentration can be that about 100 units per ml are to about 100,000 units per ml fluids.In this scope, about 100 units per ml to the concentration of about 10,000 units per ml is acceptables.
Therefore, in practice, the time of contact organized enzyme unit can influence organized enzyme unit's needed concentration in every milliliter of dosage.For example, the organized enzyme unit that is considered and provides the carrier of slow release (some nasal spray, lozenge and encapsulated enzyme) that every milliliter of low concentration can be provided, but the persistent period is longer.The organized enzyme unit of every milliliter of higher concentration can be provided than short continued treatment (for example gargarism) on the contrary.All infection site the valid density organized enzyme is provided or provide containing of enough preventive effects enough Lysin enzymes any dosage belong to fully within the normal experiment scope, therefore fully within the scope of the invention.
Compositions of the present invention also can contain at least one other additive, and described additive can be effectively used to therapeutic or prophylactic treatment streptococcal infection or alleviates its symptom.In addition, these reagent can also be used for some other treatment effectively and/or play preventive effect, for example ease the pain.Some reagent can be Topically active or whole body activity, and can contain antibiotic or pain relief medicine and comprise and for example locally be used to alleviate throat pain with antibacterial.Perhaps, can before or after using present composition processing, give such reagent.Being used for the treatment of property or the prophylactic treatment streptococcal infection or be used for the treatment of the symptom of these infection effectively of antibiotic dosage.
When these treatments are used for arbitrarily animal or mammal, preferably these products are applied to the people.
Allow time of carrier contact opening transmucosal necessity of containing each dosage of cells lysin so that the prevention or the therapeutic effect of expectation are provided.The mode that the Lysin enzyme is administered to oral mucosa can be any-mode, for example: gargarism, mouthwass (mouth rinses), lozenge, lozenge, chewing gum, confection, powder and nose or oral spray, condition are that also it can provide the prevention or the therapeutic effect of expectation to its safety.According to the present invention, those skilled in the art can know other possibility method and composition that is used for administration Lysin enzyme.
Embodiment 1
C group is had a liking for somatic cells lysin enzyme and is prepared as follows: in the 18mm test tube, in the ToddHewitt culture medium under 37 ℃ C group B streptococcus strain 26RP66 (ATCC#21597) or C group B streptococcus strain arbitrarily being cultured to its OD at the 650nm place is 0.23.Have a liking for thalline with 1 part and C is organized phage (C1) (ATCC#21597-B1) with 5 * 10 than the ratio of 4 parts of cells
6The adding of tiring.Allow this mixture under 37 ℃ of temperature, keep 18 minutes then, during infection cell is poured on the ice cube so that the temperature of solution is reduced to below 15 ℃.Collect infected cell then in refrigerated centrifuger, it is suspended in 1/300 of initial volume in the phosphate buffer of 0.1M, the pH of described buffer is 6.1, and contains 5 * 10
-3The dithiothreitol, DTT of M and 10 μ g DNA enzymes.These cells discharge dissolving has a liking for thalline and Lysin enzyme.With 100,000Xg was divided into sample aliquot to enzymatic solution to remove most of cell debris and to have a liking for thalline in centrifugal 5 hours, tested the ability of its dissolving A group B streptococcus then.
The units per ml number of measuring many enzymes makes its inverse that becomes the highly diluted of enzyme, thereby in 15 minutes the OD650 of the suspension of A group B streptococcus is reduced to 0.15 from 0.3.In typical enzyme preparation, in single 12 liters of batches, generate 4 * 10
5To 4 * 10
6Unit.
According to needed incubation time, the Lysin enzyme unit that the application need of enzyme is minimum.With containing the suitable adjustable dilution agent enzyme of stablizing buffer substance, described regulator can make the stable and performance maximum enzyme activity of enzyme.Preferred scheme is for using cryodesiccated Lysin enzyme.Described stable buffer substance can contain Reducing agent, and this Reducing agent can be a dithiothreitol, DTT, and concentration is 0.001M-1.0M, preferred 0.005M.Described stable buffer substance can contain metal-chelator, and it can be the disodium EDTA of 0.00001M to 1.0M, preferred 0.005M concentration.Should stablize buffer substance and can contain the citric acid phosphoric acid salt buffer agent, concentration is 0.001 M-1.0M, preferred 0.05M.The pH value scope of described stable buffer agent is about 4.0-8.0, preferred 6.1.Stable buffer substance can contain as the antibacterial of antiseptic or antibacterial.Such antiseptic can be a Hydrazoic acid,sodium salt, and its concentration is 0.001% to 0.1%, preferred 0.02%.
The preparation of having a liking for the thalline raw material that is used for producing Lysin can be used to infect the same procedure of having a liking for thalline and C group B streptococcus in the preparation of Lysin enzyme and carries out according to above-mentioned.Yet this preparation method is not poured into infected cell on ice, and the time of cultivating under 37 ℃ of temperature continues 1 hour altogether, so that have a liking for thalline and enzyme dissolves and discharges in cumulative volume.In order to generate having a liking for the Lysin that thalline is used for subsequently, must the deactivation residual enzyme, perhaps these enzymes are removed with the cell that prevents C group phage never rather than had a liking in the cell that thalline infects and dissolve.
Embodiment 2
Enzyme according to embodiment 1 preparation is diluted in the buffer that concentration is 100 units per ml, the consisting of of described buffer: (its pH is 6.1 and contains 0.1% rabbit immunoglobulin, 0.005M (ethylene nitro) Sequestrene AA (EDTA), 0.005M dithiothreitol, DTT, 0.02% Hydrazoic acid,sodium salt, 0.01%N-acetyl glucosamine 0.05M citrate phosphate buffer.Gold colloidal colloidal sol (OD with A group B streptococcus antibody labeling
5201.5) (its pH is 8.2 to be suspended in 0.02M Tris buffer, contain 1.0% bovine serum albumin, 0.02% Hydrazoic acid,sodium salt, 300K units heparin) in, 1 part of this suspension is joined in 3 parts of enzyme reagent, mix, and by 0.22 micron filter filtration, contain duplicate samples such as 200 microlitres in every test tube, carry out lyophilization.This cryodesiccated enzyme (promptly 45 ℃) at elevated temperatures can be stablized the short time (2 week), and at room temperature (greater than 1 year) keeps stable for a long time.
Embodiment 3 methods
1. A group B streptococcus strain S43/192/39R (anti-streptomycin type) is cultivated 1 day (from freezing biood-bouillon); Place 50ml to contain Todd Hewitt (TH) meat soup of 1% yeast extract and 100pl streptomycin/ml 500 μ l.
2. be cultured to OD
650Be 0.59.
Under 3000rpm centrifugal 15 minutes with precipitum.
4. these organisms are suspended in 1ml volume TH w/o antibiotic (3 * 10 again
5/ 100 μ l are determined by plate count).
5. the cell of 0.5 these concentration is joined in the phosphate buffer of 1.5ml pH6.1 in contrast.
6. be administered to mice preceding 5 minutes, the spissated cell suspending liquid of 0.5ml had a liking for the solution of somatic cells lysin in the pH6.1 phosphate buffer with 0.5ml mix, wherein saidly having a liking for somatic cells lysin solution and be diluted to 10,000 units per ml in advance.
5 mices of accepting 60 μ l " contrast " solution are separated equivalent oral cavity medicine and nasal cavity applied medicine.
5 mices of accepting 60 μ l Lysin and bacterial mixture are separated equivalent oral cavity medicine and nasal cavity applied medicine.Carry out larynx and clean on 5% sheep blood, peptone agar culture dish, described culture dish contains
500 μ g/ml streptomycins are arranged.The culture surface ware spends the night under 37 ℃ of temperature.Obtain following result:
7/22 7/23 7/24 7/28
1 day 2 days 3 days 7 days
CFU cytolysin L1 000 0L2 000 0L3 000 0L4 010 0L5 0010 contrast C1 26 14 7 0C2＞400 17 100 83C3,90 15 0C4＞400＞400＞400 22,0C5 22 30 0
These results show: in this model system, have a liking for the somatic cells lysin and only contact 5 minutes with the A group B streptococcus and just can prevent that described streptococcus from yarding up in the mice upper respiratory tract.
Embodiment 4
In order to duplicate contingent situation, before streptococcus enters environment, animal, antibacterial, Lysin are placed oral cavity (promptly discharging by lozenge), prepare Lysin according to the same mode of embodiment 3 (1-5) then, but in this experiment, animal does following processing:
Lysin group: allow 5 mices accept 25 μ l Lysin, allow it accept 50 μ l bacterial suspensions then immediately.
Matched group: allow 5 mices accept 25 μ l buffer, allow it accept 50 μ l bacterial suspensions then immediately.
24 hour cell lysins
L6 -
L7 -
L8 -
L9 -
L10-matched group
C6 -
C7 +
C8 -
C9 +
C10 +
Result: when adding streptococcus, have 0/5 ratio be collected for the animal that contains Lysin in the oral cavity, and have 3/5 ratio to be collected streptococcus by bacterium for the animal of accepting buffer by bacterium.Therefore, if before adding the A group B streptococcus, exist Lysin can prevent the bacterium collection.
Embodiment 5
Under 37 ℃, in Todd Hewitt culture medium, cultivate AM and organize 6 type streptococcus and spend the night.(the 50ml phosphate buffer, pH6.1) the washing organism is 1 time with aseptic Lysin buffer.Then the cell precipitation thing is suspended in the same buffer of 5ml.
In containing the Lysin buffer of 5mM DTT, be diluted to the suitable unit of twice having a liking for the somatic cells lysin, then mixture is carried out aseptic filtration.
The 1.0ml bacterial suspension is joined in the suitable Lysin diluent of 1.0ml, under 37 ℃ of temperature, cultivate this mixture then.Remove sample at a certain time interval, suitably dilute, be placed in the blood blood agar culture dish to measure number of bacteria.
The control sample of being made up of the 1.0ml bacterial suspension is joined separately in the 1.0ml Lysin buffer.Remove aliquot sample, in 10 times of diluents, dilute then, etc. duplicate samples place the blood agar culture dish to measure number of bacteria.The result contains the initial number of bacterial population Lysin unit 5 seconds 30 seconds 60 seconds 5 minutes 10 minutes 1,000 5 * 10 of Lysin
600000 (average 2 exp) 100 8.6 * 10
61,530 1,196 771 64 6 (average 4 exp) 10 9.8 * 10
6＞3000＞3000＞3000＞3000＞3000 (average 3 exp)
Can make many improvement and change to the present invention according to above-mentioned instruction.Therefore be appreciated that scope of the present invention is definite by claims, and be not limited to the scheme that description specifies.
Claims (31)
1. be used for compositions preventative or therapeutic treatment streptococcal infection, comprise:
The C group B streptococcus of effective dose is had a liking for thalline dependency Lysin enzyme; With
Be used for described Lysin enzyme is released to the carrier of mouth, larynx or nasal cavity.
2. the compositions of claim 1, wherein said carrier is selected from: confection, chewing gum, lozenge, lozenge, tablet, powder, aerosol, liquid, liquid spray, nasal spray and nose ointment.
3. the compositions of claim 1, it also contains keeps the buffer substance of described compositions pH for about 4.0-about 9.0.
4. the compositions of claim 3, the pH that wherein said buffer substance is kept said composition is about 5.5-about 7.5.
5. the compositions of claim 3, wherein said buffer substance contains Reducing agent.
6. the compositions of claim 5, wherein said Reducing agent is a dithiothreitol, DTT.
7. the compositions of claim 3, wherein said buffer substance contains metal-chelator.
8. the compositions of claim 7, wherein said metal-chelator is a disodium EDTA.
9. the compositions of claim 3, wherein said buffer substance is the citrate phosphate buffer.
10. the compositions of claim 1, it also contains as the antibacterial of antiseptic and antibacterial.
11. the compositions of claim 1, wherein said Lysin enzyme is cryodesiccated.
12. the compositions of claim 1, wherein said carrier also contains sweeting agent.
13. the compositions of claim 1, wherein in nose or oral environment, described carrier provides the about 100-of concentration about 100,000 organized enzyme units per ml fluids.
14. the compositions of claim 13, wherein in nose or oral environment, described carrier provides the about 100-of concentration about 10,000 organized enzyme units per ml fluids.
15. the compositions of claim 1, wherein said being used for the treatment of property of compositions treatment streptococcal infection.
16. the compositions of claim 1, wherein said compositions is used for prophylactic treatment streptococcal infection.
17. the compositions of claim 15, wherein said streptococcal infection are the streptococcus throat infection.
18. the compositions of claim 1, wherein said carrier are confection.
19. the compositions of claim 1, wherein said carrier are chewing gum.
20. the compositions of claim 1, wherein said carrier are lozenge.
21. the compositions of claim 1, wherein said carrier are lozenge.
22. the compositions of claim 1, wherein said carrier are powder.
23. the compositions of claim 1, wherein said carrier are aerosol.
24. the compositions of claim 1, wherein said carrier are liquid spray.
25. the compositions of claim 1, wherein said carrier are nasal spray.
26. the compositions of claim 1, wherein said mammal is behaved.
27. the compositions of claim 1, wherein said carrier are fit to described Lysin enzyme is released into mouth and larynx.
28. the compositions of claim 1, wherein said carrier are fit to described Lysin enzyme is released into nasal cavity.
29. the compositions of claim 1, at least a reagent that it also contains being used for the treatment of property or prophylactic treatment streptococcal infection effectively or alleviates its symptom.
30. method preventative or therapeutic treatment streptococcal infection comprises: the mammal that any one compositions of 1-29 is administered to needs.
31.C group B streptococcus is had a liking for the application of thalline dependency Lysin in any one pharmaceutical composition of preparation claim 1-29.
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| Application Number | Priority Date | Filing Date | Title |
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| CN 99816592 CN1352567A (en) | 1999-02-25 | 1999-02-25 | A means for the prophylactic and therapeutic treamtent of streptococcal infections |
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| CN 99816592 CN1352567A (en) | 1999-02-25 | 1999-02-25 | A means for the prophylactic and therapeutic treamtent of streptococcal infections |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108578685A (en) * | 2011-04-21 | 2018-09-28 | 洛克菲勒大学 | The streptococcus bacteriophage lysin for detecting and treating for gram-positive bacteria |
-
1999
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108578685A (en) * | 2011-04-21 | 2018-09-28 | 洛克菲勒大学 | The streptococcus bacteriophage lysin for detecting and treating for gram-positive bacteria |
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