CN108042521A - Application of the L-arginine in terms of sensibility of bacteria on antibiotic is improved - Google Patents
Application of the L-arginine in terms of sensibility of bacteria on antibiotic is improved Download PDFInfo
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- CN108042521A CN108042521A CN201810119535.9A CN201810119535A CN108042521A CN 108042521 A CN108042521 A CN 108042521A CN 201810119535 A CN201810119535 A CN 201810119535A CN 108042521 A CN108042521 A CN 108042521A
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- Prior art keywords
- arginine
- antibiotic
- bacterium
- sensibility
- kanamycins
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- 241000894006 Bacteria Species 0.000 title claims abstract description 95
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 68
- 235000014852 L-arginine Nutrition 0.000 title claims description 96
- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 title claims description 89
- 229930064664 L-arginine Natural products 0.000 title claims description 88
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 13
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 claims description 55
- 229930027917 kanamycin Natural products 0.000 claims description 55
- 241000191967 Staphylococcus aureus Species 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 14
- MGQLHRYJBWGORO-LLVKDONJSA-N Balofloxacin Chemical compound C1[C@H](NC)CCCN1C1=C(F)C=C2C(=O)C(C(O)=O)=CN(C3CC3)C2=C1OC MGQLHRYJBWGORO-LLVKDONJSA-N 0.000 claims description 9
- 229950000805 balofloxacin Drugs 0.000 claims description 9
- FLKYBGKDCCEQQM-WYUVZMMLSA-M cefazolin sodium Chemical compound [Na+].S1C(C)=NN=C1SCC1=C(C([O-])=O)N2C(=O)[C@@H](NC(=O)CN3N=NN=C3)[C@H]2SC1 FLKYBGKDCCEQQM-WYUVZMMLSA-M 0.000 claims description 8
- 229960003408 cefazolin sodium Drugs 0.000 claims description 8
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 7
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 7
- 229940079593 drug Drugs 0.000 claims description 5
- 239000003814 drug Substances 0.000 claims description 5
- 230000001954 sterilising effect Effects 0.000 claims description 5
- 238000004659 sterilization and disinfection Methods 0.000 claims description 5
- 229910021529 ammonia Inorganic materials 0.000 claims description 4
- 241000607471 Edwardsiella tarda Species 0.000 claims description 3
- 210000002429 large intestine Anatomy 0.000 claims 1
- 230000001580 bacterial effect Effects 0.000 abstract description 20
- 239000004475 Arginine Substances 0.000 abstract description 10
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 abstract description 10
- 206010059866 Drug resistance Diseases 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 6
- 229940124350 antibacterial drug Drugs 0.000 abstract description 2
- 230000004083 survival effect Effects 0.000 description 23
- 239000000243 solution Substances 0.000 description 11
- 230000002070 germicidal effect Effects 0.000 description 10
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 9
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 9
- 150000008535 L-arginines Chemical class 0.000 description 8
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 8
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 8
- 229960000723 ampicillin Drugs 0.000 description 8
- 229960000310 isoleucine Drugs 0.000 description 8
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 8
- 241000588724 Escherichia coli Species 0.000 description 6
- 235000009697 arginine Nutrition 0.000 description 6
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- 239000000523 sample Substances 0.000 description 6
- 229940024606 amino acid Drugs 0.000 description 5
- 230000002401 inhibitory effect Effects 0.000 description 5
- FRXSZNDVFUDTIR-UHFFFAOYSA-N 6-methoxy-1,2,3,4-tetrahydroquinoline Chemical compound N1CCCC2=CC(OC)=CC=C21 FRXSZNDVFUDTIR-UHFFFAOYSA-N 0.000 description 4
- AHLPHDHHMVZTML-BYPYZUCNSA-N L-Ornithine Chemical class NCCC[C@H](N)C(O)=O AHLPHDHHMVZTML-BYPYZUCNSA-N 0.000 description 4
- 235000001014 amino acid Nutrition 0.000 description 4
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- 238000002360 preparation method Methods 0.000 description 3
- 238000011160 research Methods 0.000 description 3
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- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 2
- 241000251468 Actinopterygii Species 0.000 description 2
- FIZZUEJIOKEFFZ-UHFFFAOYSA-M C3-oxacyanine Chemical compound [I-].O1C2=CC=CC=C2[N+](CC)=C1C=CC=C1N(CC)C2=CC=CC=C2O1 FIZZUEJIOKEFFZ-UHFFFAOYSA-M 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 2
- WJXSXWBOZMVFPJ-NENRSDFPSA-N N-[(2R,3R,4R,5S,6R)-4,5-dihydroxy-6-methoxy-2,4-dimethyloxan-3-yl]-N-methylacetamide Chemical compound CO[C@@H]1O[C@H](C)[C@@H](N(C)C(C)=O)[C@@](C)(O)[C@@H]1O WJXSXWBOZMVFPJ-NENRSDFPSA-N 0.000 description 2
- AHLPHDHHMVZTML-UHFFFAOYSA-N Orn-delta-NH2 Natural products NCCCC(N)C(O)=O AHLPHDHHMVZTML-UHFFFAOYSA-N 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 241000718541 Tetragastris balsamifera Species 0.000 description 2
- 241000219793 Trifolium Species 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 238000009360 aquaculture Methods 0.000 description 2
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- 150000003851 azoles Chemical class 0.000 description 2
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- 229960003104 ornithine Drugs 0.000 description 2
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
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- DWNBOPVKNPVNQG-LURJTMIESA-N (2s)-4-hydroxy-2-(propylamino)butanoic acid Chemical class CCCN[C@H](C(O)=O)CCO DWNBOPVKNPVNQG-LURJTMIESA-N 0.000 description 1
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- VZUFSMBGWBLOCB-UHFFFAOYSA-N C3-oxacyanine cation Chemical compound O1C2=CC=CC=C2[N+](CC)=C1C=CC=C1N(CC)C2=CC=CC=C2O1 VZUFSMBGWBLOCB-UHFFFAOYSA-N 0.000 description 1
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- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
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- 206010061218 Inflammation Diseases 0.000 description 1
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- 241001465754 Metazoa Species 0.000 description 1
- CHJJGSNFBQVOTG-UHFFFAOYSA-N N-methyl-guanidine Natural products CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 1
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- 241000276701 Oreochromis mossambicus Species 0.000 description 1
- UTJLXEIPEHZYQJ-UHFFFAOYSA-N Ornithine Natural products OC(=O)C(C)CCCN UTJLXEIPEHZYQJ-UHFFFAOYSA-N 0.000 description 1
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- 206010034133 Pathogen resistance Diseases 0.000 description 1
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- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 1
- 241000607142 Salmonella Species 0.000 description 1
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- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 1
- ZRALSGWEFCBTJO-UHFFFAOYSA-N anhydrous guanidine Natural products NC(N)=N ZRALSGWEFCBTJO-UHFFFAOYSA-N 0.000 description 1
- 230000002155 anti-virotic effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
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- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
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- NWFNSTOSIVLCJA-UHFFFAOYSA-L copper;diacetate;hydrate Chemical compound O.[Cu+2].CC([O-])=O.CC([O-])=O NWFNSTOSIVLCJA-UHFFFAOYSA-L 0.000 description 1
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- SWSQBOPZIKWTGO-UHFFFAOYSA-N dimethylaminoamidine Natural products CN(C)C(N)=N SWSQBOPZIKWTGO-UHFFFAOYSA-N 0.000 description 1
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- 241000894007 species Species 0.000 description 1
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- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
- A61K31/7034—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin
- A61K31/7036—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a carbocyclic compound, e.g. phloridzin having at least one amino group directly attached to the carbocyclic ring, e.g. streptomycin, gentamycin, amikacin, validamycin, fortimicins
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- 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
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- Health & Medical Sciences (AREA)
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- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The invention belongs to pharmaceutical technology fields, specifically disclose application of the L arginine in terms of sensibility of bacteria on antibiotic is improved.Present invention discover that L arginine by improving the proton dynamics of bacterium, so that increasing into the antibiotic quantity inside bacterium, finally makes bacterial death, therefore L arginine can improve the sensibility of bacterial antibiotic, so as to overcome the problems, such as bacterial drug resistance.L arginine and antibiotic combination can be significantly improved to the bactericidal effect of antibiotic, compared with existing by the use of antibiotic as anti-bacterial drug, there is better effect and higher security and operability.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular, to L-arginine is improving sensibility of bacteria on antibiotic side
The application in face.
Background technology
Pathogenic bacteria seriously endangers the sustainable development of human body health and aquaculture, it is necessary to adopt an effective measure
It is prevented.Since nineteen twenty-nine Fleming（Fleming）It was found that since penicillin, the numerous studies of various antibiotic open people
In the antibiotic epoch of class, great effect is played in the treatment of infectious disease so that the use of antibiotic is increasingly extensive.
Although using antibiotic can effective disease preventing and treating, the abuse of antibiotic and misuse can cause bacterium to generate drug resistance.Drug resistance
Bacterial strain generates tolerance to effective antibiotic originally, and infection is caused to be difficult to control.Therefore, it is special using new method control bacterium
Be drug-fast bacteria infection it is particularly significant.
The hot spot studied at present is by improving sensibility of the drug-fast bacteria to antibiotic so that originally invalid or poorly efficient is anti-
Raw element becomes effective, and drug-fast bacteria is killed.Recently, it has been discovered that some small molecules can cooperate with antibiotic to promote bactericidal effect,
It together with antibiotic is prepared into compound preparation, is of great significance to the infection for controlling bacterium particularly drug-fast bacteria.
Arginine（arginine）It is a kind of aliphatic, alkalescence, the polarity a-amino acid containing guanidine radicals, is also 20 kinds universal
One of natural amino acid, it is positively charged in physiological conditions.It is mostly L-arginine in nature, is the volume in protein synthesis
Code amino acid.D-Arg is not yet found in nature.Arginine is the intermediate metabolites of ornithine Xun Huan, and ammonia can be promoted to turn
It is turned into urea, so as to reduce Blood Ammonia Concentration.Arginine can effectively improve immunity, promote immune system secretion natural kill thin
Born of the same parents, phagocyte, interleukins（interleukin-1）Deng endogenous substance, be conducive to inhibiting tumor cell and pre- anti-virus
Infection.In addition, arginine is ornithine（L-ornithine）And proline（L-proline）Precursors, proline be form
The important element of collagen, supplement arginine are largely organized the health of maintenance to protect, are had bright for needs such as severe trauma, burns
Aobvious help, while there is the effect for reducing infection and inflammation.But it can improve antibiotic on L-arginine and remove cause of disease
The research of bacterium is there is not yet relevant report.
The content of the invention
The present invention provides L-arginine and is improving sensibility of bacteria on antibiotic to overcome the above-mentioned deficiency of the prior art
The application of aspect, present invention discover that L-arginine can improve the sensibility of bacterial antibiotic, so as to overcome bacterial drug resistance
The problem of.
Another object of the present invention is to provide a kind of antibacterial or sterilization drug.
Another object of the present invention is to provide a kind of method for improving sensibility of bacteria on antibiotic.
To achieve these goals, the present invention is achieved by following scheme：
Present invention discover that after addition L-arginine, kanamycins significantly improves the bactericidal effect of slow Ai Dehuashi drug-fast bacterias,
And L-arginine concentration dependent is presented.The result shows that L-arginine can enhance slow Ai Dehuashi drug-fast bacterias, to card, that is mould
The sensibility of element.
Present invention discover that after addition L-arginine, other antibiotic（Such as ampicillin, balofloxacin and Cefazolin
Sodium）The bactericidal effect of slow Ai Dehuashi drug-fast bacterias is significantly improved, the results showed that, L-arginine can enhance slow Edward
Family name's drug-fast bacteria is to the sensibility of other antibiotic.
Present invention discover that after addition L-arginine, kanamycins is to other bacteriums or drug-fast bacteria（As Escherichia coli, verdigris are false
Monad, beta streptococcus and staphylococcus aureus）Bactericidal effect significantly improve, the results showed that, L-arginine can increase
Strong other bacteriums or drug-fast bacteria are to the sensibility of kanamycins.
Present invention discover that L-arginine is by improving the proton dynamics of bacterium, so that into the antibiotic inside bacterium
Content increases, and finally makes bacterial death.
In conclusion L-arginine is added in antibiotic can significantly improve the sensitivity of bacterium or drug-fast bacteria to antibiotic
Property, so as to achieve the purpose that antibacterial or sterilization.Therefore, the present invention is claimed L-arginine and is improving bacterial antibiotic sensitivity
Application in terms of property.
Preferably, the bacterium is Edwardsiella tarda, Escherichia coli, pseudomonas aeruginosa, beta streptococcus or gold
At least one of staphylococcus aureus.
Preferably, the antibiotic in kanamycins, ampicillin, balofloxacin or Cefazolin sodium at least
It is a kind of.
Preferably, for L-arginine improve Wdwardsiella tarda to the application in terms of kanamycins sensibility.
Preferably, Wdwardsiella tarda is being improved to ampicillin, balofloxacin or Cefazolin sodium for L-arginine
Application in terms of sensibility.
Preferably, Escherichia coli, pseudomonas aeruginosa, beta streptococcus or Staphylococcus aureus are being improved for L-arginine
Bacterium is to the application in terms of kanamycins sensibility.
A kind of antibacterial or sterilization drug is also claimed in the present invention, contains antibiotic and L-arginine.
A kind of method for improving sensibility of bacteria on antibiotic is also claimed in the present invention, and L-arginine and antibiotic are joined
With.
In the above-mentioned methods, the bacterium is sensitive bacteria or drug-fast bacteria.
Preferably, the bacterium includes but not limited to Edwardsiella tarda, Escherichia coli, pseudomonas aeruginosa, B-mode
Streptococcus and staphylococcus aureus.Because these bacteriums are the common mankind and cultivated animals pathogenic bacteria, such as slow Edward
Salmonella, Escherichia coli and pseudomonas aeruginosa are Gram-negative bacteria, and beta streptococcus and staphylococcus aureus are leather
Lan Shi positive bacterias.These bacteriums can be drug-fast bacteria or sensitive bacteria.
Preferably, the antibiotic is selected from, but not limited to, kanamycins, ampicillin, balofloxacin and Cefazolin
Sodium.Because kanamycins is aminoglycoside antibiotics；Balofloxacin is carbostyril antibiotic；Ampicillin and cephalo azoles
Woods sodium is beta-lactam antibiotic.These include the major antibiotics type of current Clinical practice.
Preferably, the dose ratio of the L-arginine and antibiotic by weight 1：0.0015~300.
Preferably, using the above method come when improving the sensibility of bacterial antibiotic, the usage amount of L-arginine is 3mg
~30g/ administration.
Compared with prior art, the invention has the advantages that：
Present invention firstly discovers that L-arginine can improve the sensibility of bacterial antibiotic, so as to overcome asking for bacterial drug resistance
Topic, further study show that L-arginine is by improving the proton dynamics of bacterium, so that into the antibiotic inside bacterium
Content increases.L-arginine and antibiotic combination can be significantly improved to the bactericidal effect of antibiotic, antibiosis is used with existing
Element is compared as anti-bacterial drug, has better effect and higher security and operability, has preferable application
Prospect.
Description of the drawings
After Fig. 1 adds L-arginine for embodiment 1 in kanamycins, the Survival of Wdwardsiella tarda.
After Fig. 2 adds various concentration L-arginine for embodiment 1 in kanamycins, the existence feelings of Wdwardsiella tarda
Condition.
After Fig. 3 adds various concentration tyrosine for embodiment 1, the Survival of Wdwardsiella tarda.
After Fig. 4 adds various concentration isoleucine for embodiment 1, the Survival of Wdwardsiella tarda.
After Fig. 5 adds L-arginine for embodiment 2 in different antibiotic, the Survival of Wdwardsiella tarda.
After Fig. 6 adds L-arginine for embodiment 3 in kanamycins, the Survival of different bacterium.
After Fig. 7 adds L-arginine for embodiment 4 in kanamycins, kanamycins changes of contents situation in bacterial body.
After Fig. 8 adds L-arginine for embodiment 5, bacterium proton dynamics situation of change.
Specific embodiment
The present invention is made with reference to Figure of description and specific embodiment and further being elaborated, the embodiment is only used
In explaining the present invention, the scope of the present invention is not intended to limit.Test method used in following embodiments is such as without special theory
It is bright, it is conventional method；Used material, reagent etc., unless otherwise specified, for the reagent and material commercially obtained
Material.
1 L-arginine of embodiment improves sensibility of the Wdwardsiella tarda to kanamycins
1st, the measure of Wdwardsiella tarda EIB202 drug resistances
Wdwardsiella tarda is Gram-negative brevibacterium, it was reported for the first time in 1962 by Hoshina, red with Japanese eel
Disease（reddisease）It is related.From first time report, the bacterium causes disease, such as eel in more than 20 kinds of fish till now
Eel, lefteye flounder, Tilapia mossambica, Shelled Turtle Trionyx Sinensis, carp etc. cause massive losses to aquaculture.Wdwardsiella tarda be also a kind of people,
The common diseased opportunistic pathogen of fish, directly causes human health threat.
Minimum inhibitory concentration of the Wdwardsiella tarda to Multiple Classes of Antibiotics is measured first.The result shows that Edwardsiella tarda
EIB202 is 12.5 μ g/mL to the minimum inhibitory concentration of kanamycins, is 125 μ g/mL to the minimum inhibitory concentration of tetracycline, right
The minimum inhibitory concentration of chloramphenicol is 50 μ g/mL, and it is a multi-drug resistant bacteria to show Wdwardsiella tarda EIB202.
2nd, the preparation of test sample
It is inoculated in from picking Wdwardsiella tarda EIB202 single bacterium colonies on LB tablets in 5mL LB culture mediums, in 30 DEG C, 200rpm
Under the conditions of shaken cultivation for 24 hours reach saturation state.Bacterium solution is collected by centrifugation, centrifuges 5min under the conditions of 8000rpm, remove supernatant and with
0.85% brine thalline, finally with the basic fluid nutrient mediums of 1 × M9（Acetate containing 10mM）Suspension thalline adjusts bacterium
Then it is spare in test tube to dispense 5mL to 0.2 for liquid OD values.
3rd, L-arginine improves sensibility of the Wdwardsiella tarda EIB202 to kanamycins
After understanding addition L-arginine, whether Wdwardsiella tarda improves the sensibility of kanamycins.It is prepared above-mentioned
Bacteria sample be divided into 3 groups：2 control groups（Control group 1：Kanamycins and 2.5mM L-arginines are not added；Control group 2：Only
Add 40 μ g/mL kanamycins）With 1 experimental group（Add 40 μ g/mL kanamycins and 2.5mM L-arginines）.After acting on 6h
100 μ L bacterium solutions is taken to carry out TSB agar plates bacterium colony to count.Number of viable is counted, calculates survival rate.
The results are shown in Figure 1, and after L-arginine is added, Wdwardsiella tarda improves the sensibility of kanamycins
104.47 again（Survival rate by only plus kanamycins 69.84% drop to addition L-arginine and kanamycins after 0.66%）.
This result shows that：After adding L-arginine, sensibility of the Wdwardsiella tarda to kanamycins is remarkably improved.
4th, L-arginine improves Wdwardsiella tarda EIB202 has concentration dependent to the sensibility of kanamycins
It is whether dense with L-arginine to the sensibility of kanamycins to understand L-arginine raising Wdwardsiella tarda EIB202
Dependence is spent, has been carried out under the premise of kanamycins is added in, adds the experiment of various concentration L-arginine.In the bacterium prepared
In sample, first add 40 μ g/mL kanamycins, then add 0,1.25,2.5,5,10 and 20mM L-arginines respectively, in 30 DEG C,
After shaking table is incubated 6h under the conditions of 200rpm, 100 μ L bacterium solutions is taken to carry out TSB agar plates bacterium colony and are counted.Number of viable is counted, is calculated
Survival rate.
The results are shown in Figure 2, and under the premise of existing for kanamycins, within the specific limits, with adding in, L-arginine is dense
The rise of degree, kanamycins also gradually increase the germicidal efficiency of bacterium；But when L-arginine concentration continues rise, it is mould to block that
Element but reduces the germicidal efficiency of bacterium.
Specific experiment result is：When kanamycins concentration is 40 μ g/mL, addition 1.25mM L-arginines can improve it
To 113 times of the germicidal efficiency of bacterium（Survival rate by be not added with the 108.24% of L-arginine drop to addition after 0.96%）, add
Add 2.5mM L-arginines that can improve its 213 times of germicidal efficiency to bacterium（Survival rate is by being not added with the 111.43% of L-arginine
Drop to 0.52% after addition）, its 32.9 times of germicidal efficiency to bacterium can be improved by adding 5mM L-arginines（Survival rate by
Be not added with the 109.56% of L-arginine drop to addition after 3.33%）, it can be improved to bacterium by adding 10mM L-arginines
22.89 times of germicidal efficiency（Survival rate by be not added with the 106.64% of L-arginine drop to addition after 4.66%）, add 20mM
L-arginine can improve its 25.15 times of germicidal efficiency to bacterium（Survival rate is dropped to by being not added with the 106.91% of L-arginine
4.25% after addition）.
5th, tyrosine and isoleucine cannot improve sensibility of the Edwardsiella tarda EIB202 to kanamycins
To understand the bactericidal effect whether other amino acid both contribute to antibiotic, carry out under the premise of kanamycins is added in,
Add the experiment of tyrosine and isoleucine.In the above-mentioned bacteria sample prepared, 40 μ g/mL kanamycins are first added, then
Add 0,0.125,0.25,0.5,1 and 2mM tyrosine or 0,0.5,1,2,4 and 8mM isoleucine propylhomoserins respectively, in 30 DEG C,
After shaking table is incubated 6h under the conditions of 200rpm, 100 μ L bacterium solutions is taken to carry out TSB agar plates bacterium colony and are counted.Number of viable is counted, is calculated
Survival rate.
The results are shown in Figure 3 for tyrosine, after the tyrosine of addition various concentration, compared with not adding tyrosine, and sterilization
Efficiency is basically identical, improves to 1.9 times；Compared with not adding tyrosine, only add antibiotic, germicidal efficiency rises to 1.4
Times.1.36 times are differed between the two, no difference.
Isoleucine results as shown in figure 4, addition various concentration isoleucine after, with not adding isoleucine phase
Than germicidal efficiency is basically identical, improves to 1.8 times；Compared with not adding isoleucine, only add antibiotic, germicidal efficiency
It improves to 1.4 times.1.28 times are differed between the two, no difference.
The above result shows that：Tyrosine and isoleucine cannot all improve Edwardsiella tarda EIB202 to kanamycins
Sensibility.Thus deduction and not all amino acid can improve the bactericidal effect of kanamycins, so as to illustrate L-arginine
Promote the specificity of kanamycins bactericidal effect.
2 L-arginine of embodiment improves sensibility of the Wdwardsiella tarda to other antibiotic
After understanding addition L-arginine, if Wdwardsiella tarda can be improved to the quick of other antibiotic beyond kanamycins
Perception prepares bacteria sample according to the method for 1 step 2 of embodiment.Experiment is divided into 3 groups：2 control groups（Control group 1：It does not add
Antibiotic and L-arginine；Control group 2：Only addition antibiotic）With 1 experimental group（Add a kind of antibiotic and L-arginine）.
The antibiotic and activity of addition be respectively：12.5 μ g/mL ampicillins, 2 μ g/mL balofloxacins and 50 μ g/mL cephalos
Azoles woods sodium.Number of viable is counted after effect 6h, calculates survival rate.
The results are shown in Figure 5, and after L-arginine is added, Wdwardsiella tarda improves the sensibility of ampicillin
5.13 again（After survival rate drops to addition L-arginine and ampicillin by the 60.03% of only plus ampicillin
11.7%）, 2 times are improved to the sensibility of Balofloxacin（Survival rate drops to addition L- essence ammonia by only adding the 46.23% of Balofloxacin
23.5% after acid and Balofloxacin）, 5.29 times are improved to the sensibility of Cefazolin sodium（Survival rate is by only adding Cefazolin sodium
16.93% drop to addition L-arginine and Cefazolin sodium after 3.2%）.
The above result shows that：After adding L-arginine, sensitivity of the Wdwardsiella tarda to other antibiotic is remarkably improved
Property.
3 L-arginine of embodiment improves sensibility of the various bacteria to kanamycins
1st, the preparation of bacterial solution
Picking e. coli k12, pseudomonas aeruginosa, beta streptococcus and staphylococcus aureus resistance bacterium（MASA）Etc. a variety of
Bacterial colony cultivates 16h up to saturation state into 100mL LB fluid nutrient mediums under the conditions of 37 DEG C or 30 DEG C, 200rpm.
Each bacterial solutions of 20mL are collected respectively, 5min is centrifuged under the conditions of 8000rpm, remove supernatant and with 0.85% isometric physiology
Brine washing thalline, finally with the basic fluid nutrient mediums of 1 × M9（Acetate containing 10mM）Suspension thalline, adjust bacterium solution OD values to
0.5, it is spare in test tube that 5mL is then dispensed respectively.
2nd, L-arginine improves sensibility of the various bacteria to kanamycins
The above-mentioned bacterium solution prepared is respectively divided into 3 groups according to bacterial species：2 control groups（Control group 1：Not adding card, that is mould
Element and L-arginine；Control group 2：Only addition kanamycins）With 1 experimental group（Add kanamycins and L-arginine）.Addition
2.5mM L-arginines and kanamycins（The concentration that different bacterium adds in is different）, incubated in 37 DEG C or 30 DEG C, 200rpm shaking tables
After educating 6h, 100 μ L bacterium solutions is taken to carry out count plate, calculate its survival rate.
As shown in Figure 6, the results showed that, escherichia coli K12 improves 2 times to the sensibility of kanamycins（Survival rate by
Not plus L-arginine 75.49% fall to addition L-arginine after 37.7%）, pseudomonas aeruginosa is to the sensibility of kanamycins
Improve 8.64 times（Survival rate is not by adding the smart winter propylhomoserins 44% of L- to fall to 5.09% after adding L-arginine）, beta streptococcus
269 times are improved to the sensibility of kanamycins（After survival rate is not by adding L-arginine 97.73% to fall to addition L-arginine
0.36%）, staphylococcus aureus resistance bacterium（MASA）273 times are improved to the sensibility of kanamycins（Survival rate is not by adding
L-arginine 83.36% falls to 0.3% after addition L-arginine）.In conclusion after addition L-arginine, these bacteriums pair
The sensibility of kanamycins is generally obtained for raising.
4 L-arginine of embodiment improves Wdwardsiella tarda and enters kanamycins content
Bacterial death is related with into the antibiotic quantity inside bacterium, and bacterial resistance is due to entering the in vivo antibiotic of bacterium
Concentration is less than the concentration for making its dead.Improve whether Wdwardsiella tarda Antibiotic Sensitivity passes through for research L-arginine
Increase the antibiotic content into inside bacterium and work, bacteria sample is prepared according to the method for 1 step 2 of embodiment, it will be thin
Bacterium bacterium solution is divided into 3 groups, wherein 2 groups are control group（Control group 1：Any substance is not added；Control group 2：Only add kanamycins）,
Another 1 group is experimental group（Add kanamycins and L-arginine）.After 6h being incubated in 30 DEG C, 200rpm shaking tables.Eccentric cleaning bacterium
Body, ultrasonic disruption, with kanamycins ELISA detection kit（Beijing Clover Technology Co., Ltd., Clover
Technology Group Inc）Measure kanamycins content.
The results are shown in Figure 7, after adding L-arginine, is added than entering antibiotic in bacterial body during only added with antibiotic
1.7 again.Illustrate that L-arginine can be improved really into the in vivo antibiotic content of bacterium.
5 L-arginine of embodiment improves the proton dynamics of Wdwardsiella tarda
From embodiment 4, after adding L-arginine, dramatically increased into the antibiotic quantity inside Wdwardsiella tarda, but
The specific mechanism of action is unclear.For research L-arginine antibiotic is promoted to enter the mechanism of action inside bacterium, will tested
（Prepared by laboratory sample carries out according to the method for 1 step 2 of embodiment）It is divided into 2 groups：1 control group（Do not add kanamycins and L-
Arginine）With 1 experimental group（Add L-arginine）, shaking table is incubated 6h under the conditions of 30 DEG C, 200rpm.It will be treated thin
Bacterium adjusts concentration to 10 respectively6CFU/mL takes 1mL to be transferred in 1.5mL EP pipes, adds in 10 μ L 3mM DiOC2（3,3'-
diethyloxa-carbocyanine iodide）, abundant mixing is after 37 DEG C of oscillation incubation 30min.Stream is transferred to before upper machine
In formula cytometry pipe, flow cytometer FACSCalibur flow cytometer are used（Becton Dickinson,
San Jose, CA, USA）It is detected, parameter setting is carried out according to instrumentation regulation.Dyestuff DiOC2（3）Green it is glimmering
Light excitation wavelength 488nm, launch wavelength 530nm, red fluorescence excitation wavelength 488nm, launch wavelength 610nm.Red light intensity with
The ratio of green intensity represents the intensity of film potential, proton dynamics（PMF）Value calculation formula is LOG（10 3/2* Y mean/
X mean）, Y mean and X mean represent red light intensity and green intensity respectively, according to BacLight bacterial
membrane potential kit（Invitrogen）Kit explanation is measured.
The results are shown in Figure 8, and after finding addition L-arginine, the proton dynamics of bacterium increase by 2.86 times.This result table
It is bright, after adding L-arginine bacterium proton dynamics can be caused to increase, thus increase the antibiotic content into inside bacterium,
Finally make bacterial death.
Finally, it should be noted that the above embodiments are merely illustrative of the technical solutions of the present invention rather than the present invention is protected
The limitation of scope is protected, for those of ordinary skill in the art, can also be made on the basis of above description and thinking
Other various forms of variations or variation, there is no necessity and possibility to exhaust all the enbodiments.It is all the present invention
All any modification, equivalent and improvement made within spirit and principle etc., should be included in the protection of the claims in the present invention
Within the scope of.
Claims (8)
1. application of the L-arginine in terms of sensibility of bacteria on antibiotic is improved.
2. a kind of antibacterial or sterilization drug, which is characterized in that contain antibiotic and L-arginine.
A kind of 3. method for improving sensibility of bacteria on antibiotic, which is characterized in that be combined L-arginine and antibiotic.
4. according to the method described in claim 3, it is characterized in that, the bacterium is sensitive bacteria or drug-fast bacteria.
5. the method according to claim 3 or 4, which is characterized in that the bacterium is Edwardsiella tarda, large intestine bar
At least one of bacterium, pseudomonas aeruginosa, beta streptococcus or staphylococcus aureus.
6. the method according to claim 3 or 4, which is characterized in that the antibiotic is selected from kanamycins, ammonia benzyl mould
At least one of element, balofloxacin or Cefazolin sodium.
7. according to the method described in claim 3, it is characterized in that, the dose ratio of the L-arginine and antibiotic by weight
For 1：0.0015~300.
8. according to the method described in claim 3, it is characterized in that, the usage amount of the L-arginine is given for 3mg~30g/ times
Medicine.
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| 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 |
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| 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 |
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| CN111744016B (en) * | 2020-08-06 | 2021-08-13 | 中山大学 | Application of compound amino acid in preparation of medicine for improving sensitivity of bacteria to antibiotics |
| 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 |
| CN113462739A (en) * | 2021-07-01 | 2021-10-01 | 中山大学 | Method and kit for detecting substance promoting antibiotic sterilization efficiency improvement |
| 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 |
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