CN114159456A - Application of adenosine or adenosine monophosphate in preparation of anti-infective drugs - Google Patents
Application of adenosine or adenosine monophosphate in preparation of anti-infective drugs Download PDFInfo
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- CN114159456A CN114159456A CN202111564202.5A CN202111564202A CN114159456A CN 114159456 A CN114159456 A CN 114159456A CN 202111564202 A CN202111564202 A CN 202111564202A CN 114159456 A CN114159456 A CN 114159456A
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- Prior art keywords
- adenosine
- bacteria
- antibiotics
- antibiotic
- infective
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- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 title claims abstract description 94
- UDMBCSSLTHHNCD-UHFFFAOYSA-N Coenzym Q(11) Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(O)=O)C(O)C1O UDMBCSSLTHHNCD-UHFFFAOYSA-N 0.000 title claims abstract description 93
- 239000002126 C01EB10 - Adenosine Substances 0.000 title claims abstract description 64
- UDMBCSSLTHHNCD-KQYNXXCUSA-N adenosine 5'-monophosphate Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP(O)(O)=O)[C@@H](O)[C@H]1O UDMBCSSLTHHNCD-KQYNXXCUSA-N 0.000 title claims abstract description 61
- 229960003190 adenosine monophosphate Drugs 0.000 title claims abstract description 59
- LNQVTSROQXJCDD-UHFFFAOYSA-N adenosine monophosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(CO)C(OP(O)(O)=O)C1O LNQVTSROQXJCDD-UHFFFAOYSA-N 0.000 title claims abstract description 59
- 239000003814 drug Substances 0.000 title claims abstract description 37
- 229950006790 adenosine phosphate Drugs 0.000 title claims abstract description 34
- 230000002924 anti-infective effect Effects 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- 229940079593 drug Drugs 0.000 title abstract description 27
- 241000894006 Bacteria Species 0.000 claims abstract description 94
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 64
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 62
- 229960004682 cefoperazone Drugs 0.000 claims abstract description 53
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 claims abstract description 53
- 229960005256 sulbactam Drugs 0.000 claims abstract description 45
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 claims abstract description 42
- 230000035945 sensitivity Effects 0.000 claims abstract description 31
- 241000588724 Escherichia coli Species 0.000 claims abstract description 24
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims abstract description 22
- 241000607528 Aeromonas hydrophila Species 0.000 claims abstract description 17
- 241000588626 Acinetobacter baumannii Species 0.000 claims abstract description 16
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 16
- 241000607272 Vibrio parahaemolyticus Species 0.000 claims abstract description 16
- 241000193996 Streptococcus pyogenes Species 0.000 claims abstract description 14
- 241000607594 Vibrio alginolyticus Species 0.000 claims abstract description 14
- 241000588747 Klebsiella pneumoniae Species 0.000 claims abstract description 12
- 241000194056 Streptococcus iniae Species 0.000 claims abstract description 12
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims abstract description 11
- 229930182566 Gentamicin Natural products 0.000 claims abstract description 11
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims abstract description 11
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229960004821 amikacin Drugs 0.000 claims abstract description 11
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 claims abstract description 11
- 229960000484 ceftazidime Drugs 0.000 claims abstract description 11
- 229960000479 ceftriaxone sodium Drugs 0.000 claims abstract description 11
- 229960003405 ciprofloxacin Drugs 0.000 claims abstract description 11
- FDRNWTJTHBSPMW-GNXCPKRQSA-L disodium;(6r,7r)-7-[[(2e)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(2-methyl-6-oxido-5-oxo-1,2,4-triazin-3-yl)sulfanylmethyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound [Na+].[Na+].S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)/C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C([O-])=NN1C FDRNWTJTHBSPMW-GNXCPKRQSA-L 0.000 claims abstract description 11
- 229960002518 gentamicin Drugs 0.000 claims abstract description 11
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims abstract description 11
- 229960002182 imipenem Drugs 0.000 claims abstract description 11
- 229930027917 kanamycin Natural products 0.000 claims abstract description 11
- 229960000318 kanamycin Drugs 0.000 claims abstract description 11
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound 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 abstract description 11
- 229930182823 kanamycin A Natural products 0.000 claims abstract description 11
- 229960003376 levofloxacin Drugs 0.000 claims abstract description 11
- 229960002260 meropenem Drugs 0.000 claims abstract description 11
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 claims abstract description 11
- 241000193830 Bacillus <bacterium> Species 0.000 claims abstract description 10
- 229960003702 moxifloxacin Drugs 0.000 claims abstract description 9
- FABPRXSRWADJSP-MEDUHNTESA-N moxifloxacin Chemical compound COC1=C(N2C[C@H]3NCCC[C@H]3C2)C(F)=CC(C(C(C(O)=O)=C2)=O)=C1N2C1CC1 FABPRXSRWADJSP-MEDUHNTESA-N 0.000 claims abstract description 9
- -1 ampinan Chemical compound 0.000 claims abstract description 8
- 229960005305 adenosine Drugs 0.000 claims description 30
- 230000003115 biocidal effect Effects 0.000 claims description 24
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 claims description 10
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims description 9
- 239000002132 β-lactam antibiotic Substances 0.000 claims description 9
- 229940124586 β-lactam antibiotics Drugs 0.000 claims description 9
- 239000000203 mixture Substances 0.000 claims description 8
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 claims description 7
- 241000194031 Enterococcus faecium Species 0.000 claims description 5
- 229960005475 antiinfective agent Drugs 0.000 claims description 2
- 239000004599 antimicrobial Substances 0.000 claims description 2
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 claims 2
- 229940126574 aminoglycoside antibiotic Drugs 0.000 claims 2
- 239000003306 quinoline derived antiinfective agent Substances 0.000 claims 2
- 241000607598 Vibrio Species 0.000 abstract description 6
- 206010059866 Drug resistance Diseases 0.000 abstract description 5
- 238000002474 experimental method Methods 0.000 abstract description 2
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 abstract 1
- 230000004083 survival effect Effects 0.000 description 33
- 230000001954 sterilising effect Effects 0.000 description 17
- 238000004659 sterilization and disinfection Methods 0.000 description 17
- 244000052616 bacterial pathogen Species 0.000 description 15
- 230000001580 bacterial effect Effects 0.000 description 13
- 241000588748 Klebsiella Species 0.000 description 10
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 7
- AUHDWARTFSKSAC-HEIFUQTGSA-N (2S,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)-2-(6-oxo-1H-purin-9-yl)oxolane-2-carboxylic acid Chemical compound [C@]1([C@H](O)[C@H](O)[C@@H](CO)O1)(N1C=NC=2C(O)=NC=NC12)C(=O)O AUHDWARTFSKSAC-HEIFUQTGSA-N 0.000 description 6
- 229930024421 Adenine Natural products 0.000 description 6
- 229930010555 Inosine Natural products 0.000 description 6
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 6
- GRSZFWQUAKGDAV-UHFFFAOYSA-N Inosinic acid Natural products OC1C(O)C(COP(O)(O)=O)OC1N1C(NC=NC2=O)=C2N=C1 GRSZFWQUAKGDAV-UHFFFAOYSA-N 0.000 description 6
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- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 5
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- KWTSXDURSIMDCE-QMMMGPOBSA-N (S)-amphetamine Chemical compound C[C@H](N)CC1=CC=CC=C1 KWTSXDURSIMDCE-QMMMGPOBSA-N 0.000 description 2
- 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 description 2
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- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
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- 229950000805 balofloxacin Drugs 0.000 description 2
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- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
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- OQRXBXNATIHDQO-UHFFFAOYSA-N 6-chloropyridine-3,4-diamine Chemical compound NC1=CN=C(Cl)C=C1N OQRXBXNATIHDQO-UHFFFAOYSA-N 0.000 description 1
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- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 1
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- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 1
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- 206010034133 Pathogen resistance Diseases 0.000 description 1
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- PPQRONHOSHZGFQ-LMVFSUKVSA-N aldehydo-D-ribose 5-phosphate Chemical compound OP(=O)(O)OC[C@@H](O)[C@@H](O)[C@@H](O)C=O PPQRONHOSHZGFQ-LMVFSUKVSA-N 0.000 description 1
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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
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of adenosine or adenosine monophosphate in preparation of anti-infective drugs. Experiments prove that adenosine or adenosine monophosphate can remarkably improve the sensitivity of bacteria such as clinical escherichia coli, aeromonas hydrophila, vibrio including vibrio alginolyticus and vibrio parahaemolyticus, streptococcus pyogenes, pseudomonas aeruginosa, bacillus faecium, streptococcus iniae, acinetobacter baumannii, klebsiella pneumoniae and the like to antibiotics such as cefoperazone sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampinan, moxifloxacin, levofloxacin, gentamicin, amikacin, kanamycin and the like, can be used as an anti-infective medicament together with the antibiotics, kills the bacteria under the condition of low-concentration antibiotics, achieves a better anti-infective effect, and reduces the generation of drug resistance of the bacteria.
Description
Technical Field
The invention belongs to the technical field of biological medicines. More particularly, it relates to the use of adenosine or adenosine monophosphate in the preparation of anti-infective medicaments.
Background
Antibiotics can effectively inhibit or kill pathogenic bacteria, and play a key role in controlling bacterial infection diseases. However, with the widespread use of antibiotics, many pathogenic bacteria begin to develop resistance to antibiotics, which causes infection that is difficult to control and seriously harms human health. The World Health Organization (WHO) in 2007 world health reports clearly states that bacterial resistance is a major public health problem threatening human health.
At present, in order to reduce drug-resistant bacteria and treat infection caused by the drug-resistant bacteria, besides reducing and limiting the use of antibiotics, improving the sensitivity of the drug-resistant bacteria to the antibiotics becomes an important technical scheme for controlling the drug-resistant bacteria. The method mainly enables the antibiotic which is originally ineffective or low in efficiency to pathogenic bacteria to become effective or efficient under the synergistic action of other molecules, thereby killing bacteria. For example, chinese patent applications CN104606219A and CN112569251A disclose that small molecule metabolites inosine and inosinic acid have the effect of improving the pathogenic bacteria removal effect of antibiotics, and the combination of inosine or inosinic acid with antibiotics can significantly improve the bactericidal effect of antibiotics. The research finds that inosine and inosinic acid are metabolites of purine pathway, but other metabolites of purine pathway have the function of improving the sensitivity of pathogenic bacteria to antibiotics, and the inosine and the inosinic acid do not have the function of improving the sensitivity of pathogenic bacteria to antibiotics like hypoxanthine belonging to the pathway; in addition, the antibiotic sterilization promoting effects of inosine and inosinic acid have the specificity of antibiotics and bacteria species, namely, the effects of the inosine and the inosinic acid also differ among different types of antibiotics and different types of bacteria.
Therefore, the development of the application of a plurality of small molecules capable of improving the sensitivity of pathogenic bacteria to antibiotics in the preparation of anti-infective drugs is urgently needed to adapt to various types of pathogenic bacteria or antibiotics.
Disclosure of Invention
The invention aims to solve the technical problems that the existing micromolecules for improving the sensitivity of pathogenic bacteria to antibiotics are limited, the functions of the micromolecules are specific to the antibiotics and the pathogenic bacteria, and the requirements of all the antibiotics and the pathogenic bacteria cannot be met, and provides the application of a plurality of micromolecules for improving the sensitivity of the pathogenic bacteria to the antibiotics in preparing anti-infective medicaments.
The invention aims to provide application of adenosine or adenosine monophosphate in preparing anti-infective medicaments.
It is another object of the present invention to provide an anti-infective composition.
Another object of the present invention is to provide an anti-infective agent.
The above purpose of the invention is realized by the following technical scheme:
adenosine (adonine, Ado) and Adenosine Monophosphate (AMP), which are small molecule metabolites, Adenine (Adenine, a) and derivatives thereof, are important metabolites in organisms. Wherein adenosine monophosphate is an organic compound, is an ester of phosphoric acid and nucleoside adenosine, and is composed of a phosphate functional group, pentose nucleic acid sugar and base adenine. Can be used as intermediate for producing nucleic acid medicine, health food and biochemical reagent, and can be used for preparing adenosine triphosphate. Adenosine monophosphate is dephosphorylated to form adenosine under the action of nucleotidase, and adenosine can be decomposed into ribose phosphate and adenine under the action of nucleoside phosphorylase.
According to the invention, through a large amount of creative work, researches show that adenosine or adenosine monophosphate can remarkably improve the sensitivity of bacteria such as clinical escherichia coli, aeromonas hydrophila, vibrio alginolyticus, vibrio parahaemolyticus, streptococcus pyogenes, pseudomonas aeruginosa, bacillus faecium, streptococcus iniae, acinetobacter baumannii, klebsiella pneumoniae and the like to antibiotics such as cefoperazone sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampane, moxifloxacin, levofloxacin, gentamicin, amikacin, kanamycin and the like, can be used as an anti-infective medicament together with the antibiotics, kills the bacteria under the condition of low-concentration antibiotics, achieves a better anti-infective effect, and reduces the generation of bacterial drug resistance.
The application therefore claims the use of adenosine or adenosine monophosphate in the preparation of anti-infective medicaments.
Further, the adenosine or adenosine monophosphate increases the sensitivity of bacteria to antibiotics in anti-infective drugs.
Preferably, the bacteria are one or more of klebsiella pneumoniae k.pneumoniae, escherichia coli e.coli, aeromonas hydrophila a.hydrophila, vibrio alginolyticus v.alginolyticus, vibrio parahaemolyticus v.parahaemolyticus, streptococcus pyogenes s.pyogenenes, pseudomonas aeruginosa p.aeruginosa, bacillus faecium e.faecium, streptococcus iniae s.iniae, acinetobacter baumannii. The bacteria are common pathogenic bacteria of human and cultured animals, wherein Streptococcus pyogenes and Bacillus faecium are gram-positive bacteria, and Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Aeromonas hydrophila, Edwardsiella tarda, Vibrio parahaemolyticus and Vibrio alginolyticus are gram-negative bacteria.
It should be noted that these bacteria are common pathogenic bacteria and common drug-resistant strains, and meanwhile, escherichia coli and pseudomonas aeruginosa are model bacteria for studying drug resistance of bacteria, so these bacteria are better representatives of drug-resistant and non-drug-resistant bacteria. Although in the examples of the present invention, bacteria are exemplified by Escherichia coli, Aeromonas hydrophila, Vibrio including Vibrio alginolyticus and Vibrio parahaemolyticus, Streptococcus pyogenes, Pseudomonas aeruginosa, Bacillus faecium, Streptococcus iniae, Acinetobacter baumannii and Klebsiella pneumoniae. In particular, most of the verification tests of the invention take clinical klebsiella pneumoniae as a research object. However, these bacteria should not be construed as limiting the scope of the present invention. This is because: the Escherichia coli and the pseudomonas aeruginosa are model bacteria for researching a drug resistance mechanism; ② the above bacteria respectively belong to gram negative and positive bacteria, wherein the faecium and pyogenic streptococcus are gram positive bacteria, the Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Aeromonas hydrophila, Edwardsiella tarda, Vibrio parahaemolyticus and Vibrio alginolyticus are gram negative bacteria. And all human and cultured animal pathogenic bacteria can be classified according to the staining, so the bacteria have better representativeness. The bacteria can have drug-resistant and non-drug-resistant states, namely drug-resistant and non-drug-resistant strains of the same bacteria, and the clinical Klebsiella pneumoniae of the invention is in the drug-resistant state, and the sensitivity to antibiotics is also improved after adenosine or adenosine monophosphate is added. Therefore, many more species can be deduced from these species according to the above principles and are also suitable for the concept of the present invention.
Still further, the antibiotic is one or more of beta-lactam antibiotics, quinolone antibiotics and aminoglycoside antibiotics.
Preferably, the antibiotic is one or more of cefoperazone sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, amprenaline, moxifloxacin, levofloxacin, gentamicin, amikacin, kanamycin. Wherein, the cefoperazone sulbactam, the ceftazidime, the ceftriaxone sodium and the cefoperazone are cephalosporins antibiotics, the meropenem and the imipenem are carbapenems antibiotics, and the amphetamine is a monocyclic beta-lactam antibiotic (the three are beta-lactam antibiotics); balofloxacin, ciprofloxacin and levofloxacin are quinolone antibiotics; gentamicin, amikacin and kanamycin are aminoglycoside antibiotics. These include the major antibiotic types currently in clinical use.
The above antibiotics should not be construed as limiting the scope of the present invention. This is because although the variety of antibiotics is hundreds, they can be classified according to their chemical structures and antibacterial mechanisms, and similar chemical structures have the same antibacterial mechanism, and thus do not need to be verified one by one. Currently, beta-lactam antibiotics, quinolone antibiotics and aminoglycoside antibiotics are clinically common antibiotics. Wherein, the cefoperazone sulbactam, the ceftazidime, the ceftriaxone sodium and the cefoperazone are cephalosporins antibiotics, the meropenem and the imipenem are carbapenems antibiotics, and the amphetamine is a monocyclic beta-lactam antibiotic (the three are beta-lactam antibiotics); balofloxacin, ciprofloxacin and levofloxacin are quinolone antibiotics; gentamicin, amikacin and kanamycin are aminoglycoside antibiotics. Therefore, the antibiotic has good antibiotic representativeness. Those skilled in the art can easily deduce, based on the concept of the present invention, that other clinical antibiotics can be used in the method of the present invention.
In addition, the invention provides an anti-infective composition comprising adenosine and/or adenosine monophosphate and an antibiotic.
Further, the antibiotic is one or more of beta-lactam antibiotics, quinolone antibiotics and aminoglycoside antibiotics.
Preferably, the antibiotic is one or more of cefoperazone sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, amprenaline, moxifloxacin, levofloxacin, gentamicin, amikacin, kanamycin.
Preferably, the bacteria are one or more of klebsiella pneumoniae k.pneumoniae, escherichia coli e.coli, aeromonas hydrophila a.hydrophila, vibrio alginolyticus v.alginolyticus, vibrio parahaemolyticus v.parahaemolyticus, streptococcus pyogenes s.pyogenenes, pseudomonas aeruginosa p.aeruginosa, bacillus faecium e.faecium, streptococcus iniae s.iniae, acinetobacter baumannii.
Furthermore, the mass ratio of the adenosine to the antibiotic is (0.2-213.6): 1, and the mass ratio of the adenosine monophosphate to the antibiotic is (0.375-399): 1.
In addition, the invention also provides an anti-infective drug, which is characterized by containing the anti-infective composition.
Further, the anti-infective drug is an oral preparation, an injection preparation or an external preparation.
The invention has the following beneficial effects:
experiments prove that adenosine or adenosine monophosphate can remarkably improve the sensitivity of bacteria such as clinical escherichia coli, aeromonas hydrophila, vibrio including vibrio alginolyticus and vibrio parahaemolyticus, streptococcus pyogenes, pseudomonas aeruginosa, bacillus faecium, streptococcus iniae, acinetobacter baumannii, klebsiella pneumoniae and the like to antibiotics such as cefoperazone sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampinan, moxifloxacin, levofloxacin, gentamicin, amikacin, kanamycin and the like, can be used as an anti-infective medicament together with the antibiotics, kills the bacteria under the condition of low-concentration antibiotics, achieves a better anti-infective effect, and reduces the generation of drug resistance of the bacteria.
Drawings
FIG. 1 is a statistical chart of the results of adenosine and adenosine monophosphate enhanced bacterial susceptibility to cefoperazone sulbactam antibiotic.
FIG. 2 is a statistical chart of the results of improving the sensitivity of clinical Klebsiella by adenosine or adenosine monophosphate and cefoperazone sulbactam at different concentrations.
Figure 3 is a statistical plot of the results of adenosine and adenosine monophosphate enhanced sensitivity of various bacteria to cefoperazone sulbactam.
FIG. 4 is a data statistical plot of the results of adenosine and adenosine monophosphate enhanced sensitivity of clinical Klebsiella multidrug resistance bacteria to various antibiotics.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 bacterial sample preparation
Selecting bacterial single colonies, inoculating the bacterial single colonies in 5mL LB culture medium, and culturing at 37 ℃ (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Bacillus faecium, Streptococcus iniae, Acinetobacter baumannii and Streptococcus pyogenes) or 30 ℃ (Aeromonas hydrophila, Edwardsiella tarda, Vibrio alginolyticus and Vibrio parahaemolyticus) at 200rpm for 16 hours; transferring the bacterial liquid into a fresh LB culture medium according to the ratio of 1:100, and carrying out inoculation at 37 ℃ or 3 DEG CCulturing at 0 deg.C and 200rpm to OD6001.0, collecting the thallus by centrifuging at 8000rpm for 5min, removing supernatant, washing thallus with 0.85% physiological saline equal in volume for 3 times, and suspending in M9 medium (containing 10mM lactose and 2mM MgSO)4、0.1mM CaCl2) And adjusting the bacterial liquid concentration to OD with M9 culture medium600Is 0.2, and is subpackaged into 5mL test tubes for later use.
Example 2 determination of Effect of adenosine and adenosine monophosphate on improving sensitivity of clinical Klebsiella multidrug resistance bacteria to cefoperazone sulbactam antibiotics
A sample of 4 bacteria including clinical Klebsiella multidrug-resistant bacteria 2 (Kpn4 and Kpn 9) and Escherichia coli 2 (model Escherichia coli 1, i.e., K12, and clinical multidrug-resistant Escherichia coli 1, i.e., EC-Y17) was prepared according to example 1. Dividing each strain of bacteria into 5 groups, namely a control group of M9 culture medium, a cefoperazone-sulbactam (perazone-sulbactam) group, a cefoperazone-sulbactam + adenosine monophosphate group and a cefoperazone-sulbactam + adenine group; the concentration of cefoperazone sulbactam is 160ug/mL (clinical Klebsiella multidrug resistance bacteria) or 30ug/mL (Escherichia coli), adenosine monophosphate, adenosine and adenine are respectively 5mM, and each group has three biological repetitions. After adding corresponding drugs into each group, incubating the groups for 6-8 hours in a shaking table at 37 ℃ and 200rpm, then taking 100 mu L, respectively taking 10 mu L to count the spot plates by adopting a serial dilution method, and calculating the CFU/mL (colony forming unit/mL) of bacteria; the data of bacterial colony number between 20 and 200 can be used for statistical analysis; the survival rate of bacteria (percent survival) is the number of bacteria after 6-8 hours of sample treatment/the number of bacteria in the control sample x 100%.
Referring to fig. 1, it can be seen that, for the clinical klebsiella multiplex resistance strain No. 4, i.e., Kpn4, the survival rate of bacteria only added with antibiotics is 85.71%; the survival rate of bacteria is 0.001% by adding adenosine on the basis of antibiotics, and the sensitivity of the adenosine to cefoperazone sulbactam can be improved by about 8.2 multiplied by 104Doubling; the survival rate of bacteria is 0.0014% by adding adenosine monophosphate based on antibiotics, and the sensitivity of the adenosine monophosphate to cefoperazone sulbactam can be improved by about 6.1 × 104And (4) doubling.
For clinical klebsideThe survival rate of the bacteria only added with antibiotics is 85.53 percent, namely Kpn 9 which is the strain No. 9 of the drug-resistant bacteria; the survival rate of bacteria is 0.0009% by adding adenosine on the basis of antibiotics, and the sensitivity of the adenosine to cefoperazone sulbactam can be improved by about 9.3 multiplied by 104Doubling; the survival rate of bacteria is 0.0014% by adding adenosine monophosphate based on antibiotics, and the sensitivity of the adenosine monophosphate to cefoperazone sulbactam can be improved by about 5.7 multiplied by 104And (4) doubling.
For the clinical multi-drug resistant Escherichia coli No. 17 strain EC-Y17, the survival rate of bacteria only added with antibiotics is 81.72%; adenosine is added on the basis of antibiotics, the survival rate of bacteria is 0.33 percent, and the sensitivity of the adenosine to cefoperazone sulbactam can be improved by about 244.5 times; the survival rate of bacteria is 0.49% by adding adenosine monophosphate based on antibiotics, and the sensitivity of the adenosine monophosphate to cefoperazone sulbactam can be improved by about 164 times.
For escherichia coli K12, antibiotic-only bacterial survival rate 69.73 was; adenosine is added on the basis of antibiotics, the survival rate of bacteria is 3.5 percent, and the sensitivity of the adenosine to cefoperazone sulbactam can be improved by about 19.9 times; the survival rate of bacteria is 4.7% by adding adenosine monophosphate based on antibiotics, and the sensitivity of the adenosine monophosphate to cefoperazone sulbactam can be improved by about 14.8 times.
In addition, no sensitivity-improving effect was observed in any of the strains for adenine.
From the above results, adenosine and adenosine monophosphate can improve the sensitivity of clinical klebsiella multidrug resistance bacteria and escherichia coli to cefoperazone sulbactam.
Example 3 adenosine and adenosine monophosphate can improve the clinical Craber multiple drug resistant bacteria to cefoperazone sulbactam sensitivity has antibiotic concentration dependence
In order to research the optimal sterilization concentration ratio between the combined use of the cefoperazone sulbactam and the adenosine, the combined use of the cefoperazone sulbactam and the adenosine monophosphate and the sterilization efficiency, the prepared clinical Klebsiella multidrug resistance strain No. 4, namely Kpn4, is added with the cefoperazone sulbactam with different concentrations (from 20-320 micrograms/ml) and the adenosine with different concentrations (from 0.25-16 mM) or the adenosine monophosphate with different concentrations (from 0.25-16 mM) for combination; three biological replicates per combination; the control group was M9 medium. After incubation for 6 hours at 37 ℃ in a shaker at 200rpm, 100. mu.L of the resulting suspension was serially diluted and 10. mu.L of the suspension was counted on a spot plate to calculate the bacterial CFU/mL (colony forming unit/mL). Data from 20-200 bacterial colonies can be used for statistical analysis. The survival rate is expressed as the number of bacteria treated by adding different concentrations of cefoperazone sulbactam and/or adenosine (adenosine monophosphate)/the number of bacteria in the control sample multiplied by 100%.
The results are shown in fig. 2, and it can be seen from the figure that the survival rate of the bacteria is 95.57% -78.76% (20-320 micrograms/ml) after only adding cefoperazone sulbactam, and the survival rate of the bacteria is significantly reduced under the other adenosine concentrations except the adenosine concentration of 0.25mM after adding cefoperazone sulbactam and simultaneously adding adenosine. The concrete conditions are as follows:
when 0.25mM adenosine is added, the survival rate of bacteria is reduced to 16.81% from 89.38% along with the increase of cefoperazone sulbactam from 20 microgram/ml to 320 microgram/ml, and the sterilization efficiency is increased by 1.2-5.9 times; when 0.5mM adenosine is added, the survival rate of the bacteria is reduced from 67.86% to 0.13%, and the sterilization efficiency is increased by 1.4-605 times; when 1mM adenosine is added, the survival rate of the bacteria is reduced from 5.48% to 0.0713%, and the sterilization efficiency is increased by 17.4-1025 times; when 2mM adenosine is added, the survival rate of bacteria is reduced from 1.59% to 0.06%, and the sterilization efficiency is increased by 60-1181 times; when 4mM adenosine is added, the survival rate of the bacteria is reduced from 0.44% to 0.013%, and the sterilization efficiency is increased by 215 times and 6984 times; when 8mM adenosine is added, the survival rate of the bacteria is reduced from 0.74% to 0.0073%, and the sterilization efficiency is increased by 128-fold 115828 times; when 16mM adenosine is added, the survival rate of the bacteria is reduced from 0.19% to 0.001%, and the sterilization efficiency is increased by 496-78501 times.
When 0.25mM adenosine monophosphate is added, the survival rate of bacteria is reduced to 17.69% from 69.02% with the increase of cefoperazone sulbactam from 40 to 320 micrograms/ml except for 20 micrograms/ml of cefoperazone sulbactam, and the sterilization efficiency is increased by 1.6-7.4 times; when 0.5mM adenosine monophosphate is added, the survival rate of bacteria is reduced from 74.52% to 0.128% and the sterilization efficiency is increased by 1.3-590 times as the cefoperazone sulbactam is increased from 20 to 320 micrograms/ml; when 1mM adenosine monophosphate is added, the survival rate of bacteria is reduced from 3.71% to 0.075%, and the sterilization efficiency is increased by 25.7-1041 times; when 2mM adenosine monophosphate is added, the survival rate of bacteria is reduced from 1.25% to 0.062%, and the sterilization efficiency is increased by 76.8-1263 times; when 4mM adenosine monophosphate is added, the survival rate of bacteria is reduced from 0.82% to 0.02%, and the sterilization efficiency is increased by 114.8-3835.9 times; when 8mM adenosine monophosphate is added, the survival rate of bacteria is reduced from 0.66% to 0.0072%, and the sterilization efficiency is increased by 144-100978 times; when 16mM adenosine monophosphate is added, the survival rate of bacteria is reduced from 0.26% to 0.0013%, and the sterilization efficiency is increased by 363-59072 times.
These results indicate that adenosine and adenosine monophosphate increase the sensitivity of clinical klebsiella to cefoperazone sulbactam with adenosine or adenosine monophosphate concentration dependence and cefoperazone sulbactam concentration dependence.
Example 4 adenosine and adenosine monophosphate increase sensitivity of various bacteria to cefoperazone sulbactam
In order to study whether sub-adenosine and adenosine monophosphate are effective on various bacteria, the study on the improvement of sensitivity of various bacteria to cefoperazone sulbactam by adenosine and adenosine monophosphate is carried out. The bacterial species include clinical escherichia coli e.coli Y17, aeromonas hydrophila a a.hydrophila, vibrio (vibrio alginolyticus v.algolyicus, vibrio parahaemolyticus v.parahaemolyticus), streptococcus pyogenes s.pyogenenes, pseudomonas aeruginosa p.aeruginosa, coccidium faecium e.faecium, streptococcus iniae s.iniae, and acinetobacter baumannii a.baumannii specific bacteria and the antibiotic cefoperazone sulbactam dose used are shown in table 1.
TABLE 1 bacteria and dosages of cefoperazone sulbactam used therewith
Each bacterial sample was prepared according to example 1, individually, and dispensed into 5mL tubes, and different dosages of cefoperazone sulbactam were used for each bacterium according to Table 1, with or without 5mM adenosine or adenosine monophosphate for 6 hours, followed by viable cell counting and calculation of the survival rate, which is the number of bacteria after adenosine and/or adenosine monophosphate and/or antibiotic treatment/the number of bacteria in the control group x 100%.
Referring to FIG. 3, it can be seen that the sensitivity of these bacteria to cefoperazone sulbactam is generally improved by the addition of adenosine or adenosine monophosphate, as follows:
after adenosine is added exogenously, escherichia coli (e.coli Y17) is increased by 287.18 times, aeromonas hydrophila (a.hydrophila) is increased by 116.28 times, vibrio (vibrio alginolyticus) is increased by 8.65 times, vibrio parahaemolyticus (v.parahaemolyticus) is increased by 7 times, streptococcus pyogenes (s.pyogenenes) is increased by 3.37 times, pseudomonas aeruginosa (p.aeruginosa) is increased by 2.59 times, coccidium faecium is increased by 2.5 times, streptococcus iniae is increased by 1.62 times, and acinetobacter baumannii (a.baumannii) is increased by 1.39 times.
After adenosine monophosphate is added exogenously, escherichia coli (e.coli Y17) is increased by 288.66 times, aeromonas hydrophila (a.hydrophila) is increased by 125 times, vibrio (vibrio alginolyticus) is increased by 8.89 times, vibrio parahaemolyticus (v.parahaemolyticus) is increased by 6.3 times, streptococcus pyogenes (s.pyogenes) is increased by 3.3 times, pseudomonas aeruginosa (p.aeruginosa) is increased by 2.44 times, coccidium faecium is increased by 2 times, streptococcus iniae is increased by 1.48 times, and acinetobacter baumannii (a.baumannii) is increased by 1.45 times.
Example 5 adenosine and adenosine monophosphate increase the sensitivity of clinical klebsiella multidrug resistance bacteria to various antibiotics
To investigate whether clinical klebside multi-drug resistant bacteria were effective against antibiotics other than cefoperazone sulbactam after addition of adenosine or adenosine monophosphate, strain No. 4 of clinical klebside multi-drug resistant bacteria, i.e., Kpn4, was prepared according to example 1, 5mM adenosine or adenosine monophosphate and antibiotics (antibiotics were ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampane, moxifloxacin, levofloxacin, gentamicin, amikacin, kanamycin, respectively) were added, and the dosages of each antibiotic were as shown in table 2.
TABLE 2 antibiotics and dosages thereof
Counting the number of live bacteria after 6 hours of action, and calculating the survival rate. As can be seen in FIG. 4, adenosine or adenosine monophosphate increases the susceptibility of the starter bacteria to various antibiotics. The specific situation is as follows:
for adenosine: ceftazidime is improved by 7.3 ten thousand times, ceftriaxone sodium is improved by 1.1 ten thousand times, cefoperazone is improved by 7.3 times, meropenem is improved by 542 times, imipenem is improved by 1.2 ten thousand times, ciprofloxacin is improved by 244 times, ampinan is improved by 4184 times, moxifloxacin is improved by 512 times, levofloxacin is improved by 9.1 times, gentamicin is improved by 18.6 times, amikacin is improved by 298 times, and kanamycin is improved by 4.9 times.
For adenosine monophosphate: ceftazidime is improved by 8 ten thousand times, ceftriaxone sodium is improved by 1 thousand times, cefoperazone is improved by 6 times, meropenem is improved by 550 times, imipenem is improved by 1 thousand times, ciprofloxacin is improved by 4581 times, ampinan is improved by 379 times, moxifloxacin is improved by 408 times, levofloxacin is improved by 7.2 times, gentamicin is improved by 22 times, amikacin is improved by 605 times, and kanamycin is improved by 232 times.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (10)
1. Use of adenosine or adenosine monophosphate in the preparation of anti-infective medicament.
2. The use according to claim 1, wherein adenosine or adenosine monophosphate increases the sensitivity of bacteria to antibiotics in anti-infective medicaments.
3. The use according to claim 2, wherein the bacteria are one or more of Klebsiella pneumoniae K.pneumoniae, Escherichia coli E.coli, Aeromonas hydrophila A.hydrophila, Vibrio alginolyticus V.alginolyticus, Vibrio parahaemolyticus V.parahaemolyticus, Streptococcus pyogenes S.pyogenenes, Pseudomonas aeruginosa P.aeruginosa, Bacillus faecium E.faecium, Streptococcus iniae S.iniae, Acinetobacter baumannii.
4. The use according to claim 2, wherein the antibiotic is one or more of a β -lactam antibiotic, a quinolone antibiotic, and an aminoglycoside antibiotic.
5. The use according to claim 4, wherein the antibiotic is one or more of cefoperazone sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampham, moxifloxacin, levofloxacin, gentamicin, amikacin, kanamycin.
6. An anti-infective composition comprising adenosine and/or adenosine monophosphate and an antibiotic.
7. The anti-infective composition of claim 6, wherein the antibiotic is one or more of a β -lactam antibiotic, a quinolone antibiotic, and an aminoglycoside antibiotic.
8. The anti-infective composition of claim 6, wherein the bacteria is one or more of Klebsiella pneumoniae K.pneumoniae, Escherichia coli E.coli, Aeromonas hydrophila A.hydrophila, Vibrio alginolyticus V.alginolyticus, Vibrio parahaemolyticus V.parahaemolyticus, Streptococcus pyogenes S.pyogenenes, Pseudomonas aeruginosa P.aeruginosa, Bacillus faecium E.faecium, Streptococcus iniae S.iniae, Acinetobacter baumannii.
9. The anti-infective composition of any one of claims 6 to 8, wherein the mass ratio of adenosine to the antibiotic is (0.2 to 213.6):1, and the mass ratio of adenosine monophosphate to the antibiotic is (0.375 to 399): 1.
10. An anti-infective agent comprising the anti-infective composition of any one of claims 6 to 9.
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| WO1996020010A1 (en) * | 1994-12-27 | 1996-07-04 | Oridigm Corporation | Combination for reducing antimicrobial resistance using a methylation inhibitor in combination with an antibiotic |
| KR20180009167A (en) * | 2016-07-18 | 2018-01-26 | 한국해양과학기술원 | Use of purine ribonucleoside and its derivative as beta-lactamase inhibitor |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996020010A1 (en) * | 1994-12-27 | 1996-07-04 | Oridigm Corporation | Combination for reducing antimicrobial resistance using a methylation inhibitor in combination with an antibiotic |
| KR20180009167A (en) * | 2016-07-18 | 2018-01-26 | 한국해양과학기술원 | Use of purine ribonucleoside and its derivative as beta-lactamase inhibitor |
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| W.LEE HAND: "Antibiotic Inhibition of the Respiratory Burst Response in Human Polymorphonuclear Leukocytes", 《ANTIMICROBIAL AGENTS AND CHEMOTHERAPY》 * |
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