WO2023115757A1 - 腺苷或腺苷一磷酸在制备抗感染药物中的应用 - Google Patents

腺苷或腺苷一磷酸在制备抗感染药物中的应用 Download PDF

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WO2023115757A1
WO2023115757A1 PCT/CN2022/086177 CN2022086177W WO2023115757A1 WO 2023115757 A1 WO2023115757 A1 WO 2023115757A1 CN 2022086177 W CN2022086177 W CN 2022086177W WO 2023115757 A1 WO2023115757 A1 WO 2023115757A1
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adenosine
antibiotics
bacteria
cefoperazone
adenosine monophosphate
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李惠
彭博
彭宣宪
项娟娟
陶建军
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Sun Yat Sen University
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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
    • 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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  • the invention belongs to the technical field of biomedicine. More specifically, it relates to the application of adenosine or adenosine monophosphate in the preparation of anti-infective drugs.
  • Antibiotics can effectively inhibit or kill pathogenic bacteria and play a key role in the control of bacterial infections.
  • many pathogenic bacteria have begun to develop resistance to antibiotics, making the infections caused by them difficult to control and seriously endangering people's health.
  • the World Health Organization clearly pointed out in the 2007 "World Health Report" that bacterial drug resistance is a major public health problem that threatens human health.
  • Chinese patent applications CN104606219A and CN112569251A respectively disclose that the small molecule metabolites inosine and inosine nucleotides have the effect of improving the elimination of pathogenic bacteria by antibiotics, and the combination of inosine or inosine nucleotides with antibiotics can significantly improve the effectiveness of antibiotics Bactericidal effect.
  • inosine and inosine nucleotides are both metabolites of the purine pathway, but not the metabolites of the purine pathway have the effect of increasing the sensitivity of pathogenic bacteria to antibiotics, as hypoxanthine belonging to this pathway does not increase The role of pathogenic bacteria on antibiotic sensitivity; and, inosine and inosine nucleotides to promote antibiotic bactericidal action are specific to antibiotics and bacterial species, that is, their effects are also different in different types of antibiotics and different types of bacteria.
  • the technical problem to be solved by the present invention is to overcome the defects and insufficiencies of existing small molecules that can improve the sensitivity of pathogenic bacteria to antibiotics, and their effects are specific to antibiotics and pathogenic bacteria, and cannot meet the needs of all antibiotics and pathogenic bacteria.
  • the object of the present invention is to provide an application of adenosine or adenosine monophosphate in the preparation of anti-infective drugs.
  • Another object of the present invention is to provide an anti-infective composition.
  • Another object of the present invention is to provide an anti-infective drug.
  • adenosine monophosphate is an organic compound, which is an ester of phosphoric acid and nucleoside adenosine, and is composed of phosphate functional group, pentose ribose sugar and base adenine. It can be used as an intermediate in the production of nucleic acid drugs, health food and biochemical reagents, and used in the manufacture of adenosine triphosphate.
  • Adenosine monophosphate is dephosphated under the action of nucleotidase to form adenosine, and adenosine can be decomposed into phosphoribose and adenine under the action of nucleoside phosphorylase.
  • adenosine or adenosine monophosphate can significantly improve clinical Escherichia coli, Aeromonas hydrophila, Vibrio alginolyticus, Vibrio parahaemolyticus, Streptococcus pyogenes, Pseudomonas aeruginosa, coccus faecalis, streptococcus iniae, Acinetobacter baumannii and Klebsiella pneumonia Ampenem, ciprofloxacin, ampenem, moxifloxacin, levofloxacin, gentamicin, amikacin, kanamycin and other antibiotics are sensitive, and can be used in combination with antibiotics as anti-infective drugs. Kill bacteria under the condition of antibiotics, achieve better anti-infection effect, and reduce the generation of bacterial resistance at the same time.
  • adenosine or adenosine monophosphate improves the sensitivity of bacteria to antibiotics in anti-infective drugs.
  • the bacteria are Klebsiella pneumoniae K.pneumoniae, Escherichia coli E.coli, Aeromonas hydrophila A.hydrophila, Vibrio alginolyticus V.alginolyticus, Vibrio parahaemolyticus V.parahaemolyticus , Streptococcus pyogenes S.pyogenes, Pseudomonas aeruginosa P.aeruginosa, E.faecium faecium, Streptococcus iniae S.iniae, Acinetobacter baumannii A.baumannii one or more.
  • the above-mentioned bacteria are common human and farmed animal pathogenic bacteria, among which Streptococcus pyogenes and Coccus faecium are Gram-positive bacteria, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae , Aeromonas hydrophila, Edwardsiella tarda, Vibrio parahaemolyticus and Vibrio alginolyticus are Gram-negative bacteria.
  • bacteria are common pathogenic bacteria, and their drug-resistant strains are common.
  • Escherichia coli and Pseudomonas aeruginosa are model bacteria for studying bacterial drug resistance, so these bacteria are comparative examples of drug-resistant and non-drug-resistant bacteria. Good representative bacteria.
  • the enumerated bacteria include Escherichia coli, Aeromonas hydrophila, Vibrio including Vibrio alginolyticus and Vibrio parahaemolyticus, Streptococcus pyogenes, Pseudomonas aeruginosa bacterium, Streptococcus iniae, Acinetobacter baumannii, and Klebsiella pneumoniae.
  • Escherichia coli Aeromonas hydrophila
  • Vibrio including Vibrio alginolyticus and Vibrio parahaemolyticus
  • Streptococcus pyogenes Pseudomonas aeruginosa bacterium
  • Streptococcus iniae Streptococcus iniae
  • Acinetobacter baumannii and Klebsiella pneumoniae.
  • Klebsiella pneumoniae Especially most verification tests of the present invention take clinical Klebsiella pneumoniae as the research object
  • Escherichia coli and Pseudomonas aeruginosa are model bacteria for studying drug resistance mechanisms; Positive bacteria, Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumoniae, Aeromonas hydrophila, Edwardsiella tarda, Vibrio parahaemolyticus and Vibrio alginolyticus were Gram Negative bacteria. And all human and farmed animal pathogenic bacteria can be classified according to this staining, so the above-mentioned bacteria are relatively representative. 3. bacteria can have drug-resistant and non-drug-resistant states, i.e.
  • the antibiotic is one or more of ⁇ -lactam antibiotics, quinolone antibiotics, and aminoglycoside antibiotics.
  • the antibiotic is cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampenem, moxifloxacin, levofloxacin, gentamicin One or more of Amycin, Amikacin, and Kanamycin.
  • cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, and cefoperazone are cephalosporin antibiotics
  • meropenem and imipenem are carbapenem antibiotics
  • ampenem is a monocyclic ⁇ -lactam antibiotic Antibiotics (all three are ⁇ -lactam antibiotics)
  • baloxacin, ciprofloxacin, and levofloxacin are quinolone antibiotics
  • gentamicin, amikacin, and kanamycin are aminoglycoside antibiotics.
  • antibiotics should not be used as a limitation to the protection scope of the present invention. This is because although there are hundreds of varieties of antibiotics, they can be classified according to their chemical structure and antibacterial mechanism. Those with similar chemical structures have the same antibacterial mechanism, so it is not necessary to verify them one by one. At present, ⁇ -lactam antibiotics, quinolone antibiotics and aminoglycoside antibiotics are commonly used clinical antibiotics.
  • cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, and cefoperazone are cephalosporin antibiotics
  • meropenem and imipenem are carbapenem antibiotics
  • ampenem is a monocyclic ⁇ -lactam antibiotic Antibiotics (all three are ⁇ -lactam antibiotics)
  • baloxacin, ciprofloxacin, and levofloxacin are quinolone antibiotics
  • gentamicin, amikacin, and kanamycin are aminoglycoside antibiotics. Therefore, it has a good representation of antibiotics. According to the concept of the present invention, those skilled in the art can easily infer that other clinical antibiotics are also applicable to the method of the present invention.
  • the present invention also provides an anti-infective composition, which contains adenosine and/or adenosine monophosphate and antibiotics.
  • the antibiotic is one or more of ⁇ -lactam antibiotics, quinolone antibiotics, and aminoglycoside antibiotics.
  • the antibiotic is cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampenem, moxifloxacin, levofloxacin, gentamicin One or more of Amycin, Amikacin, and Kanamycin.
  • the bacteria are Klebsiella pneumoniae K.pneumoniae, Escherichia coli E.coli, Aeromonas hydrophila A.hydrophila, Vibrio alginolyticus V.alginolyticus, Vibrio parahaemolyticus V.parahaemolyticus , Streptococcus pyogenes S.pyogenes, Pseudomonas aeruginosa P.aeruginosa, E.faecium faecium, Streptococcus iniae S.iniae, Acinetobacter baumannii A.baumannii one or more.
  • 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.
  • the present invention also provides an anti-infective drug, characterized in that the anti-infective drug contains the anti-infective composition.
  • anti-infective drugs are oral preparations, injection preparations or external preparations.
  • adenosine or adenosine monophosphate can significantly improve clinical Escherichia coli, Aeromonas hydrophila, Vibrio including Vibrio alginolyticus and Vibrio parahaemolyticus, Streptococcus pyogenes , Pseudomonas aeruginosa, Coccus faecium, Streptococcus iniae, Acinetobacter baumannii and Klebsiella pneumoniae and other bacteria to cefoperazone sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem,
  • antibiotics such as imipenem, ciprofloxacin, ampenem, moxifloxacin, levofloxacin, gentamicin, amikacin and kanamycin can be used in combination with antibiotics as anti-infective drugs. Kill bacteria under the condition of high
  • Figure 1 is a statistical chart of the results of adenosine and adenosine monophosphate increasing the bacterial sensitivity to cefoperazone-sulbactam antibiotics.
  • Figure 2 is a statistical chart of the results of adenosine or adenosine monophosphate and cefoperazone-sulbactam in different concentration ratios to improve clinical Klebsiella susceptibility.
  • Figure 3 is a statistical chart of the results of adenosine and adenosine monophosphate improving the sensitivity of various bacteria to cefoperazone-sulbactam.
  • Figure 4 is a statistical chart of the results of adenosine and adenosine monophosphate improving the susceptibility of clinical Klebsiella multidrug-resistant bacteria to multiple antibiotics.
  • the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.
  • Example 2 Determination of the effect of adenosine and adenosine monophosphate on improving clinical Klebsiella multidrug-resistant bacteria to cefoperazone-sulbactam antibiotic susceptibility
  • Example 2 Prepare 4 strains of bacterial samples according to Example 1, and the bacteria include 2 strains of clinical Klebsiella multidrug-resistant bacteria (No. Kpn4 and No. Kpn 9), 2 strains of Escherichia coli (1 strain of model Escherichia coli is K12, clinical multidrug-resistant Escherichia coli One strain is EC-Y17).
  • Each bacterial strain was divided into 5 groups, which were the control group of M9 medium, cefoperazone-sulbactam (perazone-sulbactam) group, cefoperazone-sulbactam+adenosine group, cefoperazone-sulbactam+adenosine group, and cefoperazone-sulbactam+ Adenosine monophosphate group, cefoperazone-sulbactam+adenine group; the concentration of cefoperazone-sulbactam was 160ug/mL (clinical Klebsiella multidrug-resistant bacteria) or 30ug/mL (Escherichia coli), adenosine-sulbactam Phosphoric acid, adenosine, and adenine were respectively 5 mM, and each group had three biological replicates.
  • cefoperazone-sulbactam perazone-sulbactam
  • cefoperazone-sulbactam+adenosine group
  • the bacterial survival rate was 85.53% only with antibiotics; the bacterial survival rate was 0.0009% when adenosine was added on the basis of antibiotics, and adenosine can improve its resistance to cefoperazone.
  • the sensitivity of sulbactam is about 9.3 ⁇ 10 4 times; adding adenosine monophosphate on the basis of antibiotics, the bacterial survival rate is 0.0014%, and adenosine monophosphate can increase its sensitivity to cefoperazone sulbactam by about 5.7 ⁇ 10 4 times.
  • the bacterial survival rate was 81.72% only with antibiotics; the bacterial survival rate was 0.33% when adenosine was added on the basis of antibiotics.
  • the sensitivity of bactam is about 244.5 times; adding adenosine monophosphate on the basis of antibiotics, the bacterial survival rate is 0.49%, and adenosine monophosphate can increase its sensitivity to cefoperazone sulbactam by about 164 times.
  • the bacterial survival rate of antibiotics alone was 69.73%; adding adenosine on the basis of antibiotics, the bacterial survival rate was 3.5%, and adenosine can improve its sensitivity to cefoperazone sulbactam by about 19.9 times; On the basis of adding adenosine monophosphate, the bacterial survival rate is 4.7%, and adenosine monophosphate can increase its sensitivity to cefoperazone sulbactam by about 14.8 times.
  • adenosine and adenosine monophosphate can improve the sensitivity of clinical Klebsiella multidrug-resistant bacteria and Escherichia coli to cefoperazone-sulbactam.
  • Example 3 Adenosine and adenosine monophosphate can improve the sensitivity of clinical Klebsiella multidrug-resistant bacteria to cefoperazone-sulbactam in a concentration-dependent manner
  • the prepared clinical Klebsiella multi-resistant Drug No. 4 strain is Kpn 4, add different concentrations (from 20 to 320 ⁇ g/ml) of cefoperazone sulbactam and different concentrations (from 0.25 to 16 mM) of adenosine, or different concentrations of adenosine monophosphate (from 0.25 to 16mM) were combined; each combination had three biological repetitions; the control group was M9 medium.
  • the survival rate formula is the number of bacteria treated with different concentrations of cefoperazone-sulbactam and/or adenosine (adenosine monophosphate)/the number of bacteria in the control sample ⁇ 100%.
  • the survival rate of bacteria is 95.57% ⁇ 78.76% (20 ⁇ 320 micrograms/ml cefoperazone sulbactam) after only adding cefoperazone sulbactam, and after adding cefoperazone sulbactam After the addition of adenosine to Bactam at the same time, the survival rate of bacteria decreased significantly except for the adenosine concentration of 0.25mM.
  • the specific situation is:
  • Embodiment 4 adenosine and adenosine monophosphate improve the sensitivity of various bacteria to cefoperazone sulbactam
  • adenosine and adenosine monophosphate increase the sensitivity of various bacteria to cefoperazone-sulbactam.
  • Bacterial species include clinical Escherichia coli E.coli Y17, Aeromonas hydrophila A.hydrophila, Vibrio (V.alginolyticus, V.parahaemolyticus), Streptococcus pyogenes S.
  • Each bacterial sample was prepared respectively according to Example 1, distributed in 5mL test tubes, using different cefoperazone-sulbactam dosages according to each bacterial species shown in Table 1, and then adding or not adding 5mM adenosine or adenosine monophosphate After acting for 6 hours, count the viable bacteria and calculate the survival rate.
  • the formula is the number of bacteria treated with adenosine and/or adenosine monophosphate and/or antibiotics/the number of bacteria in the control group ⁇ 100%.
  • Escherichia coli Escherichia coli
  • Aeromonas hydrophila Aeromonas hydrophila
  • Vibrio V.alginolyticus
  • Vibrio parahaemolyticus V.parahaemolyticus
  • Streptococcus pyogenes S.pyogenes
  • Pseudomonas aeruginosa P.aeruginosa
  • Bacillus faecium increased increased by 2.5 times
  • Streptococcus iniae increased by 1.62 times
  • Acinetobacter baumannii A.baumannii
  • Escherichia coli Escherichia coli (E.coli Y17) increased by 288.66 times, Aeromonas hydrophila (A.hydrophila) increased by 125 times, Vibrio (V.alginolyticus ) increased by 8.89 times, Vibrio parahaemolyticus (V.parahaemolyticus) increased by 6.3 times, Streptococcus pyogenes (S.pyogenes) increased by 3.3 times, Pseudomonas aeruginosa (P.aeruginosa) increased by 2.44 times, fecal ball Bacillus increased by 2 times, Streptococcus iniae increased by 1.48 times, and Acinetobacter baumannii (A.baumannii) increased by 1.45 times.
  • Embodiment 5 adenosine and adenosine monophosphate improve clinical Klebsiella multidrug-resistant bacteria to the sensitivity of multiple antibiotics
  • Kpn 4 add 5mM adenosine or adenosine monophosphate and antibiotics (the antibiotics are ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampenem, moxifloxacin, Levofloxacin, gentamicin, amikacin, kanamycin), the dosage of each antibiotic is shown in Table 2.
  • ceftazidime increased 73,000-fold
  • ceftriaxone sodium increased 11,000-fold
  • cefoperazone increased 7.3-fold
  • meropenem increased 542-fold
  • imipenem increased 12,000-fold
  • ciprofloxacin Increased by 244 times
  • ampenem increased by 4184 times
  • moxifloxacin increased by 512 times
  • levofloxacin increased by 9.1 times
  • gentamicin increased by 18.6 times
  • amikacin increased by 298 times
  • kanamycin increased 4.9 times.
  • ceftazidime increased 80,000-fold
  • ceftriaxone sodium increased 10,000-fold
  • cefoperazone increased 6-fold
  • meropenem increased 550-fold
  • imipenem increased 10,000-fold
  • ciproterone Floxacin increased by 4581 times
  • ampenem increased by 379 times
  • moxifloxacin increased by 408 times
  • levofloxacin increased by 7.2 times
  • gentamicin increased by 22 times
  • amikacin increased by 605 times

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Abstract

腺苷或腺苷一磷酸在制备抗感染药物中的应用。腺苷或腺苷一磷酸可以显著提高临床大肠埃希氏菌、嗜水气单胞菌、包括溶藻弧菌和副溶血弧菌在内的弧菌、化脓性链球菌、铜绿假单胞菌、屎球杆菌、海豚链球菌、鲍曼不动杆菌和肺炎克雷伯菌等细菌对头孢哌酮舒巴坦、头孢他啶、头孢曲松钠、头孢哌酮、美罗培南、亚胺培南、环丙沙星、安培南、莫西沙星、左氧氟沙星、庆大霉素、阿米卡星和卡那霉素等抗生素的敏感性。腺苷或腺苷一磷酸可以与抗生素联用作为抗感染药物，在低浓度抗生素条件下杀灭细菌，同时减少细菌耐药性的产生。

Description

腺苷或腺苷一磷酸在制备抗感染药物中的应用 技术领域
本发明属于生物医药技术领域。更具体地，涉及腺苷或腺苷一磷酸在制备抗感染药物中的应用。
背景技术
抗生素能够有效抑制或杀灭病原菌，在控制细菌性感染疾病中起到关键作用。然而，随着抗生素的广泛应用，许多病原菌开始对抗生素产生耐药性，导致其引起的感染难以控制，严重危害人们的身体健康。世界卫生组织(WHO)在2007年《世界卫生报告》中明确指出，细菌耐药是威胁人类健康的重大公共卫生问题。
目前，为了减少耐药菌、治疗耐药菌引起的感染，除了减少、限制抗生素的使用外，提高耐药菌对抗生素的敏感性成为控制耐药菌的一种重要技术方案。该方法主要是在其他分子的协同作用下，使得原本对病原菌无效或低效的抗生素变得有效或高效，从而将细菌杀灭。如中国专利申请CN104606219A和CN112569251A分别公开了小分子代谢物肌苷和次黄嘌呤核苷酸具有提高抗生素清除病原菌的作用，将肌苷或次黄嘌呤核苷酸与抗生素联用可以显著提高抗生素的杀菌效果。研究发现，肌苷和次黄嘌呤核苷酸同为嘌呤通路的代谢物，但并不是嘌呤通路的代谢物就具有提高病原菌对抗生素敏感性的作用，如同属该通路的次黄嘌呤就没有提高病原菌对抗生素敏感性的作用；并且，肌苷和次黄嘌呤核苷酸促进抗生素杀菌作用都具有抗生素和细菌种类特异性，即其作用在不同类型抗生素和不同种类细菌中也有差异。
因此，迫切需要开发多几种可以提高病原菌对抗生素敏感性的小分子在制备抗感染药物中的应用，以适应各种不同种类的病原菌或抗生素。
发明内容
本发明要解决的技术问题是克服现有提高病原菌对抗生素敏感性小分子有限，且其作用对抗生素和病原菌均具有特异性，无法满足所有抗生素和病原菌需求的缺陷和不足，提供多几种可以提高病原菌对抗生素敏感性的小分子在制备抗感染药物中的应用。
本发明的目的是提供一种腺苷或腺苷一磷酸在制备抗感染药物中的应用。
本发明另一目的是提供一种抗感染组合物。
本发明另一目的是提供一种抗感染药物。
本发明上述目的通过以下技术方案实现：
小分子代谢物腺嘌呤(Adenine，A)及其衍生物腺苷(Adenosine，Ado)和腺苷一磷酸(Adenosine 3'-monophosphate，AMP)，是生物体内很重要的代谢物。其中，腺苷一磷酸是一种有机化合物，它是一种磷酸及核苷腺苷的酯，并由磷酸盐官能团、戊糖核酸糖及碱基腺嘌呤所组成。可作为生产核酸类药物中间体，保健食品及生化试剂，并用于制造腺苷三磷酸。腺苷一磷酸在核苷酸酶作用下脱去磷酸根形成腺苷，腺苷在核苷磷酸化酶作用下，可分解为磷酸核糖和腺嘌呤。
本发明通过大量的创造性劳动，研究发现，腺苷或腺苷一磷酸可以显著提高临床大肠埃希氏菌、嗜水气单胞菌、溶藻弧菌、副溶血弧菌、化脓性链球菌、铜绿假单胞菌、屎球杆菌、海豚链球菌、鲍曼不动杆菌和肺炎克雷伯菌等细菌对头孢哌酮舒巴坦、头孢他啶、头孢曲松钠、头孢哌酮、美罗培南、亚胺培南、环丙沙星、安培南、莫西沙星、左氧氟沙星、庆大霉素、阿米卡星、卡那霉素等抗生素的敏感性，可以与抗生素连用作为抗感染药物，在低浓度抗生素条件下杀灭细菌，达到较好的抗感染效果，同时减少细菌耐药性的产生。
因此，本申请要求保护腺苷或腺苷一磷酸在制备抗感染药物中的应用。
进一步地，所述腺苷或腺苷一磷酸在抗感染药物中提高细菌对抗生素的敏感性。
优选地，所述细菌为肺炎克雷伯菌K.pneumoniae、大肠埃希氏菌E.coli、嗜水气单胞菌A.hydrophila、溶藻弧菌V.alginolyticus、副溶血弧菌V.parahaemolyticus、化脓性链球菌S.pyogenes、铜绿假单胞菌P.aeruginosa、屎球杆菌E.faecium、海豚链球菌S.iniae、鲍曼不动杆菌A.baumannii中的一种或多种。上述细菌为常见人类和养殖动物致病菌，其中化脓性链球菌和屎球杆菌为革兰氏阳性菌，大肠埃希菌、铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌、嗜水气单胞菌、迟钝爱德华菌、副溶血弧菌和溶藻弧菌为革兰氏阴性菌。
需要说明的是，这些细菌为常见的病原菌，且常见其耐药菌株，同时大肠埃希菌和绿脓杆菌是研究细菌耐药的模式菌，故这些细菌为耐药和非耐药菌的较好代表菌。尽管在本发明的实施例中，所列举的细菌包括大肠埃希氏菌、嗜水气单 胞菌、包括溶藻弧菌和副溶血弧菌在内的弧菌、化脓性链球菌、铜绿假单胞菌、屎球杆菌、海豚链球菌、鲍曼不动杆菌和肺炎克雷伯菌。尤其是本发明多数验证试验是以临床肺炎克雷伯菌作为研究对象的。但是，这些细菌并不能作为对本发明保护范围的限制。这是因为：①大肠埃希菌和铜绿假单胞菌为研究耐药机制的模式菌；②上述细菌分别属于革兰氏阴性和阳性细菌，其中屎球杆菌和化脓性链球菌为革兰氏阳性菌，大肠埃希菌、铜绿假单胞菌、鲍曼不动杆菌、肺炎克雷伯菌、嗜水气单胞菌、迟钝爱德华菌、副溶血弧菌和溶藻弧菌为革兰氏阴性菌。而所有人类和养殖动物病原菌均可以按照该染色进行分类，故上述细菌具有较好的代表性。③细菌可以具有耐药和非耐药状态，即同一细菌的耐药和非耐药菌株，而本发明的临床克雷伯菌即为耐药状态，在添加腺苷或腺苷一磷酸后亦提高了对抗生素的敏感性。因此，根据上述原理从这些菌种可以推知到更多的菌种也适宜于本发明的理念。
更进一步地，所述抗生素为β-内酰胺类抗生素、喹诺酮类抗生素、氨基糖苷类抗生素中的一种或多种。
优选地，所述抗生素为头孢哌酮舒巴坦、头孢他啶、头孢曲松钠、头孢哌酮、美罗培南、亚胺培南、环丙沙星、安培南、莫西沙星、左氧氟沙星、庆大霉素、阿米卡星、卡那霉素中的一种或多种。其中，头孢哌酮舒巴坦、头孢他啶、头孢曲松钠、头孢哌酮为头孢菌类抗生素，美罗培南和亚胺培南为碳青霉烯类抗生素，安培南为单环β-内酰胺类抗生素(三者同为β-内酰胺类抗生素)；巴洛沙星、环丙沙星和左氧氟沙星为喹诺酮类抗生素；庆大霉素、阿米卡星和卡那霉素为氨基糖苷类抗生素。这些包括了目前临床使用的主要抗生素类型。
上述抗生素并不能作为对本发明保护范围的限制。这是因为虽然抗生素的品种数以百计，但可以根据其化学结构和抗菌机制分类，相似化学结构的具有相同的抗菌机制，因此不需要一一进行验证。目前，β-内酰胺类抗生素、喹诺酮类抗生素和氨基糖苷类抗生素是临床常用抗生素。其中，头孢哌酮舒巴坦、头孢他啶、头孢曲松钠、头孢哌酮为头孢菌类抗生素，美罗培南和亚胺培南为碳青霉烯类抗生素，安培南为单环β-内酰胺类抗生素(三者同为β-内酰胺类抗生素)；巴洛沙星、环丙沙星和左氧氟沙星为喹诺酮类抗生素；庆大霉素、阿米卡星和卡那霉素为氨基糖苷类抗生素。因此，具有很好的抗生素代表性。领域技术人员根据本发明的理念，可以容易地推知到，临床其余多种抗生素也同样能适用于本发明所述 的方法。
另外的，本发明还提供了一种抗感染组合物，所述组合物含有腺苷和/或腺苷一磷酸和抗生素。
进一步地，所述抗生素为β-内酰胺类抗生素、喹诺酮类抗生素、氨基糖苷类抗生素中的一种或多种。
优选地，所述抗生素为头孢哌酮舒巴坦、头孢他啶、头孢曲松钠、头孢哌酮、美罗培南、亚胺培南、环丙沙星、安培南、莫西沙星、左氧氟沙星、庆大霉素、阿米卡星、卡那霉素中的一种或多种。
优选地，所述细菌为肺炎克雷伯菌K.pneumoniae、大肠埃希氏菌E.coli、嗜水气单胞菌A.hydrophila、溶藻弧菌V.alginolyticus、副溶血弧菌V.parahaemolyticus、化脓性链球菌S.pyogenes、铜绿假单胞菌P.aeruginosa、屎球杆菌E.faecium、海豚链球菌S.iniae、鲍曼不动杆菌A.baumannii中的一种或多种。
更进一步地，所述腺苷和抗生素的质量比为(0.2～213.6):1，所述腺苷一磷酸和抗生素的质量比为(0.375～399):1。
另外的，本发明还提供了一种抗感染药物，其特征在于，所述抗感染药物含有所述抗感染组合物。
进一步地，所述抗感染药物为口服制剂、注射制剂或外用制剂。
本发明具有以下有益效果：
本发明经过实验证明，腺苷或腺苷一磷酸可以显著提高临床大肠埃希氏菌、嗜水气单胞菌、包括溶藻弧菌和副溶血弧菌在内的弧菌、化脓性链球菌、铜绿假单胞菌、屎球杆菌、海豚链球菌、鲍曼不动杆菌和肺炎克雷伯菌等细菌对头孢哌酮舒巴坦、头孢他啶、头孢曲松钠、头孢哌酮、美罗培南、亚胺培南、环丙沙星、安培南、莫西沙星、左氧氟沙星、庆大霉素、阿米卡星和卡那霉素等抗生素的敏感性，可以与抗生素连用作为抗感染药物，在低浓度抗生素条件下杀灭细菌，达到较好的抗感染效果，同时减少细菌耐药性的产生。
附图说明
图1为腺苷和腺苷一磷酸提高细菌对头孢哌酮舒巴坦抗生素敏感性的结果数据统计图。
图2为腺苷或腺苷一磷酸与头孢哌酮舒巴坦在不同浓度配比下提高临床克雷伯菌敏感性的结果数据统计图。
图3为腺苷和腺苷一磷酸提高多种细菌对头孢哌酮舒巴坦的敏感性的结果数据统计图。
图4为腺苷和腺苷一磷酸提高临床克雷伯多重耐药菌对多种抗生素的敏感性的结果数据统计图。
具体实施方式
以下结合说明书附图和具体实施例来进一步说明本发明，但实施例并不对本发明做任何形式的限定。除非特别说明，本发明采用的试剂、方法和设备为本技术领域常规试剂、方法和设备。
除非特别说明，以下实施例所用试剂和材料均为市购。
实施例1细菌样本制备
挑取细菌单菌落接种于5mL LB培养基中，37℃(大肠埃希菌、肺炎克雷伯菌、铜绿假单胞菌、屎球杆菌、海豚链球菌、鲍曼不动杆菌、化脓性链球菌)或30℃(嗜水气单胞菌、迟钝爱德华菌、溶藻弧菌、副溶血弧菌)200rpm培养16小时；按1:100转接菌液至新鲜LB培养基中，37℃或30℃200rpm培养到OD 600为1.0，取适量的菌液于8000rpm，5min离心收集菌体，除去上清并以等体积0.85％生理盐水洗涤菌体3次，悬浮于M9培养基(含10mM乳糖、2mM MgSO 4、0.1mM CaCl 2)，并用M9培养基调菌液浓度到OD 600为0.2，分装到5mL试管中备用。
实施例2腺苷和腺苷一磷酸提高临床克雷伯多重耐药菌对头孢哌酮舒巴坦抗生素敏感性效果测定
按照实施例1制备4株细菌样本，细菌包括临床克雷伯多重耐药菌2株(Kpn4号和Kpn 9号)，大肠杆菌2株(模式大肠杆菌1株即K12，临床多重耐药大肠杆菌1株即EC-Y17)。将每株细菌各分成5个组，分别为M9培养基的对照组、头孢哌酮舒巴坦(perazone-sulbactam)组、头孢哌酮舒巴坦+腺苷组、头孢哌酮舒巴坦+腺苷一磷酸组、头孢哌酮舒巴坦+腺嘌呤组；头孢哌酮舒巴坦浓度为160ug/mL(临床克雷伯多重耐药菌)或30ug/mL(大肠杆菌)，腺苷一磷酸、腺苷、腺嘌呤分别为5mM，每组各三个生物学重复。各组加入相应药物后37℃、200 rpm摇床中孵育6～8小时，然后取100μL采用系列稀释法，分别取10μL进行点板计数，计算细菌CFU/mL(菌落形成单位/毫升)；细菌菌落数在20-200的数据可用于统计分析；细菌存活率(percent survival)为样本处理6-8小时后的细菌数量/对照样本菌数量×100％。
结果参见图1，由图可见，对于临床克雷伯多重耐药菌4号菌株即Kpn 4，仅加抗生素细菌存活率为85.71％；在抗生素基础上添加腺苷，细菌存活率为0.001％，腺苷可提高其对头孢哌酮舒巴坦敏感性约8.2×10 4倍；在抗生素基础上添加腺苷一磷酸，细菌存活率为0.0014％，腺苷一磷酸可提高其对头孢哌酮舒巴坦敏感性约6.1×10 4倍。
对于临床克雷伯多重耐药菌9号菌株即Kpn 9，仅加抗生素细菌存活率为85.53％；在抗生素基础上添加腺苷，细菌存活率为0.0009％，腺苷可提高其对头孢哌酮舒巴坦敏感性约9.3×10 4倍；在抗生素基础上添加腺苷一磷酸，细菌存活率为0.0014％，腺苷一磷酸可提高其对头孢哌酮舒巴坦敏感性约5.7×10 4倍。
对于临床多重耐药大肠杆菌17号菌株即EC-Y17，仅加抗生素细菌存活率为81.72％；在抗生素基础上添加腺苷，细菌存活率为0.33％，腺苷可提高其对头孢哌酮舒巴坦敏感性约244.5倍；在抗生素基础上添加腺苷一磷酸，细菌存活率为0.49％，腺苷一磷酸可提高其对头孢哌酮舒巴坦敏感性约164倍。
对于大肠杆菌K12，仅加抗生素细菌存活率69.73为％；在抗生素基础上添加腺苷，细菌存活率为3.5％，腺苷可提高其对头孢哌酮舒巴坦敏感性约19.9倍；在抗生素基础上添加腺苷一磷酸，细菌存活率为4.7％，腺苷一磷酸可提高其对头孢哌酮舒巴坦敏感性约14.8倍。
而对于腺嘌呤，不管是哪个菌株均没有提高敏感性的效果。
从上述结果来看，腺苷和腺苷一磷酸可提高临床克雷伯多重耐药菌和大肠杆菌对头孢哌酮舒巴坦的敏感性。
实施例3腺苷和腺苷一磷酸可提高临床克雷伯多重耐药菌对头孢哌酮舒巴坦敏感性具有抗生素浓度依赖性
为研究头孢哌酮舒巴坦与腺苷联合使用、头孢哌酮舒巴坦与腺苷一磷酸联合使用与杀菌效率之间的最佳杀菌浓度配比，将制备好的临床克雷伯多重耐药菌4号菌株即Kpn 4，添加不同浓度(从20～320微克/毫升)头孢哌酮舒巴坦和不同浓度(从0.25～16mM)腺苷，或不同浓度腺苷一磷酸(从0.25～16mM)进行组 合；每种组合三个生物学重复；对照组为M9培养基。37℃、200rpm摇床中孵育6小时，然后取100μL采用系列稀释法，分别取10μL进行点板计数，计算细菌CFU/mL(菌落形成单位/毫升)。细菌菌落数在20-200的数据可用于统计分析。生存率公式为添加不同浓度头孢哌酮舒巴坦和/或腺苷(腺苷一磷酸)处理后的细菌数量/对照样本细菌数量×100％。
结果参见图2，由图可见，细菌在仅加入头孢哌酮舒巴坦后生存率为95.57％～78.76％(20～320微克/毫升头孢哌酮舒巴坦)，而在加入头孢哌酮舒巴坦同时加入腺苷后，除腺苷浓度为0.25mM外，其余腺苷浓度下，细菌的生存率显著下降。具体情况是：
在加入0.25mM腺苷时，随着头孢哌酮舒巴坦从20微克/毫升增加到320微克/毫升，细菌的生存率从89.38％下降为16.81％，杀菌效率增加了1.2～5.9倍；在加入0.5mM腺苷时，细菌的生存率从67.86％下降为0.13％，杀菌效率增加了1.4-605倍；在加入1mM腺苷时，细菌的生存率从5.48％下降为0.0713％，杀菌效率增加了17.4-1025倍；在加入2mM腺苷时，细菌的生存率从1.59％下降为0.06％，杀菌效率增加了60-1181倍；在加入4mM腺苷时，细菌的生存率从0.44％下降为0.013％，杀菌效率增加了215-6984倍；在加入8mM腺苷时，细菌的生存率从0.74％下降为0.0073％，杀菌效率增加了128-115828倍；在加入16mM腺苷时，细菌的生存率从0.19％下降为0.001％，杀菌效率增加了496-78501倍。
在加入0.25mM腺苷一磷酸时，除20微克/毫升的头孢哌酮舒巴坦外，随着头孢哌酮舒巴坦从40增加到320微克/毫升，细菌的生存率从69.02％下降为17.69％，杀菌效率增加了1.6～7.4倍；在加入0.5mM腺苷一磷酸时，随着头孢哌酮舒巴坦从20增加到320微克/毫升，细菌的生存率从74.52％下降为0.128％，杀菌效率增加了1.3-590倍；在加入1mM腺苷一磷酸时，细菌的生存率从3.71％下降为0.075％，杀菌效率增加了25.7-1041倍；在加入2mM腺苷一磷酸时，细菌的生存率从1.25％下降为0.062％，杀菌效率增加了76.8-1263倍；在加入4mM腺苷一磷酸时，细菌的生存率从0.82％下降为0.02％，杀菌效率增加了114.8-3835.9倍；在加入8mM腺苷一磷酸时，细菌的生存率从0.66％下降为0.0072％，杀菌效率增加了144-100978倍；在加入16mM腺苷一磷酸时，细菌的生存率从0.26％下降为0.0013％，杀菌效率增加了363-59072倍。
这些结果说明，腺苷和腺苷一磷酸提高临床克雷伯菌对头孢哌酮舒巴坦的敏感性具有腺苷或腺苷一磷酸浓度依赖性和头孢哌酮舒巴坦浓度依赖性。
实施例4腺苷和腺苷一磷酸提高多种细菌对头孢哌酮舒巴坦的敏感性
为研究次腺苷和腺苷一磷酸是否对多种细菌有效，进行了腺苷和腺苷一磷酸提高多种细菌对头孢哌酮舒巴坦敏感性的研究。细菌种类包括临床大肠埃希氏菌E.coli Y17、嗜水气单胞菌A.hydrophila、弧菌(溶藻弧菌V.alginolyticus、副溶血弧菌V.parahaemolyticus)、化脓性链球菌S.pyogenes，铜绿假单胞菌P.aeruginosa，屎球杆菌E.faecium，海豚链球菌S.iniae和鲍曼不动杆菌A.baumannii具体细菌及使用的抗生素头孢哌酮舒巴坦剂量参见表1。
表1细菌及其使用的头孢哌酮舒巴坦剂量
Figure PCTCN2022086177-appb-000001
按照实施例1分别制备每种细菌样本，分装于5mL试管中，根据表1所示每种细菌使用不同的头孢哌酮舒巴坦剂量，再加入或不加入5mM腺苷或腺苷一磷酸作用6小时，然后进行活菌计数，并计算生存率，公式为腺苷和/或腺苷一磷酸和/或抗生素处理后的细菌数量/对照组细菌数量×100％。
结果参见图3，由图可见，添加腺苷或腺苷一磷酸后，这些细菌对头孢哌酮舒巴坦的敏感性普遍都得到了提高，具体如下：
外源添加腺苷后，大肠埃希菌(E.coli Y17)提高了287.18倍，嗜水气单胞菌(A.hydrophila)提高了116.28倍，弧菌(溶藻弧菌V.alginolyticus)提高了8.65倍，副溶血弧菌V.parahaemolyticus)提高了7倍，化脓性链球菌(S.pyogenes) 提高了3.37倍，铜绿假单胞菌(P.aeruginosa)提高了2.59倍，屎球杆菌提高了2.5倍，海豚链球菌提高了1.62倍，鲍曼不动杆菌(A.baumannii)提高了1.39倍。
外源添加腺苷一磷酸后，大肠埃希菌(E.coli Y17)提高了288.66倍，嗜水气单胞菌(A.hydrophila)提高了125倍，弧菌(溶藻弧菌V.alginolyticus)提高了8.89倍，副溶血弧菌V.parahaemolyticus)提高了6.3倍，化脓性链球菌(S.pyogenes)提高了3.3倍，铜绿假单胞菌(P.aeruginosa)提高了2.44倍，屎球杆菌提高了2倍，海豚链球菌提高了1.48倍，鲍曼不动杆菌(A.baumannii)提高了1.45倍。
实施例5腺苷和腺苷一磷酸提高临床克雷伯多重耐药菌对多种抗生素的敏感性
为研究添加腺苷或腺苷一磷酸后，临床克雷伯多重耐药菌是否对头孢哌酮舒巴坦以外的其他抗生素有效，按照实例1制备临床克雷伯多重耐药菌4号菌株即Kpn 4，分别添加5mM腺苷或腺苷一磷酸和抗生素(抗生素分别为头孢他啶、头孢曲松钠、头孢哌酮、美罗培南、亚胺培南、环丙沙星、安培南、莫西沙星、左氧氟沙星、庆大霉素、阿米卡星、卡那霉素)，每种抗生素使用剂量见表2。
表2抗生素及其使用剂量
Figure PCTCN2022086177-appb-000002
作用6小时后统计活菌数量，计算生存率。结果参见图4，由图可见，腺苷 或腺苷一磷酸均能提高起始菌对多种抗生素的敏感性。具体情况如下：
对于腺苷：头孢他啶提高了7.3万倍，头孢曲松钠提高了1.1万倍，头孢哌酮提高了7.3倍，美罗培南提高了542倍，亚胺培南提高了1.2万倍，环丙沙星提高了244倍，安培南提高了4184倍，莫西沙星提高了512倍，左氧氟沙星提高了9.1倍，庆大霉素提高了18.6倍，阿米卡星提高了298倍，卡那霉素提高了4.9倍。
对于腺苷一磷酸：头孢他啶提高了8万倍，头孢曲松钠提高了1万倍，头孢哌酮提高了6倍，美罗培南提高了550倍，亚胺培南提高了1万倍，环丙沙星提高了4581倍，安培南提高了379倍，莫西沙星提高了408倍，左氧氟沙星提高了7.2倍，庆大霉素提高了22倍，阿米卡星提高了605倍，卡那霉素提高了232倍。
上述实施例为本发明较佳的实施方式，但本发明的实施方式并不受上述实施例的限制，其他的任何未背离本发明的精神实质与原理下所作的改变、修饰、替代、组合、简化，均应为等效的置换方式，都包含在本发明的保护范围之内。

Claims (10)

  1. 腺苷或腺苷一磷酸在制备抗感染药物中的应用。
  2. 根据权利要求1所述应用，其特征在于，所述腺苷或腺苷一磷酸在抗感染药物中提高细菌对抗生素的敏感性。
  3. 根据权利要求2所述应用，其特征在于，所述细菌为肺炎克雷伯菌K.pneumoniae、大肠埃希氏菌E.coli、嗜水气单胞菌A.hydrophila、溶藻弧菌V.alginolyticus、副溶血弧菌V.parahaemolyticus、化脓性链球菌S.pyogenes、铜绿假单胞菌P.aeruginosa、屎球杆菌E.faecium、海豚链球菌S.iniae、鲍曼不动杆菌A.baumannii中的一种或多种。
  4. 根据权利要求2所述应用，其特征在于，所述抗生素为β-内酰胺类抗生素、喹诺酮类抗生素、氨基糖苷类抗生素中的一种或多种。
  5. 根据权利要求4所述应用，其特征在于，所述抗生素为头孢哌酮舒巴坦、头孢他啶、头孢曲松钠、头孢哌酮、美罗培南、亚胺培南、环丙沙星、安培南、莫西沙星、左氧氟沙星、庆大霉素、阿米卡星、卡那霉素中的一种或多种。
  6. 一种抗感染组合物，其特征在于，所述组合物含有腺苷和/或腺苷一磷酸和抗生素。
  7. 根据权利要求6所述抗感染组合物，其特征在于，所述抗生素为β-内酰胺类抗生素、喹诺酮类抗生素、氨基糖苷类抗生素中的一种或多种。
  8. 根据权利要求6所述抗感染组合物，其特征在于，所述细菌为肺炎克雷伯菌K.pneumoniae、大肠埃希氏菌E.coli、嗜水气单胞菌A.hydrophila、溶藻弧菌V.alginolyticus、副溶血弧菌V.parahaemolyticus、化脓性链球菌S.pyogenes、铜绿假单胞菌P.aeruginosa、屎球杆菌E.faecium、海豚链球菌S.iniae、鲍曼不动杆菌A.baumannii中的一种或多种。
  9. 根据权利要求6～8任一所述抗感染组合物，其特征在于，所述腺苷和抗生素的质量比为(0.2～213.6):1，所述腺苷一磷酸和抗生素的质量比为(0.375～399):1。
  10. 一种抗感染药物，其特征在于，所述抗感染药物含有权利要求6～9任一所述抗感染组合物。
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