WO2023115757A1

WO2023115757A1 - Application of adenosine or adenosine monophosphate in preparation of anti-infective drugs

Info

Publication number: WO2023115757A1
Application number: PCT/CN2022/086177
Authority: WO
Inventors: 李惠; 彭博; 彭宣宪; 项娟娟; 陶建军
Original assignee: 中山大学
Priority date: 2021-12-20
Filing date: 2022-04-11
Publication date: 2023-06-29
Also published as: CN114159456A

Abstract

An application of adenosine or adenosine monophosphate in preparation of anti-infective drugs. Adenosine or adenosine monophosphate can significantly improve the sensitivity of clinical bacteria such as Escherichia coli, Aeromonas hydrophila, vibrio comprising vibrio alginolyticus and vibrio parahaemolyticus, streptococcus pyogenes, pseudomonas aeruginosa, Enterococcus Faecium, streptococcus iniae, Acinetobacter baumannii, and Klebsiella pneumoniae to antibiotics such as cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampenem, moxifloxacin, levofloxacin, gentamicin, amikacin, and kanamycin. Adenosine or adenosine monophosphate can be used in combination with an antibiotic as an anti-infective drug, kill bacteria under a low-concentration antibiotic condition, and reduce bacterial drug resistance.

Description

Application of adenosine or adenosine monophosphate in the preparation of anti-infective drugs

technical field

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.

Background technique

Antibiotics can effectively inhibit or kill pathogenic bacteria and play a key role in the control of bacterial infections. However, with the widespread use of antibiotics, 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 (WHO) clearly pointed out in the 2007 "World Health Report" that bacterial drug resistance is a major public health problem that threatens human health.

At present, in order to reduce drug-resistant bacteria and treat infections caused by drug-resistant bacteria, in addition to reducing and limiting the use of antibiotics, improving the sensitivity of drug-resistant bacteria to antibiotics has become an important technical solution for controlling drug-resistant bacteria. This method is mainly to make the antibiotics that were originally ineffective or ineffective against pathogenic bacteria effective or efficient under the synergistic action of other molecules, thereby killing the bacteria. For example, 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. Studies have found that 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.

Therefore, there is an urgent need to develop more small molecules that can improve the sensitivity of pathogenic bacteria to antibiotics in the preparation of anti-infective drugs, so as to adapt to various types of pathogenic bacteria or antibiotics.

Contents of the invention

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. Application of small molecules that increase the sensitivity of pathogenic bacteria to antibiotics in the preparation of anti-infective drugs.

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.

The above object of the present invention is achieved through the following technical solutions:

Small molecule metabolites adenine (Adenine, A) and its derivatives adenosine (Adenosine, Ado) and adenosine monophosphate (Adenosine 3'-monophosphate, AMP) are very important metabolites in organisms. Among them, 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.

Through a lot of creative work, the present invention has found that 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.

Therefore, this application claims to protect the application of adenosine or adenosine monophosphate in the preparation of anti-infective drugs.

Further, the adenosine or adenosine monophosphate improves the sensitivity of bacteria to antibiotics in anti-infective drugs.

Preferably, 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.

It should be noted that these bacteria are common pathogenic bacteria, and their drug-resistant strains are common. At the same time, 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. Although in the examples of the present invention, 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. Especially most verification tests of the present invention take clinical Klebsiella pneumoniae as the research object. However, these bacteria should not be used as a limitation to the protection scope of the present invention. This is because: ① 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. drug-resistant and non-drug-resistant bacterial strains of the same bacterium, and the clinical Klebsiella of the present invention is drug-resistant state, also after adding adenosine or adenosine monophosphate Increased susceptibility to antibiotics. Therefore, it can be deduced from these strains according to the above principles that more strains are also suitable for the concept of the present invention.

Furthermore, the antibiotic is one or more of β-lactam antibiotics, quinolone antibiotics, and aminoglycoside antibiotics.

Preferably, the antibiotic is cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampenem, moxifloxacin, levofloxacin, gentamicin One or more of Amycin, Amikacin, and Kanamycin. Among them, cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, and cefoperazone are cephalosporin antibiotics, meropenem and imipenem are carbapenem antibiotics, and ampenem is a monocyclic β-lactam antibiotic Antibiotics (all three are β-lactam antibiotics); baloxacin, ciprofloxacin, and levofloxacin are quinolone antibiotics; gentamicin, amikacin, and kanamycin are aminoglycoside antibiotics. These include the major types of antibiotics currently in clinical use.

The above-mentioned 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, β-lactam antibiotics, quinolone antibiotics and aminoglycoside antibiotics are commonly used clinical antibiotics. Among them, cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, and cefoperazone are cephalosporin antibiotics, meropenem and imipenem are carbapenem antibiotics, and ampenem is a monocyclic β-lactam antibiotic Antibiotics (all three are β-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.

In addition, the present invention also provides an anti-infective composition, which contains adenosine and/or adenosine monophosphate and antibiotics.

Further, the antibiotic is one or more of β-lactam antibiotics, quinolone antibiotics, and aminoglycoside antibiotics.

Preferably, the antibiotic is cefoperazone-sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampenem, moxifloxacin, levofloxacin, gentamicin One or more of Amycin, Amikacin, and Kanamycin.

Preferably, 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.

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 present invention also provides an anti-infective drug, characterized in that the anti-infective drug contains the anti-infective composition.

Further, the anti-infective drugs are oral preparations, injection preparations or external preparations.

The present invention has the following beneficial effects:

The present invention has been proved by experiments that 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, The susceptibility of 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 concentration of antibiotics, achieve better anti-infection effect, and reduce the generation of bacterial resistance at the same time.

Description of drawings

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.

Detailed ways

The present invention will be further described below in conjunction with the accompanying drawings and specific embodiments, but the embodiments do not limit the present invention in any form. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in the technical field.

Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

Example 1 Bacterial Sample Preparation

Pick a single bacterial colony and inoculate it in 5mL LB medium, at 37°C (Escherichia coli, Klebsiella pneumoniae, Pseudomonas aeruginosa, Coccus faecium, Streptococcus iniae, Acinetobacter baumannii, Streptococcus pyogenes cocci) or 30°C (Aeromonas hydrophila, Edwardsiella tarda, Vibrio alginolyticus, Vibrio parahaemolyticus) at 200rpm for 16 hours; transfer the bacterial solution to fresh LB medium at a ratio of 1:100, at 37°C or Cultivate at 30°C and 200rpm until the _OD600 is 1.0, take an appropriate amount of bacterial solution at 8000rpm, centrifuge for 5min to collect the bacterial cells, remove the supernatant and wash the bacterial cells with an equal volume of 0.85% saline for 3 times, suspend in M9 medium (containing 10mM lactose , 2mM MgSO ₄ , 0.1mM CaCl ₂ ), and use M9 medium to adjust the concentration of the bacterium to an OD ₆₀₀ of 0.2, and dispense it into 5mL test tubes for later use.

Example 2 Determination of the effect of adenosine and adenosine monophosphate on improving clinical Klebsiella multidrug-resistant bacteria to cefoperazone-sulbactam antibiotic susceptibility

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. After adding the corresponding drugs in each group, incubate in a shaker at 37°C and 200 rpm for 6-8 hours, then take 100 μL and use serial dilution method, take 10 μL respectively for plate counting, and calculate the bacterial CFU/mL (colony forming unit/ml); The data with the number of colonies in the range of 20-200 can be used for statistical analysis; the percent survival is the number of bacteria in the sample after 6-8 hours of treatment/the number of bacteria in the control sample×100%.

The results are shown in Figure 1. It can be seen from the figure that for the No. 4 strain of Klebsiella multidrug-resistant bacteria, that is, Kpn 4, the bacterial survival rate was 85.71% when only antibiotics were added; when adenosine was added on the basis of antibiotics, the bacterial survival rate was 0.001%. Adenosine can increase its sensitivity to cefoperazone sulbactam by about 8.2× ¹⁰⁴ 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 The sensitivity of Bactam is about 6.1×10 ⁴ times.

For clinical Klebsiella multidrug-resistant strain No. 9, namely Kpn 9, 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.

For clinical multi-drug resistant Escherichia coli No. 17 strain EC-Y17, 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.

For Escherichia coli K12, 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.

As for adenine, no matter which strain was used, there was no effect of improving sensitivity.

From the above results, 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

In order to study the optimal bactericidal concentration ratio between the combined use of cefoperazone sulbactam and adenosine, the combined use of cefoperazone sulbactam and adenosine monophosphate and the bactericidal efficiency, the prepared clinical Klebsiella multi-resistant Drug No. 4 strain is Kpn 4, add different concentrations (from 20 to 320 μg/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. Incubate in a shaker at 37°C and 200rpm for 6 hours, then take 100μL and use serial dilution method, take 10μL respectively for plate counting, and calculate bacterial CFU/mL (colony forming unit/ml). The data with the number of bacterial colonies in the range of 20-200 can be used for statistical analysis. 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 results are shown in Fig. 2, as can be seen from the figure, 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:

When adding 0.25mM adenosine, as cefoperazone sulbactam increased from 20 μg/ml to 320 μg/ml, the survival rate of bacteria decreased from 89.38% to 16.81%, and the bactericidal efficiency increased by 1.2 to 5.9 times; When 0.5mM adenosine is added, the survival rate of bacteria decreases from 67.86% to 0.13%, and the bactericidal efficiency increases by 1.4-605 times; when 1mM adenosine is added, the survival rate of bacteria decreases from 5.48% to 0.0713%, and the bactericidal efficiency increases increased by 17.4-1025 times; when adding 2mM adenosine, the survival rate of bacteria decreased from 1.59% to 0.06%, and the bactericidal efficiency increased by 60-1181 times; when adding 4mM adenosine, the survival rate of bacteria decreased from 0.44% to 0.013%, the bactericidal efficiency increased by 215-6984 times; when 8mM adenosine was added, the bacterial survival rate decreased from 0.74% to 0.0073%, and the bactericidal efficiency increased by 128-115828 times; when 16mM adenosine was added, the bacterial survival The rate dropped from 0.19% to 0.001%, and the bactericidal efficiency increased by 496-78501 times.

When 0.25 mM adenosine monophosphate was added, the survival rate of bacteria decreased from 69.02% to 17.69%, the bactericidal efficiency increased by 1.6 to 7.4 times; when adding 0.5mM adenosine monophosphate, as cefoperazone sulbactam increased from 20 to 320 μg/ml, the bacterial survival rate decreased from 74.52% to 0.128% , the bactericidal efficiency increased by 1.3-590 times; when adding 1mM adenosine monophosphate, the survival rate of bacteria decreased from 3.71% to 0.075%, and the bactericidal efficiency increased by 25.7-1041 times; when adding 2mM adenosine monophosphate, the bacteria The survival rate of bacteria decreased from 1.25% to 0.062%, and the bactericidal efficiency increased by 76.8-1263 times; when 4mM adenosine monophosphate was added, the bacterial survival rate decreased from 0.82% to 0.02%, and the bactericidal efficiency increased by 114.8-3835.9 times; When 8mM adenosine monophosphate was added, the survival rate of bacteria decreased from 0.66% to 0.0072%, and the bactericidal efficiency increased by 144-100978 times; when 16mM adenosine monophosphate was added, the survival rate of bacteria decreased from 0.26% to 0.0013% , The bactericidal efficiency increased by 363-59072 times.

These results indicate that adenosine and adenosine monophosphate enhance the sensitivity of clinical Klebsiella to cefoperazone-sulbactam in a concentration-dependent manner of adenosine or adenosine-monophosphate and cefoperazone-sulbactam.

Embodiment 4 adenosine and adenosine monophosphate improve the sensitivity of various bacteria to cefoperazone sulbactam

In order to study whether hypoadenosine and adenosine monophosphate are effective against various bacteria, 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. pyogenes, Pseudomonas aeruginosa P.aeruginosa, coccus faecalis E.faecium, Streptococcus iniae S.iniae and Acinetobacter baumannii A.baumannii specific bacteria and the dose of the antibiotic cefoperazone sulbactam used are shown in Table 1.

Table 1 Bacteria and their doses of cefoperazone-sulbactam used

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%.

See Figure 3 for the results. It can be seen from the figure that after adding adenosine or adenosine monophosphate, the sensitivity of these bacteria to cefoperazone-sulbactam has generally been improved, as follows:

After the exogenous addition of adenosine, Escherichia coli (E.coli Y17) increased by 287.18 times, Aeromonas hydrophila (A.hydrophila) increased by 116.28 times, Vibrio (V.alginolyticus) increased 8.65 times, Vibrio parahaemolyticus (V.parahaemolyticus) increased 7 times, Streptococcus pyogenes (S.pyogenes) increased 3.37 times, Pseudomonas aeruginosa (P.aeruginosa) increased 2.59 times, Bacillus faecium increased increased by 2.5 times, Streptococcus iniae increased by 1.62 times, and Acinetobacter baumannii (A.baumannii) increased by 1.39 times.

After exogenous addition of adenosine monophosphate, 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

After adding adenosine or adenosine monophosphate, whether clinical Klebsiella multidrug-resistant bacteria are effective to other antibiotics other than cefoperazone and sulbactam after adding adenosine or adenosine monophosphate, the No. 4 strain of clinical Klebsiella multidrug-resistant bacteria was prepared according to Example 1. 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.

Table 2 Antibiotics and their dosage

After 6 hours of action, the number of viable bacteria was counted, and the survival rate was calculated. The results are shown in Figure 4, as can be seen from the figure, adenosine or adenosine monophosphate can improve the sensitivity of the starter bacteria to multiple antibiotics. Details are as follows:

For adenosine: 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.

For adenosine monophosphate: 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, kanamycin Increased by 232 times.

The above-mentioned embodiment is a preferred embodiment of the present invention, but the embodiment of the present invention is not limited by the above-mentioned embodiment, and any other changes, modifications, substitutions, combinations, Simplifications should be equivalent replacement methods, and all are included in the protection scope of the present invention.

Claims

The application of adenosine or adenosine monophosphate in the preparation of anti-infective drugs.
The use according to claim 1, characterized in that the adenosine or adenosine monophosphate improves the sensitivity of bacteria to antibiotics in anti-infective drugs.
According to the described application of claim 2, it is characterized in that, the bacterium is 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 of .
The application according to claim 2, wherein the antibiotic is one or more of β-lactam antibiotics, quinolone antibiotics, and aminoglycoside antibiotics.
According to the application according to claim 4, it is characterized in that the antibiotic is cefoperazone sulbactam, ceftazidime, ceftriaxone sodium, cefoperazone, meropenem, imipenem, ciprofloxacin, ampenem, One or more of moxifloxacin, levofloxacin, gentamicin, amikacin, and kanamycin.
An anti-infection composition is characterized in that the composition contains adenosine and/or adenosine monophosphate and antibiotics.
The anti-infective composition according to claim 6, wherein the antibiotic is one or more of β-lactam antibiotics, quinolone antibiotics, and aminoglycoside antibiotics.
According to the described anti-infection composition of claim 6, it is characterized in that, described bacterium is Klebsiella pneumoniae K.pneumoniae, Escherichia coli E.coli, Aeromonas hydrophila A.hydrophila, alginolytic arc Bacteria V.alginolyticus, Vibrio parahaemolyticus V.parahaemolyticus, Streptococcus pyogenes S.pyogenes, Pseudomonas aeruginosa P.aeruginosa, E.faecium faecium, Streptococcus iniae S.iniae, Acinetobacter baumannii A One or more of .baumannii.
According to the anti-infective composition described in any one of claims 6-8, it is characterized in that, the mass ratio of described adenosine and antibiotic is (0.2～213.6):1, and the mass ratio of described adenosine monophosphate and antibiotic is ( 0.375～399):1.
An anti-infective drug, characterized in that the anti-infective drug contains the anti-infective composition according to any one of claims 6-9.