CN108042521B - Application of L-arginine in improving sensitivity of bacteria to antibiotics - Google Patents
Application of L-arginine in improving sensitivity of bacteria to antibiotics Download PDFInfo
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- CN108042521B CN108042521B CN201810119535.9A CN201810119535A CN108042521B CN 108042521 B CN108042521 B CN 108042521B CN 201810119535 A CN201810119535 A CN 201810119535A CN 108042521 B CN108042521 B CN 108042521B
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- arginine
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- kanamycin
- sensitivity
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- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
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- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
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Abstract
The invention belongs to the technical field of medicines, and particularly discloses application of L-arginine in improving the sensitivity of bacteria to antibiotics. The invention discovers that L-arginine can increase the number of antibiotics entering the bacteria by improving the proton dynamic potential of the bacteria, and finally the bacteria die, so that the L-arginine can improve the sensitivity of the bacteria to the antibiotics, thereby overcoming the problem of drug resistance of the bacteria. The L-arginine is combined with the antibiotic, so that the bactericidal effect of the antibiotic can be obviously improved, and compared with the existing method of only using the antibiotic as an antibacterial drug, the antibacterial agent has better effect and higher safety and operability.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of L-arginine in improving the sensitivity of bacteria to antibiotics.
Background
Pathogenic bacteria seriously harm human health and sustainable development of the breeding industry, and effective measures need to be taken for prevention and treatment. Since the discovery of penicillins by Fleming (Fleming) in 1929, a great deal of research into various antibiotics has opened the antibiotic era in humans, which plays a significant role in the treatment of infectious diseases, making the use of antibiotics increasingly widespread. Although effective in preventing and treating diseases, the abuse and misuse of antibiotics can lead to bacterial resistance. Drug-resistant strains are resistant to the originally effective antibiotics, resulting in infection that is difficult to control. Therefore, it is important to adopt new methods for controlling the infection of bacteria, particularly drug-resistant bacteria.
The focus of current research is to kill resistant bacteria by increasing their sensitivity to antibiotics such that the otherwise ineffective or ineffective antibiotics become effective. In recent years, some small molecules have been found to be capable of promoting the bactericidal action in cooperation with antibiotics, and the preparation of the small molecules and the antibiotics into compound preparations has important significance for controlling the infection of bacteria, particularly drug-resistant bacteria.
Arginine (arginin) is an aliphatic, basic, guanidino-containing polar alpha-amino acid, also one of the 20 prevalent natural amino acids, and is positively charged under physiological conditions. L-arginine is the most common amino acid in nature and is the coding amino acid in protein synthesis. D-arginine has not been found in nature. Arginine is an intermediate metabolite of the ornithine cycle and can promote the conversion of ammonia to urea, thereby reducing blood ammonia content. Arginine can effectively improve immunity, promote the immune system to secrete natural killer cells, phagocytes, interleukin (interleukin-1) and other endogenous substances, and is favorable for resisting cancer cells and preventing virus infection. In addition, arginine is a precursor of ornithine (L-ornithline) and proline (L-proline), proline is an important element constituting collagen, and arginine supplementation has obvious help for health care requiring a large amount of tissue repair for severe trauma, burns and the like, and also has the effect of reducing infection and inflammation. However, no relevant report is found on whether L-arginine can improve the pathogenic bacteria clearance of antibiotics.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provides application of L-arginine in improving the sensitivity of bacteria to antibiotics.
Another object of the present invention is to provide a bacteriostatic or bactericidal medicament.
It is another object of the present invention to provide a method for increasing the sensitivity of bacteria to antibiotics.
In order to achieve the purpose, the invention is realized by the following scheme:
the invention discovers that after the L-arginine is added, the bactericidal effect of kanamycin on Edwardsiella tarda drug-resistant bacteria is obviously improved, and L-arginine concentration dependency is presented. The result shows that the L-arginine can enhance the sensitivity of the Edwardsiella tarda drug-resistant bacteria to kanamycin.
The invention discovers that after the L-arginine is added, the bactericidal effect of other antibiotics (such as ampicillin, balofloxacin and cefazolin sodium) on the Edwardsiella tarda drug-resistant bacteria is obviously improved, and the result shows that the L-arginine can enhance the sensitivity of the Edwardsiella tarda drug-resistant bacteria on other antibiotics.
The invention discovers that after the L-arginine is added, the bactericidal effect of kanamycin on other bacteria or drug-resistant bacteria (such as escherichia coli, pseudomonas aeruginosa, streptococcus B and staphylococcus aureus) is obviously improved, and the result shows that the L-arginine can enhance the sensitivity of other bacteria or drug-resistant bacteria on kanamycin.
The invention discovers that L-arginine increases the content of antibiotics entering the bacteria by improving the proton dynamic potential of the bacteria, and finally leads the bacteria to die.
In conclusion, the addition of L-arginine in antibiotics can obviously improve the sensitivity of bacteria or drug-resistant bacteria to the antibiotics, thereby achieving the purpose of bacteriostasis or sterilization. The invention therefore claims the use of L-arginine for increasing the sensitivity of bacteria to antibiotics.
Preferably, the bacteria is at least one of edwardsiella tarda, escherichia coli, pseudomonas aeruginosa, streptococcus b or staphylococcus aureus.
Preferably, the antibiotic is selected from at least one of kanamycin, ampicillin, balofloxacin or cefazolin sodium.
Preferably, the L-arginine is used for improving the sensitivity of Edwardsiella tarda to kanamycin.
Preferably L-arginine, in improving the sensitivity of Edwardsiella tarda to ampicillin, balofloxacin or cefazolin sodium.
Preferably, the L-arginine is used for improving the kanamycin sensitivity of escherichia coli, pseudomonas aeruginosa, streptococcus b or staphylococcus aureus.
The invention also claims a bacteriostatic or bactericidal medicament containing antibiotics and L-arginine.
The invention also claims a method for improving the sensitivity of bacteria to antibiotics, and the L-arginine is combined with the antibiotics.
In the above method, the bacterium is a sensitive bacterium or a drug-resistant bacterium.
Preferably, the bacteria include, but are not limited to, Edwardsiella tarda, Escherichia coli, Pseudomonas aeruginosa, Streptococcus type B and Staphylococcus aureus. Since these bacteria are common human and farm animal pathogenic bacteria, such as Edwardsiella tarda, Escherichia coli and Pseudomonas aeruginosa are gram-negative bacteria, and Streptococcus B and Staphylococcus aureus are gram-positive bacteria. These bacteria may be drug-resistant bacteria or sensitive bacteria.
Preferably, the antibiotic is selected from, but not limited to, kanamycin, ampicillin, balofloxacin and cefazolin sodium. Because kanamycin is an aminoglycoside antibiotic; balofloxacin is quinolone antibiotics; ampicillin and cefazolin sodium are beta-lactam antibiotics. These include the major antibiotic types currently in clinical use.
Preferably, the dosage ratio of the L-arginine to the antibiotic is 1: 0.0015 to 300.
Preferably, when the method is applied to improve the sensitivity of bacteria to antibiotics, the L-arginine is used in an amount of 3mg to 30g per administration.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers for the first time that the L-arginine can improve the sensitivity of bacteria to antibiotics, thereby overcoming the problem of bacterial drug resistance, and further researches show that the L-arginine can increase the content of antibiotics entering the bacteria by improving the proton dynamic potential of the bacteria. The L-arginine is combined with the antibiotic, so that the bactericidal effect of the antibiotic can be obviously improved, and compared with the existing method of only using the antibiotic as an antibacterial drug, the antibacterial composition has better effect, higher safety and operability and better application prospect.
Drawings
FIG. 1 shows the survival of Edwardsiella tarda after adding L-arginine to kanamycin in example 1.
FIG. 2 shows the survival of Edwardsiella tarda after different concentrations of L-arginine were added to kanamycin in example 1.
FIG. 3 shows the survival of Edwardsiella tarda after adding tyrosine at different concentrations in example 1.
FIG. 4 shows the survival of Edwardsiella tarda after different concentrations of isoleucine were added in example 1.
FIG. 5 shows the survival of Edwardsiella tarda in example 2 after addition of L-arginine to various antibiotics.
FIG. 6 shows the survival of different bacteria after addition of L-arginine to kanamycin in example 3.
FIG. 7 shows the change of kanamycin content in bacteria after adding L-arginine to kanamycin in example 4.
FIG. 8 shows the change of the proton kinetic potential of bacteria after addition of L-arginine in example 5.
Detailed Description
The present invention will be described in further detail with reference to the drawings and specific examples, which are provided for illustration only and are not intended to limit the scope of the present invention. The test methods used in the following examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are, unless otherwise specified, commercially available reagents and materials.
Example 1L-arginine increases sensitivity of Edwardsiella tarda to kanamycin
1. Determination of resistance to EIB202 of Edwardsiella tarda
Edwardsiella tarda is a gram-negative Brevibacterium, which was first reported by Hoshina in 1962 and is related to Japanese eel red disease (reddisoase). From the first report, the strain causes diseases in more than twenty kinds of fishes, such as eel, paralichthys olivaceus, tilapia, Chinese soft-shelled turtle, carp and the like, and huge loss is caused to aquaculture. The Edwardsiella tarda is also a pathogenic bacterium which is commonly suffered by people and fishes and directly poses a threat to human health.
Firstly, the minimum inhibitory concentration of the Edwardsiella tarda to various antibiotics is determined. The result shows that the minimum inhibitory concentration of the Edwardsiella tarda EIB202 to kanamycin is 12.5 mug/mL, the minimum inhibitory concentration to tetracycline is 125 mug/mL, the minimum inhibitory concentration to chloramphenicol is 50 mug/mL, and the result shows that the Edwardsiella tarda EIB202 is a multi-drug-resistant bacterium.
2. Preparation of test specimens
A single colony of Edwardsiella tarda EIB202 was picked from an LB plate, inoculated into 5mL of LB medium, and cultured with shaking at 30 ℃ and 200rpm for 24 hours to reach saturation. The bacterial liquid is collected by centrifugation, centrifuged for 5min at 8000rpm, the supernatant is removed, the bacterial cells are washed with 0.85% physiological saline, and finally suspended in 1 XM 9 basic liquid medium (containing 10mM acetate), the OD value of the bacterial liquid is adjusted to 0.2, and then 5mL of the bacterial liquid is dispensed into test tubes for later use.
3. L-arginine increases sensitivity of Edwardsiella tarda EIB202 to kanamycin
To determine whether the sensitivity of Edwardsiella tarda to kanamycin was increased by the addition of L-arginine. The prepared bacterial samples were divided into 3 groups: 2 control groups (control group 1: kanamycin and 2.5mM L-arginine were not added; control group 2: kanamycin alone 40. mu.g/mL) and 1 experimental group (kanamycin and 2.5mM L-arginine were added 40. mu.g/mL). After 6h of action, 100. mu.L of the bacterial suspension was subjected to colony counting on TSB agar plates. Counting the number of live bacteria and calculating the survival rate.
As shown in FIG. 1, the sensitivity of Edwardsiella tarda to kanamycin was 104.47-fold increased when L-arginine was added (the survival rate decreased from 69.84% with kanamycin alone to 0.66% with L-arginine and kanamycin added). This result shows that: after the L-arginine is added, the sensitivity of the Edwardsiella tarda to kanamycin can be obviously improved.
4. The L-arginine improves the sensitivity of Edwardsiella tarda EIB202 to kanamycin and has concentration dependence
In order to know whether the sensitivity of the Edwardsiella tarda EIB202 on kanamycin improved by L-arginine has L-arginine concentration dependency or not, experiments of adding L-arginine with different concentrations on the premise of adding kanamycin are carried out. In the prepared bacterial sample, 40 mu g/mL kanamycin is firstly added, 0, 1.25, 2.5, 5, 10 and 20mM L-arginine are respectively added, after shaking table incubation for 6h under the conditions of 30 ℃ and 200rpm, 100 mu L bacterial liquid is taken to carry out TSB agar plate colony counting. Counting the number of live bacteria and calculating the survival rate.
As shown in FIG. 2, in the presence of kanamycin, the bacterial killing efficiency of kanamycin is gradually increased along with the increase of the concentration of the added L-arginine within a certain range; however, as the L-arginine concentration continued to increase, kanamycin was less effective in sterilizing bacteria.
The specific experimental results are as follows: when the kanamycin concentration is 40 mug/mL, the bacterial sterilization efficiency can be improved by 113 times by adding 1.25mM L-arginine (the survival rate is reduced from 108.24% without adding L-arginine to 0.96% after adding), the bacterial sterilization efficiency can be improved by 213 times by adding 2.5mM L-arginine (the survival rate is reduced from 111.43% without adding L-arginine to 0.52% after adding), the bacterial sterilization efficiency can be improved by 32.9 times by adding 5mM L-arginine (the survival rate is reduced from 109.56% without adding L-arginine to 3.33% after adding), the bacterial sterilization efficiency can be improved by 22.89 times by adding 10mM L-arginine (the survival rate is reduced from 106.64% without adding L-arginine to 4.66% after adding), and the bacterial sterilization efficiency can be improved by 25.15 times by adding 20mM L-arginine (the survival rate is reduced from 106.91% without adding L-arginine to 4.25% after adding L-arginine %).
5. Tyrosine and isoleucine can not improve the sensitivity of Edwardsiella tarda EIB202 to kanamycin
To see if other amino acids all contribute to the bactericidal effect of antibiotics, experiments were performed in which tyrosine and isoleucine were added under the precondition that kanamycin was added. To the prepared bacterial sample, 40. mu.g/mL kanamycin was added, and 0, 0.125, 0.25, 0.5, 1 and 2mM tyrosine or 0, 0.5, 1, 2, 4 and 8mM isoleucine were added, respectively, and after incubating in a shaker at 30 ℃ and 200rpm for 6 hours, 100. mu.L of the bacterial suspension was counted by TSB agar plate colonies. Counting the number of live bacteria and calculating the survival rate.
The results of tyrosine are shown in fig. 3, and after tyrosine with different concentrations is added, compared with the tyrosine not added, the sterilization efficiency is basically consistent and is improved to 1.9 times; compared with the method of adding no tyrosine and only antibiotics, the sterilization efficiency is improved by 1.4 times. The difference between the two is 1.36 times, and no significant difference exists.
The results of isoleucine are shown in fig. 4, after different concentrations of isoleucine are added, compared with the case of not adding isoleucine, the sterilization efficiency is basically consistent, and is improved to 1.8 times; compared with the method of adding no isoleucine and only antibiotics, the sterilization efficiency is improved by 1.4 times. The difference between the two is 1.28 times, and no significant difference exists.
The above results show that: neither tyrosine nor isoleucine can increase the sensitivity of edwardsiella tarda EIB202 to kanamycin. It was concluded that not all amino acids could enhance kanamycin bactericidal activity, indicating the specificity of L-arginine in promoting kanamycin bactericidal activity.
Example 2L-arginine increases the susceptibility of Edwardsiella tarda to other antibiotics
To see if the L-arginine addition could increase the sensitivity of Edwardsiella tarda to other antibiotics than kanamycin, bacterial samples were prepared as in step 2 of example 1. The experiments were divided into 3 groups: 2 control groups (control group 1: no antibiotic and L-arginine; control group 2: antibiotic only) and 1 experimental group (antibiotic and L-arginine). The added antibiotics and the action concentrations are respectively as follows: 12.5. mu.g/mL ampicillin, 2. mu.g/mL balofloxacin and 50. mu.g/mL cefazolin sodium. Counting the number of live bacteria after 6h of action, and calculating the survival rate.
As shown in FIG. 5, the sensitivity of Edwardsiella tarda to ampicillin was improved by 5.13 times (survival rate decreased from 60.03% with ampicillin only to 11.7% with L-arginine and ampicillin) and the sensitivity to balofloxacin was improved by 2 times (survival rate decreased from 46.23% with balofloxacin only to 23.5% with L-arginine and balofloxacin), and the sensitivity to cefazolin sodium was improved by 5.29 times (survival rate decreased from 16.93% with cefazolin sodium only to 3.2% with L-arginine and cefazolin sodium) when L-arginine was added.
The above results show that: after the L-arginine is added, the sensitivity of the Edwardsiella tarda to other antibiotics can be obviously improved.
Example 3L-arginine increases the sensitivity of various bacteria to kanamycin
1. Preparation of bacterial liquid
Selecting various bacteria such as Escherichia coli K12, Pseudomonas aeruginosa, Streptococcus B and Staphylococcus aureus resistant bacteria (MASA), etc., monoclonally culturing in 100mL LB liquid culture medium at 37 deg.C or 30 deg.C and 200rpm for 16h to reach saturation state. 20mL of each bacterial suspension was collected, centrifuged at 8000rpm for 5min, the supernatant was removed, the cells were washed with an equal volume of 0.85% saline, suspended in 1 XM 9 basic liquid medium (containing 10mM acetate), the OD of the suspension was adjusted to 0.5, and then 5mL of each suspension was dispensed into a test tube.
2. L-arginine increases the sensitivity of various bacteria to kanamycin
The prepared bacterial liquid is divided into 3 groups according to the bacterial species: 2 control groups (control group 1: no kanamycin and L-arginine were added; control group 2: kanamycin only was added) and 1 experimental group (kanamycin and L-arginine were added). Adding 2.5mM L-arginine and kanamycin (different concentrations of different bacteria), incubating in a shaker at 37 deg.C or 30 deg.C and 200rpm for 6h, taking 100 μ L bacterial liquid, counting viable bacteria, and calculating the survival rate.
As shown in FIG. 6, the results showed that the sensitivity of Escherichia coli K12 to kanamycin was increased by 2 times (survival rate decreased from 75.49% without L-arginine to 37.7% after L-arginine addition), the sensitivity of Pseudomonas aeruginosa to kanamycin was increased by 8.64 times (survival rate decreased from 44% without L-arginine to 5.09% after L-arginine addition), the sensitivity of Streptococcus B to kanamycin was increased by 269 times (survival rate decreased from 97.73% without L-arginine to 0.36% after L-arginine addition), and the sensitivity of Staphylococcus aureus (MASA) to kanamycin was increased by 273 times (survival rate decreased from 83.36% without L-arginine to 0.3% after L-arginine addition). As described above, the sensitivity of these bacteria to kanamycin was generally improved by the addition of L-arginine.
Example 4L-arginine increases the kanamycin content of Edwardsiella tarda
Bacterial death is related to the amount of antibiotic that enters the interior of the bacteria, and bacterial resistance is due to the antibiotic entering the bacteria at a concentration below that at which it dies. To investigate whether L-arginine increased the sensitivity of Edwardsiella tarda to antibiotics by increasing the content of antibiotics that entered the interior of the bacteria, bacterial samples were prepared according to the method of step 2 of example 1, and bacterial suspension was divided into 3 groups, of which 2 was a control group (control group 1: no substance was added; control group 2: kanamycin only was added), and the other 1 was an experimental group (kanamycin and L-arginine were added). After incubation for 6h at 30 ℃ on a shaker at 200 rpm. The cells were washed by centrifugation, disrupted by ultrasonication, and the kanamycin content was determined using a kanamycin ELISA detection kit (Clevel Technology Group Inc., Tokyo, Navkon).
As shown in FIG. 7, the addition of L-arginine increased the amount of antibiotic introduced into the bacteria by 1.7-fold compared to the addition of antibiotic alone. It is shown that L-arginine can indeed increase the content of antibiotics that enter the body of bacteria.
Example 5L-arginine increases the proton motive force of Edwardsiella tarda
As is clear from example 4, the addition of L-arginine retards entryThe number of antibiotics in the interior of edwardsiella species is significantly increased, but the specific mechanism of action is not known. To investigate the mechanism of action of L-arginine to promote the entry of antibiotics into the interior of bacteria, experiments (experimental sample preparation was performed according to the method of step 2 of example 1) were divided into 2 groups: 1 control group (without adding kanamycin and L-arginine) and 1 experimental group (with the addition of L-arginine), at 30 degrees C, 200rpm conditions were incubated for 6h shaking table. The treated bacteria were individually adjusted to a concentration of 106CFU/mL, 1mL was transferred to a 1.5mL EP tube and 10. mu.L of 3mM DiOC was added2(3, 3' -dimethyloxa-carbacyanin iodide), mixed well and incubated at 37 ℃ for 30min with shaking. Before being loaded onto a machine, the sample is transferred into a flow cytometry analysis tube, and is detected by using a flow cytometer FACSCalibur flow cytometer (Becton Dickinson, San Jose, Calif., USA), and the parameter setting is carried out according to the operation protocol of the instrument. Dye DiOC2(3) The green fluorescence excitation wavelength of 488nm, the emission wavelength of 530nm, the red fluorescence excitation wavelength of 488nm and the emission wavelength of 610 nm. The ratio of red light intensity to green light intensity represents the intensity of the membrane potential, and the Proton Motive Force (PMF) value was calculated as LOG (103/2 × Y mean/X mean), and Y mean and X mean represent the red light intensity and green light intensity, respectively, and were measured according to the instructions of the back light bacterial membrane potential kit (Invitrogen).
As a result, as shown in FIG. 8, it was found that the proton motive force of the bacterium increased 2.86 times by adding L-arginine. This result indicates that the addition of L-arginine causes an increase in the proton kinetic potential of the bacteria, thereby increasing the content of antibiotics that enter the interior of the bacteria, and eventually, the bacteria die.
It should be finally noted that the above examples are only intended to illustrate the technical solutions of the present invention, and not to limit the scope of the present invention, and that other variations and modifications based on the above description and thought may be made by those skilled in the art, and that all embodiments need not be exhaustive. Any modification, equivalent replacement, and improvement made within the spirit and principle of the present invention should be included in the protection scope of the claims of the present invention.
Claims (4)
- The application of L-arginine in preparing medicine for raising the sensitivity of bacteria to antibiotic, the bacteria being Edwardsiella tarda; the antibiotic is at least one of kanamycin, ampicillin, balofloxacin or cefazolin sodium.
- The application of the combination of the L-arginine and the antibiotic in preparing the bacteriostatic or bactericidal medicine, wherein the bacterium is Edwardsiella tarda; the antibiotic is at least one of kanamycin, ampicillin, balofloxacin or cefazolin sodium.
- 3. The use according to claim 2, wherein the dosage ratio of L-arginine to antibiotic is 1: 0.0015 to 300.
- 4. The use according to claim 2, wherein the L-arginine is used in an amount of 3mg to 30g per administration.
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