CN117017983B - Application of triptan medicine in preparation of anti-infective medicine - Google Patents
Application of triptan medicine in preparation of anti-infective medicine Download PDFInfo
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- CN117017983B CN117017983B CN202311299574.9A CN202311299574A CN117017983B CN 117017983 B CN117017983 B CN 117017983B CN 202311299574 A CN202311299574 A CN 202311299574A CN 117017983 B CN117017983 B CN 117017983B
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- Prior art keywords
- antibiotics
- bacteria
- triptan
- drug
- ampicillin
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- 239000003814 drug Substances 0.000 title claims abstract description 104
- ZISSAWUMDACLOM-UHFFFAOYSA-N triptane Chemical compound CC(C)C(C)(C)C ZISSAWUMDACLOM-UHFFFAOYSA-N 0.000 title claims abstract description 78
- 230000002924 anti-infective effect Effects 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title abstract description 8
- 241000894006 Bacteria Species 0.000 claims abstract description 99
- 229940079593 drug Drugs 0.000 claims abstract description 86
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 74
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 72
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 claims description 93
- 241000588724 Escherichia coli Species 0.000 claims description 31
- 230000003115 biocidal effect Effects 0.000 claims description 26
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 claims description 12
- 229960005091 chloramphenicol Drugs 0.000 claims description 10
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 10
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- WKEMJKQOLOHJLZ-UHFFFAOYSA-N Almogran Chemical compound C1=C2C(CCN(C)C)=CNC2=CC=C1CS(=O)(=O)N1CCCC1 WKEMJKQOLOHJLZ-UHFFFAOYSA-N 0.000 claims description 6
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- 229960002472 eletriptan Drugs 0.000 claims description 6
- OTLDLQZJRFYOJR-LJQANCHMSA-N eletriptan Chemical compound CN1CCC[C@@H]1CC1=CN=C2[C]1C=C(CCS(=O)(=O)C=1C=CC=CC=1)C=C2 OTLDLQZJRFYOJR-LJQANCHMSA-N 0.000 claims description 6
- 229960005254 naratriptan Drugs 0.000 claims description 6
- UNHGSHHVDNGCFN-UHFFFAOYSA-N naratriptan Chemical compound C=12[CH]C(CCS(=O)(=O)NC)=CC=C2N=CC=1C1CCN(C)CC1 UNHGSHHVDNGCFN-UHFFFAOYSA-N 0.000 claims description 6
- 229940049954 penicillin Drugs 0.000 claims description 6
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 claims description 6
- 229960000425 rizatriptan Drugs 0.000 claims description 6
- TXHZXHICDBAVJW-UHFFFAOYSA-N rizatriptan Chemical compound C=1[C]2C(CCN(C)C)=CN=C2C=CC=1CN1C=NC=N1 TXHZXHICDBAVJW-UHFFFAOYSA-N 0.000 claims description 6
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- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims description 3
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Classifications
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
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- 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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- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Abstract
The invention belongs to the technical field of biological medicines, and particularly relates to application of triptan medicines in preparation of anti-infective medicines. According to the invention, researches show that the triptan medicine can obviously improve the sensitivity of bacteria to antibiotics, so that the antibacterial effect of antibiotics which are ineffective or inefficient to bacteria is obviously improved, thereby killing the bacteria and achieving the anti-infection effect. The anti-infective drug composition is further formed by the triptan drug and the antibiotics, so that on one hand, a remarkable anti-infective effect can be achieved under the condition of low concentration of the antibiotics, and on the other hand, the possibility of drug resistance of bacteria can be remarkably reduced due to the fact that the use amount of the antibiotics is reduced; the triptan drug is marketed as a drug, and clinical safety has been confirmed.
Description
Technical Field
The invention belongs to the technical field of biological medicine. More particularly, relates to the application of triptan drugs in preparing anti-infective drugs.
Background
For the problem of bacterial drug resistance, the current method for controlling drug-resistant bacteria mainly comprises the following steps: first, newer antibiotics are used for treatment, such as some modern new antibiotics; secondly, antibiotics are used jointly, and synergistic effect is generated to kill drug-resistant bacteria through superposition of antibacterial effects among the antibiotics; thirdly, the dosage of the antibiotics is increased, and the dosage of the antibiotics is properly increased within the safety range, so that the sterilization effect is improved; fourth, the administration mode of the antibiotic is finely adjusted, for example, for time-dependent antibiotics, the input time of the antibiotic is prolonged by a venous micropump method, so that the sterilization effect of the antibiotic on drug-resistant bacteria is improved. However, even by means of the above method, the anti-infective therapeutic effect of the drug-resistant bacteria is still limited.
In order to solve the problems, the application of sodium formate in preparing anti-infective drugs is disclosed in Chinese patent application CN115192561A, and the research shows that the sodium formate can obviously improve the sensitivity of bacteria to antibiotics, so that the antibiotics which are ineffective or inefficient on pathogenic bacteria originally become effective or efficient, thereby killing the bacteria and achieving the anti-infective effect. However, the number of drugs known in the prior art to increase the susceptibility of bacteria to antibiotics is limited, and there is still an urgent need to develop more drugs to increase the susceptibility of bacteria to antibiotics.
Disclosure of Invention
The invention aims to overcome the defect and the defect of limited quantity of medicines capable of improving the sensitivity of bacteria to antibiotics in the prior art, and provides application of triptan medicines in preparation of anti-infective medicines.
The invention aims to provide an anti-infective pharmaceutical composition.
The above object of the present invention is achieved by the following technical scheme:
triptans are currently the only drug developed for migraine, which is a selective 5-hydroxytryptamine receptor agonist that relieves the onset of migraine by activating the 5-HTIB/ID receptors on the sympathetic nerves of the intracranial blood vessel and trigeminal system, constricting the blood vessel and inhibiting the release of neuropeptides. And triptan medicines are marketed, the clinical medication safety of the triptan medicines is verified, but no relevant report exists in the prior art on whether the triptan medicines can improve the sensitivity of the existing antibiotics.
According to the invention, when the triptan medicine and the antibiotics act on bacteria such as pseudomonas aeruginosa, klebsiella pneumoniae, escherichia coli and edwardsiella tarda together, the sensitivity of the bacteria to the antibiotics can be obviously improved, and the sterilization effect of the antibiotics can be obviously improved.
Therefore, the invention claims the application of triptan drugs in preparing anti-infective drugs, which improves the sensibility of bacteria to antibiotics in the anti-infective drugs; the antibiotics include penicillin, cephalosporin, quinolone, tetracycline, aminoglycoside, chloramphenicol or carbapenem antibiotics; the bacteria include Pseudomonas aeruginosa, klebsiella pneumoniae, escherichia coli or Edwardsiella tarda, or drug-resistant bacteria of the above bacteria.
Among these, the mechanism by which triptans increase the sensitivity of bacteria to antibiotics may be to effectively increase ROS levels in bacteria, increase the amount of antibiotics that enter the bacterial cells, and thus increase their sensitivity to antibiotics.
Further, the triptan drug comprises zolmitriptan, rizatriptan, naratriptan, eletriptan, almotriptan, sumatriptan succinate, or pharmaceutically acceptable salts thereof. The action mechanisms of the triptan medicines are the same, and the invention also has relevant experimental data to prove that the zolmitriptan, rizatriptan, naratriptan, eletriptan, almotriptan and sumatriptan succinate can achieve better effect of improving the sensitivity of bacteria to antibiotics, so that the triptan medicines (comprising pharmaceutically acceptable salts thereof) can achieve the effect of the invention, and the optional range of the medicines is not limited to the specific examples.
Preferably, the penicillin antibiotics comprise amoxicillin, penicillin G and the like; cephalosporin antibiotics including cefoperazone, ceftriaxone and the like; quinolone antibiotics include ciprofloxacin, norfloxacin, and the like; the tetracycline antibiotics include tetracycline, aureomycin, etc.; aminoglycoside antibiotics include kanamycin, gentamicin, and the like; chloramphenicol antibiotics include chloramphenicol and the like; carbapenem antibiotics include meropenem and the like.
The above antibiotics should not be construed as limiting the scope of the invention. This is because, although the variety of antibiotics is hundreds, it can be classified according to its chemical structure and antibacterial mechanism, and the similar chemical structure has the same antibacterial mechanism, so that one-to-one verification is not required. It will be readily apparent to those skilled in the art from the concepts of the present invention that the remaining antibiotics described above are equally applicable to the methods of the present invention.
It should be noted that these bacteria are common pathogenic bacteria and drug-resistant strains thereof, and escherichia coli and pseudomonas aeruginosa are model bacteria for studying bacterial drug resistance, so these bacteria are better representatives of drug-resistant and non-drug-resistant bacteria. Although in the examples of the present invention, the bacteria exemplified include clinical Klebsiella pneumoniae, pseudomonas aeruginosa, escherichia coli, edwardsiella tarda, and in particular, the present invention has been most validated against multidrug-resistant Escherichia coli Y17, these bacteria are not intended as limitations on the scope of the present invention. This is because: 1) Escherichia coli and Pseudomonas aeruginosa are model bacteria for researching drug resistance mechanisms; 2) 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 escherichia coli is in a drug-resistant state, so that the sensitivity to antibiotics is improved after the triptan drugs are added. It is therefore deduced from these species that more species are suitable for the inventive concept according to the principles described above.
Furthermore, the in-vitro use concentration of the triptan medicine is 0.01-2 mM. The above-mentioned use concentration is a use concentration when acting on bacteria in vitro, and when the triptan drug is applied to animals or humans, conversion may be performed according to a standard.
In addition, the invention also provides an anti-infective pharmaceutical composition, which comprises a triptan drug and an antibiotic; the antibiotics include penicillins, cephalosporins, quinolones, tetracyclines, aminoglycosides, chloramphenicol or carbapenem antibiotics.
The triptan medicine and the antibiotics are used together for bacterial infection, and have obvious synergistic effect, so that the obvious bacterial inhibition effect which cannot be achieved by a single antibiotic can be achieved by the combined effect.
Further, the triptan drug comprises zolmitriptan, rizatriptan, naratriptan, eletriptan, almotriptan, sumatriptan succinate, or pharmaceutically acceptable salts thereof.
Further, the molar ratio of the triptan drug to the antibiotic is (0.14-20): 1.
the medicine can be used for treating bacterial infection of animals, livestock and poultry and the like, such as mammals, rodents and the like, besides being used for treating bacterial infection of mice and human beings. Examples of other animals include horses, dogs, cats, and the like.
Furthermore, the anti-infective drug also contains pharmaceutically acceptable auxiliary materials.
Further, the anti-infective medicament is an oral preparation, an injection preparation or an external preparation.
The invention has the following beneficial effects:
according to the invention, researches show that the triptan medicine can obviously improve the sensitivity of bacteria to antibiotics, so that the antibacterial effect of antibiotics which are ineffective or inefficient to bacteria is obviously improved, thereby killing the bacteria and achieving the anti-infection effect. The anti-infective drug composition is further formed by the triptan drug and the antibiotics, so that on one hand, a remarkable anti-infective effect can be achieved under the condition of low concentration of the antibiotics, and on the other hand, the possibility of drug resistance of bacteria can be remarkably reduced due to the fact that the use amount of the antibiotics is reduced; in addition, the triptan drug is marketed as a drug, and the clinical safety has been confirmed.
Drawings
FIG. 1 is a statistical chart showing the results of increasing the sensitivity of multi-resistant Escherichia coli to ampicillin by adding a triptan drug in example 2.
FIG. 2 is a statistical graph showing the effects of sumatriptan succinate on antibiotic concentration (A), sumatriptan succinate concentration (B) and time of action (C) of multi-drug resistant Escherichia coli on ampicillin sensitivity in example 3.
FIG. 3 is a statistical plot of the results of the addition of sumatriptan succinate to increase the sensitivity of various bacteria to minocycline in example 4; wherein A is Klebsiella pneumoniae, B is Pseudomonas aeruginosa, C is multi-drug resistant Escherichia coli, and D is Edwardsiella tarda resistant bacteria.
FIG. 4 is a statistical graph showing the results of increasing the sensitivity of multi-resistant Escherichia coli to various antibiotics by adding sumatriptan succinate in example 5.
FIG. 5 is a statistical graph showing the results of the improvement of survival rate (A) and organ clearance (B) of mice infected with multi-drug resistant Escherichia coli by sumatriptan succinate in combination with ampicillin in example 6.
FIG. 6 is a statistical chart of the experimental results of the effect of different pyruvate circulating genes of Escherichia coli on sumatriptan succinate synergistic ampicillin in example 7.
FIG. 7 is a statistical plot of the results of exogenous sumatriptan succinate in combination with AMP and alpha-tocopherol or thiourea on bacterial ROS (A) and survival (B) in example 7.
FIG. 8 is a statistical chart showing the results of measuring the intracellular ampicillin content of the bacterium after externally adding sumatriptan succinate in example 7.
Detailed Description
The invention is further illustrated in the following drawings and specific examples, which are not intended to limit the invention in any way. Unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art.
Reagents and materials used in the following examples are commercially available unless otherwise specified.
Example 1 preparation of bacterial samples
Bacterial single colony is selected and inoculated in 5 mL LB culture medium, and cultured for 16 hours at 37 ℃ and 200 rpm; according to 1:100 in fresh LB medium, at 37 ℃,200 rpm culture to OD600 = 0.6. Collecting appropriate amount of bacterial liquid at 8000 rpm for 5 min, centrifuging to collect bacterial body, removing supernatantThe cells were washed 3 times with 0.85% physiological saline, suspended in M9 medium, and further diluted to 5X 10 with M9 medium to adjust the concentration of the cells to OD600 of 0.6 6 And (5) subpackaging 5 mL into test tubes for later use.
Example 2 triptan drugs increasing the sensitivity of multi-resistant E.coli to ampicillin
A multi-drug resistant Escherichia coli YT17 was prepared as in example 1 (minimum inhibitory concentrations of the multi-drug resistant Escherichia coli YT17 and the common Escherichia coli K12 are shown in Table 1).
Table 1 minimum inhibitory concentration (MIC, microgram/milliliter) of YT17 and K12 for 8 antibiotics
Dividing the bacterial samples into 4 groups, namely M9 culture medium Control group (Control), triptan drug group (Triptans), ampicillin group (AMP) and ampicillin+triptan drug group (AMP+triptans); ampicillin concentration was 0.5 mg/mL (mg/mL) and triptan concentration was 1 mM. Each group had three biological replicates. After adding the corresponding drugs into each group, incubating the groups in a shaking table at 37 ℃ and 200 rpm for 6 hours, then taking 100 mu L of each group, performing serial dilution, taking 5 mu L of each group, putting the groups on LB solid medium, and culturing the groups in a culture box at 37 ℃ for 12 hours, and counting the bacterial number. The viability of each group of treated bacteria was the number of bacteria after sample treatment/the number of sample bacteria in the control group x 100%.
As a result, referring to fig. 1, it can be seen that the triptan drugs can increase the sensitivity of multi-drug resistant escherichia coli to ampicillin, and the increases of the sensitivity are as follows: zolmitriptan (8.13 times), rizatriptan (9.28 times), naratriptan (5.8 times), eletriptan (10.47 times), almotriptan (3.99 times), sumatriptan succinate (18.42 times). From the results, sumatriptan succinate and ampicillin are combined to improve the sterilization effect optimally.
EXAMPLE 3 sumatriptan succinate to enhance ampicillin bactericidal effect
Taking multi-drug resistant escherichia coli Y17 as a research object, adding sumatriptan succinate with different concentrationssumatriptan succinateSPS) or different concentrations of antibiotics, and under different time of action conditions, the effect of increasing the sensitivity of the bacteria to ampicillin was studied. Experimental operation reference example 2, in particular as follows:
3.1, sumatriptan succinate has antibiotic concentration gradient effect for improving drug-resistant bacteria sensitivity
In order to understand that sumatriptan succinate improves the sensitivity of bacteria to ampicillin at different antibiotic concentrations, the bacteria are treated by adding ampicillin at a concentration of 0.1-0.7 mg/mL on the basis of externally adding sumatriptan succinate of 1.1 mM, and living bacteria are counted after 6 hours by taking no antibiotic as a control, and the survival rate of the bacteria is compared when sumatriptan succinate is added and sumatriptan succinate is not added under the condition of the same antibiotic concentration.
As shown in A in FIG. 2, it is seen from the graph that the more remarkable the increase of the sterilization efficiency of drug-resistant bacteria is with the increase of the concentration of ampicillin under the premise of adding sumatriptan 1 mM succinate, particularly when ampicillin antibiotic of 0.7 mg/mL is added, the sterilization efficiency of 70 times can be improved. The specific conditions are as follows: after adding sumatriptan 1 mM succinate, the sterilization efficiency of the drug-resistant bacteria is improved by 1.83 times (the survival rate is reduced from 93.5% after adding to 51% after adding) when the ampicillin concentration is 0.1 mg/mL, the sterilization efficiency of the drug-resistant bacteria is improved by 5.58 times (the survival rate is reduced from 92% after adding to 16.5% after adding) when the ampicillin concentration is 0.2 mg/mL, and the sterilization efficiency of the drug-resistant bacteria is respectively improved by 17.37 times (the survival rate is reduced from 82.5% after adding to 4.75% after adding, the survival rate is reduced from 77.5% after adding to 1.55%) and 70 times (the survival rate is reduced from 52.5% after adding to 0.75% after adding) when the ampicillin concentration is 0.3, 0.5 and 0.7 mg/mL in sequence.
3.2 improving the sensitivity of drug-resistant bacteria by sumatriptan succinate and having the concentration gradient effect of sumatriptan succinate
To study whether there is a gradient effect between the concentration of sumatriptan succinate and the sterilization efficiency, and the optimal sterilization concentration, sumatriptan succinate (0.01 mM-2 mM) with different concentrations is added to act for 6 hours on the basis of adding ampicillin with 0.5 mg/mL, then viable bacteria count is carried out, and the survival rate of bacteria with ampicillin added and bacteria without ampicillin added under the same concentration of sumatriptan succinate is compared.
As a result, as shown in B in fig. 2, it was found that the bacterial survival rate was 75.75% when only the antibiotic was added, whereas the bacterial survival rate was reduced from 68.3% to 1.125% and the sterilization efficiency was increased from 1.37 to 88 times as the sumatriptan succinate concentration was increased. Meanwhile, the addition of sumatriptan succinate at different concentrations was found to have no effect on the survival rate of the bacteria.
3.3 sumatriptan succinate has time effect in improving drug-resistant bacteria sensitivity
Further studies were performed to observe the relationship between sterilization efficiency and time by counting viable bacteria at different times when sumatriptan succinate 1 mM and ampicillin 0.5 mg/mL were added.
As shown in C of fig. 2, it can be seen that the sterilization efficiency of the drug-resistant bacteria after the simultaneous addition of ampicillin and sumatriptan succinate was higher at each time point than that of the ampicillin alone. And the sterilization times are obviously increased along with the time extension. The specific conditions are as follows: the survival rate of only adding ampicillin in 2 hours is 93%, and after adding sumatriptan succinate again, the survival rate is reduced to 32%, and the sensitivity is improved by 2.91 times. After 4 hours of action, the survival rate is reduced from 83% after only ampicillin addition to 9.5% after sumatriptan succinate addition, and the sensitivity is improved by 8.71 times. And the number of viable bacteria is obviously reduced along with the extension of the action time, the sensitivity is obviously improved, and the sensitivity is improved by 46-200 times in 6-12 hours. Meanwhile, it was found that the addition of sumatriptan succinate had no effect on the survival rate of the bacteria within 12 hours.
EXAMPLE 4 ubiquity of sumatriptan succinate in combination with ampicillin to eliminate multiple resistant bacteria
A variety of bacterial samples were prepared as in example 1. Bacteria and method for producing sameThe strain comprises clinical klebsiella pneumoniae resistant bacteria（K. pneumoniae43. 50, 55 and 64), pseudomonas aeruginosa drug-resistant bacteriaP. aeruginosa10. 28, 44 and 70), escherichia coliE.ColiYT8, YT16, YT21 and YT 32) and edwardsiella tarda resistant bacteriaEdwardsiella tardaLTB4-R AMP ). The MIC of each strain for ampicillin is shown in Table 2.
TABLE 2 minimum inhibitory concentration (MIC, mg/ml) of ampicillin for different strains
Each strain was divided into 4 groups, control with M9 medium, sumatriptan succinate (SPS) 1 mM, ampicillin (AMP) and ampicillin+sumatriptan succinate (AMP+SPS), respectively. Ampicillin was added at various concentrations to each strain of bacteria, with specific amounts added being shown in Table 3. Three biological replicates.
TABLE 3 doses of ampicillin antibiotics used by different strains
As a result, referring to FIG. 3, it can be seen that the sensitivity of these bacteria to ampicillin is generally significantly improved by a factor of at least 5 and up to 59 upon addition of sumatriptan succinate. It is demonstrated that sumatriptan succinate can significantly increase the sensitivity of bacteria to ampicillin.
Example 5 sterilizing action of sumatriptan succinate in combination with seven classes of antibiotics
To investigate whether or not the multi-drug resistant E.coli was effective against antibiotics other than ampicillin after the addition of sumatriptan succinate, a multi-drug resistant E.coli strain Y17 was prepared as in example 1, 1 mM sumatriptan succinate and various antibiotics (the antibiotic addition concentrations are shown in Table 4) were added, the number of viable bacteria was counted after 6 hours of action, and the survival rate of the strain was calculated for the various antibiotics after the addition of sumatriptan succinate.
Table 4 antibiotics and dosages thereof
As shown in the graph of FIG. 4, sumatriptan succinate can improve the sensitivity of multi-drug resistant escherichia coli strains to most antibiotics, and the improvement times of the sensitivity are respectively 1.5-23.54 times.
EXAMPLE 6 sumatriptan succinate promotes ampicillin efficacy in animals
6.1, sumatriptan succinate and ampicillin can improve the survival rate of mice infected with multi-drug resistant escherichia coli
Kunming mice (5-7 weeks, body weight about 20 g) were randomly divided into 4 groups (10 each) of physiological Saline control group (Saline), 50 mg/kg sumatriptan succinate control group (SPS), 125 mg/kg ampicillin treatment group (AMP), 50 mg/kg sumatriptan succinate+125 mg/kg ampicillin treatment group (AMP+SPS), respectively. The pathogenic bacteria are multi-drug resistant Escherichia coli Y17, mice are infected by intraperitoneal injection, and the injection amount is 1×10 8 CFU/CFU. 1 h and 12 h after bacterial injection, respectively, were administered. Mice were observed daily for mortality, recorded for one week, and survival of the mice was calculated.
As shown in a of fig. 5, it can be seen from the graph that the normal saline control group died at all after 24 h hours of challenge, the survival rate of the ampicillin group was 40%, and the survival rates of sumatriptan succinate and ampicillin group were 90%;48 h, the time is: the survival rate of the ampicillin group is 20%, and the survival rates of sumatriptan succinate and ampicillin group are 80%; the survival rate of the ampicillin group remained at 20% and the survival rates of sumatriptan succinate and ampicillin group remained at 80% for seven days thereafter. Therefore, the sumatriptan succinate can improve the survival rate of ampicillin on drug-resistant bacteria to reach 60%, and the result shows that the sumatriptan succinate cooperates with the ampicillin to improve the survival rate of mice on drug-resistant bacteria infection.
6.2, sumatriptan succinate and ampicillin are cooperated to improve the clearance capacity of mouse organs to drug-resistant bacteria
The retention of drug-resistant bacteria in organs of mice after the mice are injected with sumatriptan succinate and ampicillin is further studied. Kunming mice (5-7 weeks, body weight about 20 g) were randomly divided into 4 groups (6 each) of physiological saline control group, 50 mg/kg sumatriptan succinate control group, 25 mg/kg ampicillin treatment group, and 50 mg/kg sumatriptan succinate+25 mg/kg ampicillin treatment group, respectively. The pathogenic bacteria are multi-drug resistant Escherichia coli Y17, mice are infected by intraperitoneal injection, and the injection amount is 1×10 6 CFU/CFU. 1 h and 12 h after bacterial injection, respectively, were administered. After the final administration treatment, the organs of the mice were taken out 12 h, weighed, 1 ml of physiological saline was added per gram, and after sufficient grinding, the supernatant was subjected to gradient dilution, and the bacterial content (viable bacteria count/gram) in the organs was measured by plate counting.
The statistical results are shown in fig. 5B, and the number of bacteria in the organs of mice was significantly reduced after injection of sumatriptan succinate + ampicillin compared to mice in the ampicillin group alone. The specific conditions are as follows: for the liver, 6.53E+05 CFU/g from the ampicillin group was reduced to 3.96E+04 CFU/g from sumatriptan succinate and ampicillin group by a factor of 1.65. For spleen, 1.04E+06 CFU/g from ampicillin group was decreased to 3.79E+04 CFU/g from sumatriptan succinate and ampicillin group, the decrease multiple was 2.73 times. For the kidneys, 6.4E+05 CFU/g from the ampicillin group was reduced to 2.44E+04 CFU/g from sumatriptan succinate and ampicillin group, the fold reduction was 2.63 fold. The results demonstrate that sumatriptan succinate greatly promotes the clearance of ampicillin from multi-drug resistant E.coli Y17 in mice.
According to the results of animal experiments, sumatriptan succinate can improve the sensitivity of multi-drug resistant bacteria in the body to ampicillin.
Example 7 sumatriptan succinate enhances the mechanism of bacteria sensitivity to ampicillin
In order to research the mechanism of improving the sensitivity of the bacteria to ampicillin by sumatriptan succinate, the metabolic mechanism research of improving the sensitivity of the bacteria to ampicillin by sumatriptan succinate is carried out by taking escherichia coli K12 BW25113 as a research object.
7.1 increasing the sensitivity of bacteria to ampicillin by promoting ROS production
After the escherichia coli is treated by exogenously adding sumatriptan succinate, the change of the metabolism of the bacteria is analyzed, and the fact that most of metabolites are up-regulated after the bacteria are treated by sumatriptan succinate, particularly the metabolites related to pyruvic acid circulation are obviously up-regulated is found. To verify this analysis, the gene-deleted strains of Escherichia coli, which had been subjected to pyruvic acid cycle, were used, and after addition of sumatriptan succinate, the sensitivity of these gene-deleted strains to ampicillin was investigated.
As a result, as shown in FIG. 6, it was revealed that the effect of sumatriptan succinate on improving the sensitivity of the bacterium to AMP was lost when the genes frdA/B/C/D, sdhA/B/C/D, aceE and acnA/B were deleted. The results demonstrate that the gene of E.coli pyruvate circulation is indeed associated with exogenous addition of sumatriptan succinate.
Literature (Messner KR, imlay JA. Mechanism of superoxide and hydrogen peroxide formation by fumarate reductase, succinate dehydrogenase, and aspartate oxidase, J Biol chem 2002,277 (45): 42563-71) suggests that FrdABCD, sdhABCD is associated with oxidative stress. Then the effect of SPS synergistic AMP sterilization was lost after these funds were lost, suggesting that SPS synergistic AMP sterilization may be correlated with ROS, and thus ROS production was determined. Samples of E.coli K12 bacteria were prepared as in example 1 and metabolites or/and antibiotics were added as in example 2 sterilization. After incubation at 37℃for 6 hours, 10 were taken 7 Was mixed with 10. Mu.M ROS assay dye (2 ',7' -Dichlorofluorescin diacetate, D6883, sigma), incubated at 37℃for 30 min, and ROS fluorescence values (F485 nm/F535 nm) were determined using a Victor instrument.
The results are shown in FIG. 7, A, which shows that bacterial addition of AMP while SPS is added, the ROS do rise significantly, 1.61-fold and 2.53-fold, respectively, from SPS and AMP alone. On this basis, the ROS scavenger Thiourea (Thiourea) and the antioxidant alpha-tocopherol (alpha-tocopherol) were added again, and ROS were reduced by 3.38 and 2.38 times respectively.
The corresponding survival rates were also determined and are shown in FIG. 7, B, which shows that bacterial addition of AMP with SPS addition significantly decreased by 44.24 and 33.41 fold compared to single SPS and AMP addition, respectively. On the basis, the ROS scavenger Thiourea (Thiourea) and the antioxidant alpha-tocopherol (alpha-tocopherol) are added, so that the survival rate is respectively improved by 35.02 times and 27.88 times.
In summary, exogenous addition of SPS can effectively increase ROS levels in bacteria to increase their sensitivity to antibiotics; thiourea and alpha-tocopherol reduce the level of bacteria-resistant ROS, thereby reducing the bactericidal effect of SPS on AMP.
7.2 exogenous addition of sumatriptan succinate to increase intracellular antibiotic concentration in bacteria
Bacterial death is related to the amount of antibiotic that enters the interior of the bacteria, and bacterial resistance is due to the fact that the concentration of antibiotic that enters the bacteria is lower than the concentration that causes it to die. To investigate the mechanism of action of sumatriptan succinate to increase the sensitivity of escherichia coli to antibiotics, it was verified whether or not the action was performed by increasing the number of antibiotics entering the inside of the bacteria, the bacteria prepared according to example 1 were divided into 3 groups: 1 control group (ampicillin-only group) and 2 experimental groups (ampicillin + sumatriptan succinate; 2 ampicillin + sumatriptan succinate + thiourea) were incubated on a shaker at 37℃and 200 rpm for 6 h. The cultured bacteria are washed and resuspended in normal saline, OD600 is regulated to 1.0, 1 milliliter of thalli is taken for ultrasonic crushing, and supernatant is taken for antibiotic content measurement after centrifugation. An ampicillin ELISA rapid diagnosis kit of Shenzhen green poetry biotechnology Co.
The results are shown in FIG. 8, and it can be seen from the graph that the antibiotic amount in bacteria of the experimental group to which ampicillin and sumatriptan succinate were added was increased by 3.54 times as compared with the control group to which ampicillin alone was added; on the basis, the amount of antibiotics in the experimental group added with thiourea is obviously reduced by 5.04 times compared with the experimental group added with ampicillin and sumatriptan succinate. This result suggests that sumatriptan succinate does increase the amount of antibiotic that enters the bacteria while ROS levels in bacteria are related to antibiotic intake.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (3)
1. The application of the triptan medicine in preparing the anti-infective medicine is characterized in that the triptan medicine improves the sensibility of bacteria to antibiotics in the anti-infective medicine;
the antibiotics include penicillin, cephalosporin, quinolone, tetracycline, aminoglycoside, chloramphenicol or carbapenem antibiotics;
the penicillin antibiotics are amoxicillin or penicillin G; the cephalosporin antibiotics are cefoperazone or ceftriaxone; the quinolone antibiotics are ciprofloxacin or norfloxacin; the tetracycline antibiotics are tetracycline or aureomycin; the aminoglycoside antibiotics are kanamycin or gentamicin; the chloramphenicol antibiotic is chloramphenicol; the carbapenem antibiotic is meropenem;
the triptan medicine comprises zolmitriptan, rizatriptan, naratriptan, eletriptan, almotriptan, sumatriptan or pharmaceutically acceptable salts thereof;
the bacteria include Pseudomonas aeruginosa, klebsiella pneumoniae, escherichia coli or Edwardsiella tarda, or drug-resistant bacteria of the above bacteria.
2. The use according to claim 1, wherein the triptan is used in vitro at a concentration of 0.01 to 2 mM.
3. An anti-infective pharmaceutical composition comprising a triptan and an antibiotic; the antibiotics include penicillin, cephalosporin, quinolone, tetracycline, aminoglycoside, chloramphenicol or carbapenem antibiotics;
the penicillin antibiotics are amoxicillin or penicillin G; the cephalosporin antibiotics are cefoperazone or ceftriaxone; the quinolone antibiotics are ciprofloxacin or norfloxacin; the tetracycline antibiotics are tetracycline or aureomycin; the aminoglycoside antibiotics are kanamycin or gentamicin; the chloramphenicol antibiotic is chloramphenicol; the carbapenem antibiotic is meropenem;
the triptan medicine comprises zolmitriptan, rizatriptan, naratriptan, eletriptan, almotriptan, sumatriptan or pharmaceutically acceptable salts thereof;
the molar ratio of the triptan drug to the antibiotics is (0.14-20): 1.
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108403676A (en) * | 2018-03-20 | 2018-08-17 | 中山大学 | Application of the succinic acid in terms of improving sensibility of bacteria on antibiotic |
| CA3213383A1 (en) * | 2021-03-25 | 2022-09-29 | Michael Wood | Pharmaceutical compositions comprising zolmitriptan |
| CN115192561A (en) * | 2022-08-24 | 2022-10-18 | 中山大学 | Application of sodium formate in preparing anti-infective medicine |
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| WO2020176554A1 (en) * | 2019-02-28 | 2020-09-03 | Genentech, Inc. | Antibacterial peptides and methods of use |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108403676A (en) * | 2018-03-20 | 2018-08-17 | 中山大学 | Application of the succinic acid in terms of improving sensibility of bacteria on antibiotic |
| CA3213383A1 (en) * | 2021-03-25 | 2022-09-29 | Michael Wood | Pharmaceutical compositions comprising zolmitriptan |
| CN115192561A (en) * | 2022-08-24 | 2022-10-18 | 中山大学 | Application of sodium formate in preparing anti-infective medicine |
Non-Patent Citations (2)
| Title |
|---|
| 国产氨舒钠体外抗菌活性;雷军, 凌保东, 张淑华, 洪峥, 吴文蓉, 王浴生;川北医学院学报(第01期);摘要、第3页左栏第1段 * |
| 曲坦类药物的安全性与合理应用;徐蜀远, 季晓丽;国外医药.合成药.生化药.制剂分册(第04期);摘要 * |
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