CN112791073A - Application of alpha-bromocinnamaldehyde in preventing and treating bacterial infectious diseases - Google Patents
Application of alpha-bromocinnamaldehyde in preventing and treating bacterial infectious diseases Download PDFInfo
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention discloses application of alpha-bromocinnamaldehyde in preventing and treating bacterial infectious diseases, wherein the alpha-bromocinnamaldehyde can inhibit FtsZ protein polymerization, interfere normal division of bacteria and show broad-spectrum antibacterial activity on gram-positive bacteria and gram-negative bacteria. In a mouse multi-drug resistant bacteria abdominal cavity infection model, the alpha-bromocinnamaldehyde can obviously improve the survival rate of infected animals, has the characteristics of safety and low toxicity, and shows that the alpha-bromocinnamaldehyde has good antibacterial activity and can be used as a lead medicament for treating bacterial infectious diseases.
Description
Technical Field
The invention belongs to the technical field of prevention and treatment of bacterial infectious diseases, and relates to application of alpha-bromocinnamaldehyde in prevention and treatment of bacterial infectious diseases.
Background
Bacterial infection is one of the most major diseases threatening human health, and the number of cases of death due to infection is over 1000 ten thousand per year, and the spread of multi-drug resistant bacteria greatly limits the effectiveness of clinical antibacterial drug treatment.
The FtsZ protein is a key molecule for bacterial division, and is widely distributed in various bacteria and has high homology. In a non-proliferative state of the bacterium, FtsZ protein is dispersed in cytoplasm in a monomer form and an oligomer form; when the bacteria enter the division stage, FtsZ protein is polymerized to form protofilament, and participates in forming a division body complex in the middle of the bacteria to mediate the contraction and sinking of the middle of the bacteria, thereby completing the division process. The FtsZ protein inhibitor can specifically block the polymerization process of FtsZ protein and interfere the bacterial division. Therefore, the bacterial FtsZ protein has great development potential as an antibacterial drug design target.
Many natural products such as berberine, Cinnamaldehyde (CA), totarol, etc. have been demonstrated to have certain antibacterial activity, and numerous studies have demonstrated that bacterial FtsZ proteins are their targets of action. However, the lipid bilayer outer membrane structure of bacteria can prevent a plurality of substances from permeating, so that it is difficult to screen FtsZ protein targeting molecules which can be practically used for bacterial infectious diseases according to the FtsZ protein inhibition activity. alpha-Bromocinnamaldehyde (BCA) is often used for mildew prevention, antibiosis, deodorization and the like of articles, but the antibacterial spectrum and the antibacterial action mechanism are not clear, and the action of the alpha-bromocinnamaldehyde in treating in-vivo bacterial infectious diseases is not reported.
Disclosure of Invention
The invention aims to provide application of alpha-bromocinnamaldehyde in preventing and treating bacterial infectious diseases, and the alpha-bromocinnamaldehyde can be applied to preparation of medicines for preventing and treating the bacterial infectious diseases.
In order to achieve the purpose, the invention adopts the following technical scheme:
application of alpha-bromocinnamaldehyde in preparing medicine for preventing and treating bacterial infection diseases.
Preferably, the bacterium is selected from the group consisting of staphylococcus aureus, enterococcus faecalis, staphylococcus epidermidis, bacillus subtilis, escherichia coli, acinetobacter baumannii, pseudomonas aeruginosa, klebsiella pneumoniae, and salmonella typhimurium.
Preferably, the bacteria are selected from multidrug resistant strains of staphylococcus aureus, staphylococcus epidermidis, escherichia coli, and the like.
Preferably, the infectious disease is selected from sepsis.
Preferably, the use of α -bromocinnamaldehyde in the manufacture of a medicament for interfering with normal division of bacteria.
Preferably, the use of α -bromocinnamaldehyde in the manufacture of a medicament for inhibiting the polymerization process of FtsZ protein.
Preferably, the mouse gavage administration dosage of the alpha-bromocinnamaldehyde is 1-5 mg/kg.
The invention has the following beneficial technical effects:
the alpha-bromocinnamaldehyde has good antibacterial activity on gram-negative bacteria and gram-positive bacteria, can interfere normal division of bacteria by inhibiting FtsZ protein polymerization of the bacteria, can play an effective protection role on a mouse multi-drug resistant bacteria abdominal cavity infection model (improving survival rate of infected animals), has the characteristics of safety and low toxicity, and can be used as a lead medicament for research and development of bacterial infectious diseases.
Furthermore, the alpha-bromocinnamaldehyde has obvious antibacterial effect on multiple clinically separated multi-drug resistant strains.
Drawings
FIG. 1-1 shows the inhibition of FtsZ protein polymerization by α -bromocinnamaldehyde at various concentrations; the concentration of 0. mu.g/mL was used as a Control (Control).
FIGS. 1-2 show the effect of various concentrations of α -bromocinnamaldehyde on the activity of FtsZ protein GTPase.
FIGS. 1-3 show the effect of different concentrations of α -bromocinnamaldehyde on bacterial morphology, wherein A is 1% DMSO (0 μ g/mL α -bromocinnamaldehyde, Control); b, 8 mu g/mL alpha-bromocinnamaldehyde; c, 24 mu g/mL of alpha-bromocinnamaldehyde; the magnification was 5k and 10k times, and the arrow indicates that the bacteria became long.
FIG. 2-1 shows the effect of alpha-bromocinnamaldehyde on the survival rate of mouse peritoneal infection with multidrug resistant bacteria.
FIG. 2-2 shows the effect of alpha-bromocinnamaldehyde on organ bacterial titer of a mouse multidrug resistant bacteria peritoneal infection model.
FIGS. 2-3 show the effect of alpha-bromocinnamaldehyde on lung pathology in a mouse multidrug resistant bacteria peritoneal infection model.
FIG. 3-1 shows the effect of α -bromocinnamaldehyde on liver and kidney function in mice.
Detailed Description
The present invention will be further described in detail with reference to the drawings and examples, which are illustrative of the present invention and are not intended to limit the scope of the present invention.
1. Evaluation of alpha-Bromocinnamaldehyde antibacterial Activity in vitro
1.1 Minimum Inhibitory Concentration (MIC) assay: the MIC of α -bromocinnamaldehyde was determined by broth dilution on 6 gram-negative and 6 gram-positive bacteria. Taking a sterile 96-well plate, adding 100 mu L of MHB culture medium into each well, respectively sucking 100 mu L of antibacterial drug solution (comprising alpha-bromocinnamaldehyde, cinnamaldehyde, ampicillin, ceftazidime and ciprofloxacin) with the concentration of 1024 mu g/mL into the first well of each row, and adjusting the antibacterial drug concentration to be 256, 128, 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25 and 0.125 mu g/mL by dilution in multiple proportion. Incubation at 37 ℃ for 12-16 hours and OD measurement600And (3) absorbance, wherein the lowest drug concentration corresponding to a clear culture medium in each antibacterial drug group is the MIC of the drug.
The results are shown in table 1-1, and the α -bromocinnamaldehyde has broad-spectrum antibacterial activity against gram-negative bacteria and gram-positive bacteria, and especially has antibacterial activity against clinically drug-resistant strains significantly better than that against control antibacterial drugs (cinnamaldehyde, ampicillin, ceftazidime, and ciprofloxacin).
TABLE 1-1. Minimum Inhibitory Concentration (MIC) of alpha-Bromocinnamaldehyde (BCA) against drug-resistant and sensitive bacteria
Note: "S" represents sensitivity; "I" represents an intermediary; "R" represents drug resistance; "-" represents no measurement
1.2 FtsZ protein polymerization inhibition assay: mu.L of FtsZ protein solution (24. mu.M) was added to 55. mu.L of solutions containing different concentrations of alpha-bromocinnamaldehyde (0. mu.g/mL, 30. mu.g/mL, 60. mu.g/mL, and 120. mu.g/mL), mixed and incubated at room temperature for 30 minutes. The excitation wavelength and the emission wavelength of the fluorescence spectrophotometer are both set to be 500nm, the slit width is 5nm, and the gain is 700V. mu.L of the mixture was added to a spectrofluorometer cuvette (1 cm path length) and after the baseline plateaued, 4. mu.L of GTP solution (50mM) was added to initiate the FtsZ protein aggregation process for 2800 seconds of continuous detection.
As shown in fig. 1-1 (abscissa is time, ordinate is light scattering intensity, FtsZ protein aggregation may cause light scattering to increase), α -bromocinnamaldehyde can attenuate the light scattering intensity of a solution in a concentration-dependent manner, thereby indicating that it can inhibit the polymerization of FtsZ protein, and α -bromocinnamaldehyde can target FtsZ protein on a cell membrane (FtsZ protein is in a dispersed form in cytoplasm, and is localized on a bacterial cell membrane after aggregation), and exert an antibacterial effect.
1.3 FtsZ protein GTPase Activity inhibition assay: the FtsZ protein has gtpase activity and is capable of hydrolyzing GTP to release phosphate ions. In the experiment, the concentration of Phosphate ions released in a compound, FtsZ protein and GTP reaction system is detected by a Malachite Green Phosphate detection Kit (Sigma-Aldrich), so that the hydrolysis degree of GTP is determined, and the degree of inhibition of the FtsZ protein by alpha-bromocinnamaldehyde is finally determined. The system of action of the compound and FtsZ protein is 100 mu L, alpha-bromocinnamaldehyde is added to make the final concentration respectively 100, 10, 1, 0.1, 0.01, 0.001, 0.0001 and 0 mu g/mL, then FtsZ protein solution is added to make the final concentration respectively 160 mu g/mL, after mixing uniformly, the mixture is incubated for 15 minutes at room temperature. Finally, a GTP solution is added to a final concentration of 0.2mM, mixed evenly and placed in a water bath at 37 ℃ for incubation for 30 minutes. And (4) taking out 80 mu L of each group to a 96-well plate, adding 20 mu L of working reagent, uniformly mixing, and incubating at room temperature for 30 min. After the incubation was completed, the absorbance OD630 of each group was measured.
As a result, as shown in FIGS. 1-2, α -bromocinnamaldehyde was able to inhibit GTPase activity of FtsZ protein in a concentration-dependent manner. When the concentration of the alpha-bromocinnamaldehyde is about 212.9ng/mL, the GTP enzyme activity of the FtsZ protein can be inhibited by 50 percent. Experiments show that the FtsZ protein is the action target of alpha-bromocinnamaldehyde, and the alpha-bromocinnamaldehyde interferes the normal division of bacteria by inhibiting the GTP enzyme activity of the FtsZ protein.
1.4 morphological detection of bacteria: this experiment was performed by scanning electron microscopyAnd observing the influence of the alpha-bromocinnamaldehyde under different concentrations on the growth morphology of the Escherichia coli. Coli (E.coli ATCC 25922) was selected and inoculated into 3mL of LB medium, and the medium was placed on a 37 ℃ constant temperature shaker at 280rpm for overnight culture. The next day, the bacterial solution was re-inoculated according to a volume ratio of 1:100, placed in a 37 ℃ constant temperature shaking table at a rotation speed of 280rpm, cultured until the logarithmic growth phase, and placed on ice for storage. The co-incubation system of the compound and the bacteria is 2mL, and the bacterial liquid in the three groups of MHB culture media is diluted to OD600Is 0.1 (about 1X 10)8CFU/mL). Adding alpha-bromocinnamaldehyde to make the final concentrations of the three groups of compounds respectively 0, 8 and 24 mu g/mL, placing the three groups of compounds in a constant temperature shaking table at 37 ℃, rotating at 280rpm, and culturing for 6 h. After the incubation, the three groups of bacteria solutions were placed in a 1.5mL centrifuge tube at 12000rpm and centrifuged for 10 min. After discarding the supernatant, 1mL of glutaraldehyde was added to immobilize the bacteria, and the morphological changes of the bacteria were observed under a scanning electron microscope.
As shown in FIGS. 1 to 3, the control group of E.coli cells were uniform in size and normal in morphological size. Administration group Escherichia coli was administered with alpha-bromocinnamaldehyde at 1-fold MIC (8. mu.g/mL) and 3-fold MIC (24. mu.g/mL), respectively, to lengthen the bacterial morphology. These results indicate that α -bromocinnamaldehyde can inhibit bacterial growth, lengthening the cell, and thus interfere with normal bacterial growth. The number of bacterial lengthens increases with increasing concentration administered. Thus, alpha-bromocinnamaldehyde can affect bacterial FtsZ protein function, thereby interfering with normal bacterial division.
2. Evaluation of in vivo alpha-Bromocinnamaldehyde antibacterial Activity
2.1 mouse multidrug resistant bacteria abdominal cavity infection model survival curve: 20-22g male BALB/c mice were randomly divided into 2 groups (model group and alpha-bromocinnamaldehyde-treated group), 12 mice per group, fasted for 12h before infection, and freely drunk water. Clinically isolated multidrug-resistant E.coli (NDM-1E. coli XJ141015) was used as a mouse-infected strain. 100. mu.L of the bacterial suspension (about 4X 10) was intraperitoneally injected with a 1mL syringe8CFU/mL). The mice in the alpha-bromocinnamaldehyde-treated group were administered 200. mu.L of 0.5mg/mL alpha-bromocinnamaldehyde by intragastric administration (5mg/kg) 3h before infection, 1h and 8h after infection, respectively. The model group mice were treated by gavage with 200. mu.L of sterilized physiological saline (containing 5% DMSO) 3h before infection, 1h and 8h after infection, respectively. Animals were recorded every 12 hoursSurvival was observed for 7 consecutive days.
As shown in FIG. 2-1, all mice in the model group died within 2 days, indicating that the construction of the mouse sepsis model (the mice were infected by multidrug-resistant Escherichia coli by intraperitoneal injection, resulting in sepsis) was successful. The mice in the alpha-bromocinnamaldehyde treatment group all survive within 7 days, and the survival rate is 100 percent, which shows that compared with the model group, the survival rate of the BALB/c mice can be obviously improved by the intragastric administration treatment of 5mg/kg of alpha-bromocinnamaldehyde to the mice.
2.2 visceral colony count: opening the abdominal cavities of the model group and the alpha-bromocinnamaldehyde treatment group mice 18h after infection in a sterile environment, taking the Liver (Liver), the Spleen (Spleen), the Lung (Lung) and the Kidney (Kidney), weighing, placing in a homogenizer, adding 1mL of sterile PBS solution, fully grinding, homogenizing and diluting the tissue to 10 degrees2、103、104、105And 106After doubling, the mixture is evenly coated on an MHA plate, placed in an electrothermal constant temperature incubator at 37 ℃, incubated for 18h, and the bacteria CFU are counted.
As shown in FIG. 2-2, the average numbers of bacteria in the liver, spleen, lung and kidney of the model mice were 1.97X 107CFU、1.76×107CFU、2.89×106CFU and 6.11X 106And (4) CFU. The average bacterial numbers of the liver, spleen, lung and kidney of the mice treated by the alpha-bromocinnamaldehyde are respectively reduced to 8.05 multiplied by 105CFU、5.78×105CFU、1.33×105CFU and 1.21X 105CFU, the number of visceral colonies in the treatment group was significantly reduced compared to the model group, indicating that α -bromocinnamaldehyde was able to significantly inhibit the in vivo growth of bacteria.
2.3 lung HE staining: and (4) 18h and 72h after infection, respectively taking lungs of mice in a normal control group, a model group and an alpha-bromocinnamaldehyde treatment group, washing the lungs with physiological saline, placing the lungs in a 4% paraformaldehyde solution for fixation for 24h, then carrying out tissue wax coating, slicing and HE staining, and observing pathological changes of tissues.
As shown in FIGS. 2-3, the lung tissue of the mice in the model group was severely damaged, the alveolar spaces were atrophied or disappeared, the alveolar spaces were significantly widened, the alveolar walls were significantly thickened, bleeding was observed in the alveolar spaces, and fibrous tissues were significantly proliferated, as compared with the normal control group. Compared with the model group, the mice in the alpha-bromocinnamaldehyde treatment group have the advantages that the lung tissue damage is reduced, after the mice are infected for 18 hours by gastric lavage, the pulmonary alveolus structures of the mice are partially fused, the pulmonary alveolus interval is widened, fibrous tissues are proliferated, and hemorrhage is caused in the pulmonary alveolus. After 72 hours of intragastric administration and infection, the pulmonary alveolar structure of the mouse has no obvious difference compared with a normal control group, which indicates that the alpha-bromocinnamaldehyde can effectively reduce the inflammatory injury of the lung of the mouse.
3. Alpha-bromocinnamaldehyde safety assessment
3.1 detecting the functions of the liver and the kidney: 20-22g of male BALB/c mice were randomly divided into 2 groups (normal control group and α -bromocinnamaldehyde group) of 6 mice each. Sterilized normal saline (containing 5% DMSO) and alpha-bromocinnamaldehyde (5mg/kg) were administered to the stomach at 0, 4, and 11 hours, respectively, and then eyeball blood was taken 21 hours later. Standing the blood at 4 deg.C overnight, centrifuging at 2000rpm for 20min the next day, collecting serum, and detecting alanine Aminotransferase (ALT), aspartate Aminotransferase (AST), urea nitrogen (BU), and Creatinine (CRE) levels with a full-automatic biochemical analyzer.
The results are shown in figure 3-1, and the indexes of liver and kidney functions of the two groups of animals have no significant difference.
In conclusion, the alpha-bromocinnamaldehyde has broad-spectrum antibacterial activity on gram-positive bacteria and gram-negative bacteria, and has obvious antibacterial effect on clinically separated multi-drug resistant strains; the alpha-bromocinnamaldehyde interferes the normal division of bacteria by inhibiting the polymerization process of FtsZ protein, so that the shape of the bacteria is obviously lengthened; in a mouse multi-drug resistant bacteria abdominal cavity infection model, the alpha-bromocinnamaldehyde can obviously reduce the titer of visceral bacteria of an infected animal and improve the survival rate of the infected animal, and has the characteristics of safety and low toxicity, which indicates that the alpha-bromocinnamaldehyde can play a good antibacterial activity in vivo and in vitro. Therefore, the alpha-bromocinnamaldehyde can be applied to prevention and treatment of bacterial infectious diseases and preparation of medicines for preventing and treating the bacterial infectious diseases.
Claims (7)
1. Application of alpha-bromocinnamaldehyde in preparing medicine for preventing and treating bacterial infection diseases.
2. Use according to claim 1, characterized in that: the bacteria is selected from staphylococcus aureus, enterococcus faecalis, staphylococcus epidermidis, bacillus subtilis, escherichia coli, acinetobacter baumannii, pseudomonas aeruginosa, klebsiella pneumoniae or salmonella typhimurium.
3. Use according to claim 1 or 2, characterized in that: the bacteria are multidrug resistant strains.
4. Use according to claim 1, characterized in that: the infectious disease is selected from sepsis.
5. Use according to claim 1, characterized in that: alpha-bromocinnamaldehyde interferes with bacterial division.
6. Use according to claim 1, characterized in that: alpha-bromocinnamaldehyde inhibits the FtsZ protein polymerization process.
7. Use according to claim 1, characterized in that: the dosage of the alpha-bromocinnamaldehyde is 1-5 mg/kg.
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