CN116236466A - Application of hinokitiol composition in preparation of staphylococcus aureus inhibitor - Google Patents
Application of hinokitiol composition in preparation of staphylococcus aureus inhibitor Download PDFInfo
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- CN116236466A CN116236466A CN202310111188.6A CN202310111188A CN116236466A CN 116236466 A CN116236466 A CN 116236466A CN 202310111188 A CN202310111188 A CN 202310111188A CN 116236466 A CN116236466 A CN 116236466A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/12—Ketones
- A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
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- A61K31/65—Tetracyclines
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Abstract
The invention discloses an application of a cypress alcohol composition in preparing a staphylococcus aureus inhibitor, wherein after cypress alcohol is added, the survival rate of staphylococcus aureus drug-resistant bacteria is obviously reduced when the staphylococcus aureus drug-resistant bacteria are treated by tetracycline, tigecycline and aureomycin, which indicates that the two substances can improve the sensitivity of the staphylococcus aureus drug-resistant bacteria to the tetracycline, tigecycline and aureomycin and have a synergistic effect. Animal experiments show that the combination of the hinokitiol and the tetracycline can obviously reduce the staphylococcus aureus loading capacity planted in the nasal cavity of the mouse. The hinokitiol provided by the invention can be combined with tetracycline antibiotics to have a strong synergistic antibacterial effect in vivo and in vitro, and provides a brand-new technical method for preventing and controlling diseases of human beings and cultured animals.
Description
Field of the art
The invention relates to application of a juniper alcohol composition in preparation of a staphylococcus aureus inhibitor.
(II) background art
Staphylococcus aureus (Staphylococcus aureus) is a dangerous human pathogen, asymptomatic colonizing 30% of healthy individuals worldwide, but can cause invasive opportunistic infections. It is a major cause of hospital and community related infections, ranging from mild skin infections to life threatening diseases such as severe sepsis, necrotizing pneumonia, endocarditis and bacteremia. With the advent and rapid spread of multidrug-resistant bacteria, particularly methicillin-resistant staphylococcus aureus (MRSA), infection with staphylococcus aureus has become increasingly difficult to treat. Currently, MRSA has become one of the most important causes of antibiotic-resistant medical-related infections worldwide, with morbidity and mortality remaining high.
Tetracyclines are an ancient broad-spectrum antibiotic. As one of the "tetra-large" antibiotics, tetracycline represents a wide variety of active compounds, ranging from naturally occurring aureomycin to second and third generation semisynthetic derivatives such as minocycline, tigecycline, and more recently, olo Ma Dahuan. Tetracyclines exert their antibiotic activity by binding to the 30S ribosomal subunit, thereby interfering with bacterial protein synthesis. Due to their potent antimicrobial activity against a variety of pathogenic organisms, tetracycline antibiotics have been widely used in animal husbandry and in the treatment of clinical diseases, including infections caused by MRSA. However, with the massive application of tetracyclines, the problem of bacterial resistance is more and more serious, and the clinical use of tetracyclines is severely limited. The synthesis of novel tetracycline antibiotics through structural modification is an important way for overcoming bacterial drug resistance, however, the research and development investment and the output are seriously insufficient at present, and the development efficiency of the novel antibiotics is far from keeping pace with the evolution speed of bacterial drug resistance. Thus, there is an urgent need to employ other approaches to cope with increasingly resistant bacterial infections. One currently accepted effective strategy is to develop antimicrobial potentiators.
Hinokitiol (β -thujaplicin) is a natural monoterpene compound that is found in the xylem of trees of the Cupressaceae family. It is a tolfenidone derivative which is widely used in oral care and therapeutic products due to its highly effective, broad-spectrum antibacterial, anti-inflammatory, and anticancer properties. A recent study showed that E.coli harboring the plasmid-encoded tetA efflux pump gene, which resulted in the loss of the tetA resistance gene after treatment with hinokitiol. Despite extensive research on the antibacterial activity of hinokitiol, few reports have been made on the efficacy of hinokitiol in combination with antibiotics. To date, no one has studied the combination of hinokitiol with a tetracycline antibiotic.
(III) summary of the invention
The invention aims to provide an application of a hinokitiol composition in preparing a staphylococcus aureus inhibitor, wherein the composition of hinokitiol and tetracycline antibiotics can specifically enhance the synergistic antibacterial activity of the tetracycline antibiotics on staphylococcus aureus, but has no synergistic antibacterial activity on Escherichia coli (Escherichia coli) and bacillus subtilis (Bacillus subtilis), and the composition can solve the problem of increasingly serious multi-drug-resistant staphylococcus aureus infection.
The technical scheme adopted by the invention is as follows:
the invention provides an application of a hinokitiol composition in preparing a staphylococcus aureus inhibitor, wherein the hinokitiol composition is formed by combining hinokitiol and a tetracycline antibiotic, and the tetracycline antibiotic comprises tetracycline, tigecycline, minocycline and aureomycin.
The concentration ratio of the tetracycline antibiotics to the hinokitiol is 1:0.01-320.
The staphylococcus aureus can be an antibiotic sensitive or drug resistant strain, and the drug resistant bacteria can be selected from one of methicillin-resistant staphylococcus aureus (MRSA), tetracycline-resistant staphylococcus aureus or multi-drug resistant bacteria.
Compared with the prior art, the invention has the beneficial effects that:
according to the invention, after hinokitiol is added, the survival rate of staphylococcus aureus resistant bacteria is obviously reduced when the staphylococcus aureus resistant bacteria are treated by tetracycline, tigecycline and aureomycin, so that the two substances can improve the sensitivity of the staphylococcus aureus resistant bacteria to the tetracycline, tigecycline and aureomycin and have a synergistic effect. Animal experiments show that the combination of the hinokitiol and the tetracycline can obviously reduce the staphylococcus aureus loading capacity planted in the nasal cavity of the mouse.
The hinokitiol provided by the invention can be combined with tetracycline antibiotics to have a strong synergistic antibacterial effect in vivo and in vitro, and provides a brand-new technical method for preventing and controlling diseases of human beings and cultured animals.
(IV) description of the drawings
FIG. 1 shows the bactericidal effect of hinokitiol in combination with tetracycline against methicillin-resistant Staphylococcus aureus ATCC 43300.
Fig. 2 shows the bactericidal effect of sabinol in combination with tigecycline against tetracycline-resistant staphylococcus aureus ATCC 51153.
Fig. 3 shows the bactericidal effect of sabinol and aureomycin on methicillin-resistant staphylococcus aureus CGMCC 1.12409.
Fig. 4 shows the deflocculation of staphylococcus aureus in the nasal cavity of mice with hinokitiol in combination with tetracycline.
(fifth) detailed description of the invention
The invention will be further described with reference to the following specific examples, but the scope of the invention is not limited thereto:
unless specifically stated otherwise, the reagents, methods and apparatus employed in the present invention are those conventional in the art. DMSO stands for dimethyl sulfoxide.
MH broth composition (g/L): 2.0 parts of beef powder, 1.5 parts of soluble starch and 17.5 parts of acid hydrolyzed casein, wherein the solvent is water, and the pH value is 7.3+/-0.2.
MH plate: (g/L): 2.0 parts of beef powder, 1.5 parts of soluble starch, 17.5 parts of acid hydrolyzed casein, 20 parts of agar, and water as a solvent, wherein the pH value is 7.3+/-0.2.
Protease soy agar (TSA) plate composition (g/L): 15g of tryptone, 5g of soybean peptone, 5g of sodium chloride and 15g of agar, wherein the solvent is water, and the pH value is 7.3+/-0.2.
Example 1 drug sensitivity test by microdilution method
The Minimum Inhibitory Concentration (MIC) of the antibacterial drug against the bacteria was determined using a 96-well plate microdilution method. The Minimum Inhibitory Concentration (MIC) of the antibacterial agent against bacteria was determined by broth microdilution following the experimental guidelines of the american society for clinical laboratory standardization CLSI, and the specific experimental procedure was as follows:
(1) Each of the test bacteria shown in Table 1 was inoculated onto MH plates and cultured at 37℃for 24 hours. One single colony is selected from each flat plate and connected to an MH inclined plane for culturing for 24 hours at 37 ℃ for later use. Selecting a loop of test bacteria from activated slant, adding into MH liquid culture medium, shaking culturing at 37deg.C and 160rpm overnight, diluting with MH liquid culture medium to bacterial concentration of 10 6 cfu/ml is used as a test bacterial liquid.
(2) The minimum inhibitory concentration was determined by double dilution, and the operations were all performed in an ultra clean bench. The test compound was diluted with MH broth to a final concentration of 128 μg/mL. 100 mu L of each of the above-mentioned substances is added into a 96-well plate, then 100 mu L of a test bacterial liquid is added into each well, and the above-mentioned materials are uniformly mixed, incubated at 37 ℃ for 20 hours, and OD is measured 600 Values were also visually observed and the lowest concentration at which indicator bacteria were completely inhibited from growing was defined as the lowest inhibitory concentration, and the results are shown in table 1.
According to the CLSI drug sensitivity folding point standard, when the MIC of staphylococcus aureus to tetracycline is more than or equal to 16 mug/mL, the staphylococcus aureus can be judged to be a tetracycline resistant strain. As can be seen from Table 1, staphylococcus aureus ATCC 43300, ATCC 29213 and ATCC 25923 each had a MIC of 0.25 μg/mL for tetracycline, and were tetracycline-sensitive strains; and staphylococcus aureus ATCC 51153 and CGMCC1.12409 have MIC of 16-32 mug/mL for tetracycline, thus being a tetracycline resistant strain. The MIC of these resistant Staphylococcus aureus against hinokitiol is close to that of tetracycline-sensitive strain.
Table 1 MIC of hinokitiol and Tetracycline for different strains
Example 2 hinokitiol selectively enhances the synergistic antibacterial effect of tetracycline against Staphylococcus aureus
Synergistic antibacterial effects between hinokitiol and different antibiotics were measured by checkerboard broth dilution, and E.coli, B.subtilis and Staphylococcus aureus (Staphylococcus aureus) were used as test bacteria. The MIC when the two medicines are combined singly is recorded, and the combined use effect of the two medicines is calculated and judged by using the FICI index, and the specific operation is as follows:
1. hinokitiol selectivity
Synergistic antibacterial effect between hinokitiol and tetracycline was determined using a checkerboard broth dilution method. The concentration range of the combined medicine comprises 1/64 MIC-2 MIC concentration (0.5-64 mu g/mL) of hinokitiol, 1/32 MIC-2 MIC concentration (0.015-64 mu g/mL) of tetracycline, fresh MH broth is taken as a culture medium, and 50 mu L of hinokitiol with 8 concentration gradients is added to lines A-H of a 96-well plate. 8 concentration gradients of tetracycline 50. Mu.L was added to 1-7 columns, column 8 serving as growth control. The concentration of the bacterial liquid prepared by taking fresh test bacteria is adjusted to 1 multiplied by 10 by MH broth 6 The CFU/mL bacterial suspension, 100 mu L of bacterial suspension is added into each hole, the mixture is uniformly mixed, and after incubation for 20 hours at 37 ℃, MIC results are judged by the method of the example 1. And judging the combined effect by adopting partial bacteriostasis concentration indexes (fractional inhibitory concentration index, FICI). Fici=mic A Drug combination/MIC A +MIC for drug list B Drug combination/MIC B The medicine is singly used. When the FICI is less than or equal to 0.5, judging that the two medicines have a synergistic effect; when FICI is more than 0.5 and less than or equal to 1, judging that the two medicines have additive effect; when FICI is more than 1 and less than or equal to 2, judging that the two medicines have irrelevant effects; when FICI > 2, both drugs are judged to be antagonistic.
As shown in Table 2, the antibacterial activity of the tetracycline on staphylococcus aureus is greatly improved by the hinokitiol, and the antibacterial activity of the tetracycline on staphylococcus aureus can be selectively enhanced by 1-2 mug/ml hinokitiol, so that the MIC of the tetracycline on staphylococcus aureus is reduced by 4-64 times, the FICI of the two medicines on all tested staphylococcus aureus is less than 0.5, but the synergistic enhancement on bacillus subtilis and escherichia coli is not realized, and the hinokitiol can specifically enhance the antibacterial activity of the tetracycline on staphylococcus aureus.
TABLE 2 synergistic antibacterial effect of hinokitiol on Staphylococcus aureus by tetracycline
2. Detection of hinokitiol in combination with other antibiotics
Synergistic antibacterial effects between hinoki and different antibiotics were determined using checkerboard broth dilution. The test bacteria were staphylococcus aureus ATCC 51153 and ATCC 43300. The concentration range of the combined medicine comprises 1/64 MIC-2 MIC concentration (0.5-64 mu g/mL) of hinokitiol, the concentration of different antibiotics is 1/64 MIC-2 MIC concentration (0.015-64 mu g/mL), fresh MH broth is used as a culture medium, and 50 mu L of hinokitiol with 8 concentration gradients is added to lines A-H of a 96-well plate. 50. Mu.L of 8 concentration gradients of antibiotics was added to columns 1-7, column 9 serving as growth control. The concentration of the bacterial liquid prepared by taking fresh test bacteria is adjusted to 1 multiplied by 10 by MH broth 6 The CFU/mL bacterial suspension, 100 mu L of bacterial suspension is added into each hole, the mixture is uniformly mixed, and after incubation for 20 hours at 37 ℃, MIC results are judged by the method of the example 1. And judging the combined effect by adopting partial bacteriostasis concentration index FICI.
In addition to tetracycline, hinokitiol and other tetracycline antibiotics such as tigecycline, minocycline, aureomycin and the like are combined to show good synergistic antibacterial activity (FICI < 0.5) on staphylococcus aureus (Table 3), but no synergistic effect (FICI > 0.5) is caused when the hinokitiol and other antibiotics such as ciprofloxacin, vancomycin and the like are combined to show that hinokitiol can specifically enhance the antibacterial activity of the tetracycline antibiotics on staphylococcus aureus.
TABLE 3 Sabina alcohol selectively improves synergistic antibacterial effect of tigecycline, aureomycin against Staphylococcus aureus
Example 3 addition of hinokitiol improves the antibacterial effect of tetracycline antibiotics against clinically resistant Staphylococcus aureus
The synergistic antibacterial activity of the combination of hinokitiol and a tetracycline antibiotic against staphylococcus aureus was further evaluated by a time-sterilization experiment, and the specific procedure is as follows:
1. hinokitiol combined tetracycline
(1) A loop of the test staphylococcus aureus ATCC 43300 was inoculated into a tube containing 4mL of MH broth and incubated at 37℃with shaking at 120rpm for 16h. Sucking the bacterial liquid into a test tube containing 4mL MH broth, and mixing thoroughly to obtain bacterial liquid with concentration of 10 8 CFU/mL。
(2) Another 4 tubes were taken and divided into 4 groups: group 1 was a control group, with 4mL of MH broth added; group 2 was a hinokitiol group, 4mL of MH broth containing hinokitiol at a final concentration of 1 μg/mL was added; group 3 was a tetracycline group, with the addition of 4mL of MH broth containing a final concentration of 4 μg/mL tetracycline; group 4 was a hinokitiol+tetracycline group, with 4mL of MH broth containing hinokitiol and 4. Mu.g/mL tetracycline at a final concentration of 1. Mu.g/mL.
(3) Respectively adding the bacterial liquid in the step (1) into the test tubes of each group in the step (2), adding 50 mu L of each group, uniformly mixing, and carrying out shaking culture at 37 ℃ and 120 rpm; respectively taking 100 mu L of bacterial liquid at different times (0, 1, 2, 4, 8 and 24 hours), and diluting to 10 times by using sterile normal saline 4 About CFU/mL, then spread on MH agar plates, and after 24h stationary culture at 37℃colony counting was performed.
The results are shown in figure 1, and after 24h treatment, the survival number of bacteria in the combined group (combined of 1 mug/mL hinokitiol and 4 mug/mL tetracycline) is 1000 times lower than that of the single hinokitiol or tetracycline group, which shows that the combined group and the combined group have synergistic bactericidal effect on the drug-resistant staphylococcus aureus.
2. Sabina chinensis wood alcohol combined tigecycline
The procedure was the same except that Staphylococcus aureus in step 1 was changed to Staphylococcus aureus ATCC 51153, and tetracycline was replaced with tigecycline at 0.03 μg/mL, and the results are shown in FIG. 2.
As shown in FIG. 2, after 24 hours treatment, the combined group (combination of 1. Mu.g/mL hinokitiol and 0.03. Mu.g/mL tigecycline) had a bacterial survival number 10 lower than that of the hinokitiol or tetracycline alone group 8 The synergistic bactericidal effect of the combination of the two is shown.
3. Sabinol and aureomycin combination
The staphylococcus aureus in the step 1 is changed into staphylococcus aureus CGMCC1.12409, the tetracycline is replaced by 1 mug/mL aureomycin, other operations are the same, and the result is shown in figure 3.
As shown in FIG. 3, after 24 hours treatment of drug-resistant Staphylococcus aureus, the survival number of bacteria in the combination group (combination of 1. Mu.g/mL hinokitiol and 1. Mu.g/mL aureomycin) was 10 lower than that of the single hinokitiol or aureomycin group 4 The synergistic bactericidal effect of the combination of the two is shown.
1-3, the combination of hinokitiol and tetracycline (figure 1), tigecycline (figure 2) and aureomycin (figure 3) has a remarkable enhancement effect on the sterilization effect of clinically isolated staphylococcus aureus.
EXAMPLE 4 hinokitiol enhances the De-colonization of Staphylococcus aureus by tetracycline in the nasal cavity of mice
Staphylococcus aureus ATCC 43300 was plated on Tryptic Soy Agar (TSA) plates containing 500. Mu.g/mL streptomycin, and mutant strain 43300 was selected for resistance to streptomycin R MIC of antibacterial agent on bacteria was determined by 96-well plate microdilution method, and 43300 was confirmed R The MIC for streptomycin is greater than 500 μg/mL for a streptomycin resistant strain.
Inoculating the mutant strain into MH broth culture medium, shaking culturing at 37deg.C and 160rpm overnight, centrifuging at 6000rpm for 10 min, removing supernatant, washing thallus with sterile physiological saline of the same volume for 2 times, and thenResuspension of the cells with sterile physiological saline and adjustment of the cell concentration to 10 9 CFU/mL. mu.L of the fungus was dropped into the nasal cavity of an ICR mouse (weight: 18-26 g) and allowed to colonize the nasal cavity of the mouse. After the mice were kept for 24 hours, 10. Mu.L of a drug of a prescribed concentration (physiological saline, 0.5mg/kg tetracycline, 160mg/kg hinokitiol, 0.5mg/kg tetracycline+160 mg/kg hinokitiol) was dropped into the nasal cavity, and after the mice were kept for 48 hours, the animals were subjected to a cervical breakage treatment to evaluate the nasal cavity carrying condition of Staphylococcus aureus. Nasal were rubbed with 75% ethanol and dissected with sterile scissors to resect nasal tissue. The sample was then vortexed vigorously in 200 μl saline for 15 seconds. Mu.l of the nasal suspension for each nose was applied to TSA medium plates containing streptomycin (500. Mu.g/ml) and after incubation at 37℃for 24h, colonies were counted by visual inspection.
As shown in FIG. 4, both hinokitiol (160 mg/kg) and tetracycline (0.5 mg/kg) reduced the number of nasal bacteria in mice compared to the saline control treatment group; however, when hinokitiol (160 mg/kg) and tetracycline (0.5 mg/kg) were used in combination, the antibacterial effect was stronger than that of both alone, indicating that the combined application of hinokitiol and tetracycline in vivo also exhibited a remarkable synergistic antibacterial effect.
Claims (6)
1. Application of hinokitiol composition in preparing Staphylococcus aureus inhibitor is provided.
2. The use according to claim 1, wherein said sabinol composition is formed by combining sabinol with a tetracycline antibiotic.
3. The use according to claim 2, wherein the tetracycline antibiotic comprises tetracycline, tigecycline, minocycline, aureomycin.
4. The use according to claim 2, wherein the concentration ratio of the tetracycline antibiotic to hinokitiol is 1:0.01-320.
5. The use according to claim 1, wherein the staphylococcus aureus is an antibiotic-sensitive or resistant strain.
6. The use according to claim 1, wherein the resistant bacteria are selected from one of methicillin-resistant staphylococcus aureus, tetracycline-resistant staphylococcus aureus or multidrug-resistant bacteria.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116617220A (en) * | 2023-07-26 | 2023-08-22 | 南京农业大学 | Chlorogenic acid-berberine nano-medicament for resisting penicillin-resistant bacteria, pharmaceutical composition and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN116617220A (en) * | 2023-07-26 | 2023-08-22 | 南京农业大学 | Chlorogenic acid-berberine nano-medicament for resisting penicillin-resistant bacteria, pharmaceutical composition and preparation method thereof |
| CN116617220B (en) * | 2023-07-26 | 2023-09-22 | 南京农业大学 | Chlorogenic acid-berberine nano-medicament for resisting penicillin-resistant bacteria, pharmaceutical composition and preparation method thereof |
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