CN110151741B - New application of protocatechualdehyde - Google Patents
New application of protocatechualdehyde Download PDFInfo
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- CN110151741B CN110151741B CN201910615961.6A CN201910615961A CN110151741B CN 110151741 B CN110151741 B CN 110151741B CN 201910615961 A CN201910615961 A CN 201910615961A CN 110151741 B CN110151741 B CN 110151741B
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- pseudomonas aeruginosa
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/11—Aldehydes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- 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 application relates to the technical field of medicines, in particular to a new application of protocatechualdehyde. The application provides a new application of protocatechuic aldehyde, the natural medicine protocatechuic aldehyde has a good inhibition effect on a bacterial quorum sensing system, the protocatechuic aldehyde has an excellent QS signal molecule inhibition effect, and the protocatechuic aldehyde is a natural substance and has low toxicity and side effects, so that the technical problem of antibiotic resistance is well solved.
Description
Technical Field
The application relates to the technical field of medicines, in particular to a new application of protocatechualdehyde.
Background
With the widespread use of antibiotics, which aim to kill bacteria or inhibit bacterial growth, the resistance of microorganisms is becoming higher and higher under such a great selection pressure, and the rate of resistance formation is also increasing in proportion to the sterilization capacity of antibiotics. Once resistance is developed, it will remain. The continued use of antibiotics only provides selective pressure for the high-drug resistant strains to promote replication, organization and sharing of drug resistant genes, resulting in the accelerated formation of multi-drug resistant strains. Currently, antibiotic resistance has become a serious public health problem worldwide.
Another strategy for current anti-bacteria is an anti-virulence (anti-virus) strategy, namely, the anti-virulence strategy is used for directly inhibiting the expression of virulence factors of bacteria without killing or inhibiting the growth of the bacteria, so that the bacteria are locked in an avirulent or low-virulence state, and the injury capability to a host is lost or reduced. On the other hand, since the growth of bacteria is not inhibited, the bacteria are less likely to develop drug resistance. The virulence of the bacteria is regulated and controlled by a bacterial signal system, namely bacterial quorum sensing, so that the bacterial quorum sensing is inhibited, the virulence of the bacteria can be reduced, the damage of the bacteria to host cells is reduced, and the drug resistance is not easy to generate. This is bacterial Quorum Sensing (QS) system, which has become an important target for the study of novel anti-drug resistant bacterial drugs. The quorum sensing system can influence the pathogenicity of a plurality of pathogenic bacteria, and the pathogenic bacteria are regulated and controlled by the quorum sensing system in a host body to express related virulence factors so as to cause the host to suffer from diseases; the pathogenic bacteria are induced and regulated by the population to form a biofilm, so that the immune mechanism of a host can be resisted, and meanwhile, the drug resistance to chemical agents is generated. QS is a mode of signal transmission in or among bacterial cells, and controls and coordinates the behavior of the whole bacterial population by monitoring the concentration of certain signal molecules (also called self-induced molecules) such As Homoserine Lactone (AHL), responds to the stimulation of the surrounding environment together, and greatly enhances the viability of the whole bacterial population. The expression of various pathogenic factors such as extracellular protease (such as elastase), toxin (such as pyocin), rhamnolipid and the like, which are found in the prior art, is related to the regulation of the formation of biofilm (biofilm) causing bacterial drug resistance, and can regulate the motor behavior capability of pathogenic bacteria. By inhibiting the quorum sensing of bacteria, the virulence regulated by the quorum sensing system of the bacteria is also inhibited, the harm of the bacteria to a host is reduced, and the aim of preventing or assisting antibiotics to treat bacterial infection is achieved. The bacterial quorum sensing inhibitor can be used alone, and also can be used as an auxiliary therapeutic agent of antibiotics to achieve the purpose of preventing and treating bacterial infection.
China has abundant resources of traditional Chinese medicines and natural medicines, nearly ten thousand medicinal plants provide abundant material basis and sources for new medicine discovery. Moreover, the Chinese patent medicine is used for replacing antibiotics to carry out antibiosis and antiphlogosis, and has the advantages of relatively small adverse reaction and side effect, no drug resistance and the like. Therefore, many researchers do not focus on natural medicine "antibiotics" independently. An antibiotic substitute product with the same antibacterial and anti-inflammatory curative effects is found from the traditional Chinese medicine resources, and the world problem of antibiotic resistance can be well solved.
Disclosure of Invention
The application provides a new application of protocatechuic aldehyde, and the natural medicine protocatechuic aldehyde has good inhibition effect on a bacterial quorum sensing system, so that the technical problem of antibiotic resistance is well solved.
In view of the above, the present application finds an application of protocatechualdehyde in preparing a drug for inhibiting a bacterial quorum sensing system.
Preferably, the protocatechualdehyde produces an inhibitory effect on quorum sensing by pseudomonas aeruginosa and/or drug-resistant pseudomonas aeruginosa.
More preferably, the protocatechuic aldehyde produces an inhibitory effect on quorum sensing by one or more of pseudomonas aeruginosa 9027, pseudomonas aeruginosa 27853 and drug-resistant pseudomonas aeruginosa.
Preferably, the protocatechuic aldehyde produces an inhibitory effect on a biofilm of pseudomonas aeruginosa and/or drug-resistant pseudomonas aeruginosa to produce an inhibitory effect on quorum sensing by pseudomonas aeruginosa and/or drug-resistant pseudomonas aeruginosa.
Preferably, the inhibitory drug comprises a pharmaceutically acceptable excipient.
Preferably, the inhibitory drug is selected from oral formulations or injectable formulations; the oral preparation is one of dripping pills, tablets, capsules or granules; the injection preparation is selected from injection or powder injection.
Preferably, the inhibitory drugs include: 10 to 90 weight percent of protocatechuic aldehyde and 10 to 90 weight percent of pharmaceutically acceptable auxiliary materials.
More preferably, the inhibitory drugs include: 28 to 39 weight percent of protocatechuic aldehyde and 61 to 72 weight percent of pharmaceutically acceptable auxiliary materials.
It should be noted that protocatechualdehyde (3, 4-dihydroxybenzaldehyde) has the formula: c7H6O3Molecular weight: 138.12 has effects in resisting atherosclerosis, protecting nerve cells, preventing hepatic fibrosis, and resisting virus.
According to the technical scheme, the method has the following advantages:
the application provides a new application of protocatechualdehyde in preparing a drug for inhibiting bacterial quorum sensing. The experimental result shows that the protocatechualdehyde can inhibit biological membranes of pseudomonas aeruginosa 9027, pseudomonas aeruginosa 27853 and drug-resistant pseudomonas aeruginosa, and shows that the protocatechualdehyde can inhibit a quorum sensing system of bacteria, so that the effects of reducing the virulence and pathogenicity of the bacteria, not inhibiting the growth of the bacteria and not easily generating the drug resistance of the bacteria are achieved. Meanwhile, the invention also provides a non-antibiotic drug-resistant bacterium drug based on protocatechualdehyde as a main component, and is helpful for avoiding the problem of antibiotic resistance. The experimental result also shows that the protocatechuic aldehyde has better inhibition effect on the biological membranes of three pseudomonas aeruginosa.
Detailed Description
The present invention provides a novel use of protocatechualdehyde, which has excellent QS signal molecule inhibitory effect, and is a natural substance with low toxicity and side effects.
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
The raw materials used in the following examples are commercially available or self-made, pseudomonas aeruginosa 9027 (the number of the following examples is ATCC 9027), pseudomonas aeruginosa 27853 (the number of the following examples is ATCC 27853) and drug-resistant pseudomonas aeruginosa (the number of the following examples is drug-resistant strains).
Example 1
This example is a biofilm inhibition assay of protocatechuic aldehyde, comprising the steps of:
test compounds: the compound to be tested was prepared by using furanone compound (Z) -4-bromo-5- (bromomethylene) -2(5H) -furanone as a positive control and DMSO as a negative control, and preparing the positive drug and protocatechualdehyde, which is the compound of example 1 of the present application, into 32. mu.g/mL, 64. mu.g/mL, and 128. mu.g/mL, respectively.
The experimental method comprises the following steps: mu.L of each of the prepared compounds to be tested was added to the well plate, and 100. mu.L of the bacterial suspension was inoculated. A blank control (200. mu.L of LB medium) and a negative control (100. mu.L of each of LB medium and bacterial suspension) were prepared. And placing the eggs in an incubator at 37 ℃ for incubation. After 20h, absorbing bacteria liquid on the surface layer in the hole, washing with distilled water for three times, and washing off floating bacteria. Drying or oven drying, adding 220 μ L of crystal violet with concentration of 1%, standing at room temperature for 30min, and carefully washing with distilled water for 3 times; adding 230 mu L of 95% ethanol to dissolve the biological membrane-crystal violet compound, measuring the absorbance value of the pore plate at the wavelength of 630nm by an enzyme-labeling instrument, and measuring in parallel for three times.
TABLE 1 inhibition of three Pseudomonas aeruginosa biofilms by protocatechualdehyde
In Table 1, "-" indicates no inhibitory effect.
The results of the inhibition experiments of the three pseudomonas aeruginosa biofilms show that the protocatechualdehyde of the invention has inhibition effects on the biofilms of ATCC-9027 and ATCC-27853 and drug-resistant pseudomonas aeruginosa, and achieves the effect equivalent to that of a furanone compound serving as a positive drug. The protocatechualdehyde can inhibit a quorum sensing system of bacteria so as to achieve the effects of reducing the virulence and pathogenicity of the bacteria, not inhibiting the growth of the bacteria and not easily generating the drug resistance of the bacteria.
Example 2
The present example is a preparation of granules against pseudomonas aeruginosa, and the components of the granules against pseudomonas aeruginosa comprise:
7mg of protocatechualdehyde;
15mg of lactose;
3mg of 10% starch slurry;
the preparation method of the pseudomonas aeruginosa resistant granules comprises the following steps:
(1) protocatechuic aldehyde is firstly mixed with lactose for 10-15 minutes;
(2) adding 10% starch slurry to prepare soft material, sieving with 14 mesh sieve, granulating, and drying;
(3) sieving with a 12-mesh sieve, finishing granules and drying to obtain the anti-pseudomonas aeruginosa granules of the embodiment of the application.
Example 3
The embodiment is a preparation method of an anti-pseudomonas aeruginosa capsule, and the anti-pseudomonas aeruginosa capsule comprises the following components:
the preparation method of the pseudomonas aeruginosa-resistant capsule comprises the following steps:
(1) protocatechuic aldehyde is firstly mixed with lactose for 10-15 minutes;
(2) adding microcrystalline cellulose and mixing for 10-15 minutes;
(3) adding talcum powder and mixing for 3-5 min;
(4) the mixture is filled into a gelatin capsule shell to obtain the pseudomonas aeruginosa resistant capsule of the embodiment of the application.
Example 4
This example is a preparation of a drug-resistant pseudomonas aeruginosa tablet comprising:
the preparation method of the drug-resistant pseudomonas aeruginosa tablet comprises the following steps:
(1) protocatechuic aldehyde is firstly mixed with lactose for 10-15 minutes;
(2) adding 10% starch slurry to make soft material, sieving with 14 mesh sieve, granulating, drying, sieving with 12 mesh sieve, and grading;
(3) then adding the crospovidone and the magnesium stearate, and mixing for 3-5 minutes;
(4) and (3) uniformly mixing and tabletting to obtain the drug-resistant pseudomonas aeruginosa tablet of the embodiment of the application.
Example 5
This example is a biofilm inhibition assay for protocatechuic aldehyde preparations comprising the steps of:
the protocatechualdehyde granules prepared in example 2, the contents of the capsules prepared in example 3, and the tablets prepared in example 4 were taken and tested for their biofilm inhibitory activity, respectively, in the same manner as in example 1, and the test results are shown in table 2.
TABLE 2 protocatechualdehyde formulations inhibition of three Pseudomonas aeruginosa biofilms
In Table 2, "-" indicates no inhibitory effect.
The results of the three pseudomonas aeruginosa biofilms inhibition experiments show that the protocatechualdehyde preparation disclosed by the invention has an inhibition effect on the biofilms of ATCC-9027 and ATCC-27853 and drug-resistant pseudomonas aeruginosa. The protocatechualdehyde preparation can inhibit a quorum sensing system of bacteria, so that the protocatechualdehyde preparation can reduce the virulence and pathogenicity of the bacteria, does not inhibit the growth of the bacteria and does not easily generate the drug resistance of the bacteria.
The above embodiments are only used for illustrating the technical solutions of the present application, and not for limiting the same; although the present application has been described in detail with reference to the foregoing embodiments, it should be understood by those of ordinary skill in the art that: the technical solutions described in the foregoing embodiments may still be modified, or some technical features may be equivalently replaced; and such modifications or substitutions do not depart from the spirit and scope of the corresponding technical solutions in the embodiments of the present application.
Claims (5)
1. The application of protocatechualdehyde in preparing a medicament for inhibiting a bacterial quorum sensing system; the protocatechualdehyde produces an inhibitory effect on a biofilm of pseudomonas aeruginosa and/or drug-resistant pseudomonas aeruginosa to produce an inhibitory effect on quorum sensing by pseudomonas aeruginosa and/or drug-resistant pseudomonas aeruginosa.
2. The use of claim 1, wherein the inhibitory drug comprises a pharmaceutically acceptable excipient.
3. The use according to claim 1, wherein the inhibitory drug is selected from the group consisting of an oral formulation or an injectable formulation; the oral preparation is one of dripping pills, tablets, capsules or granules; the injection preparation is selected from injection or powder injection.
4. The use of claim 1, wherein the inhibitory drug comprises: 10 to 90 weight percent of protocatechuic aldehyde and 10 to 90 weight percent of pharmaceutically acceptable auxiliary materials.
5. The use of claim 1, wherein the inhibitory drug comprises: 28 to 39 weight percent of protocatechuic aldehyde and 61 to 72 weight percent of pharmaceutically acceptable auxiliary materials.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910615961.6A CN110151741B (en) | 2019-07-09 | 2019-07-09 | New application of protocatechualdehyde |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201910615961.6A CN110151741B (en) | 2019-07-09 | 2019-07-09 | New application of protocatechualdehyde |
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| CN110151741A CN110151741A (en) | 2019-08-23 |
| CN110151741B true CN110151741B (en) | 2021-09-03 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN115844861B (en) * | 2022-12-21 | 2024-01-26 | 青岛农业大学 | Application of protocatechuic aldehyde in inhibiting MRSA and medicine for reducing MRSA resistance |
| CN117045661B (en) * | 2023-10-11 | 2024-01-30 | 广东医科大学附属医院 | Application of SAHH reversible inhibitor, pharmaceutical composition and application thereof |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160339071A1 (en) * | 2015-05-22 | 2016-11-24 | The Royal Institution For The Advancement Of Learning/Mcgill University | Synergistic combination of a phenolic-rich maple syrup extract and an antibiotic |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20160339071A1 (en) * | 2015-05-22 | 2016-11-24 | The Royal Institution For The Advancement Of Learning/Mcgill University | Synergistic combination of a phenolic-rich maple syrup extract and an antibiotic |
Non-Patent Citations (2)
| Title |
|---|
| Developing natural products as potential anti-bioflm agents;Lan Lu等;《Chin Med》;20190320;第14卷(第11期);第1-17页 * |
| Polyphenolic Extract from Maple Syrup Potentiates Antibiotic Susceptibility and Reduces Biofilm Formation of Pathogenic Bacteria;Vimal B. Maisuria等;《Applied and Environmental Microbiology》;20150630;第81卷(第11期);第3782-3792页 * |
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