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CN111714490B - Application of a compound in the preparation of drugs for inhibiting bacterial quorum sensing system - Google Patents

Application of a compound in the preparation of drugs for inhibiting bacterial quorum sensing system Download PDF

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CN111714490B
CN111714490B CN202010697514.2A CN202010697514A CN111714490B CN 111714490 B CN111714490 B CN 111714490B CN 202010697514 A CN202010697514 A CN 202010697514A CN 111714490 B CN111714490 B CN 111714490B
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dihydroxyphenyl
aldehyde
piperonyl
quorum sensing
pseudomonas aeruginosa
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CN111714490A (en
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郑俊霞
黄智霖
陈鸿庚
孙平华
苏亚伦
黄家晋
王立抗
谢俊涛
杨超
田文月
胡炎鹏
朱展良
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Guangdong University of Technology
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Abstract

本发明属于医药技术领域，尤其涉及一种化合物在制备抑制细菌群体感应系统药物中的应用。本发明提供了化合物在制备抑制细菌群体感应系统药物中的应用，实验结果表明，2‑(3’,4’‑二羟苯基)‑1,3‑胡椒环‑5‑醛能够在不抑制铜绿假单胞菌生长的情况下，抑制铜绿假单胞菌群体感应系统pqsA、lasB和rhlA三种信号通路，抑制铜绿假单胞菌群体感应系统活性，进而降低细菌致病力及毒力而又不抑制其生长，减缓细菌多重耐药性的产生。

Figure 202010697514

The invention belongs to the technical field of medicine, and particularly relates to the application of a compound in the preparation of a medicine for inhibiting bacterial quorum sensing system. The invention provides the application of compounds in the preparation of drugs for inhibiting bacterial quorum sensing system. The experimental results show that 2-(3',4'-dihydroxyphenyl)-1,3-piperonyl-5-aldehyde can inhibit the In the case of Pseudomonas aeruginosa growth, it inhibits the three signaling pathways of Pseudomonas aeruginosa quorum sensing system pqsA, lasB and rhlA, inhibits the activity of Pseudomonas aeruginosa quorum sensing system, thereby reducing the pathogenicity and virulence of bacteria. It does not inhibit its growth and slows down the generation of multi-drug resistance of bacteria.

Figure 202010697514

Description

Application of compound in preparation of medicine for inhibiting bacterial quorum sensing system
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a compound in preparation of a medicine for inhibiting a bacterial quorum sensing system.
Background
With the wide clinical use of antibiotics, the drug resistance of bacteria is gradually enhanced, which not only reduces the sensitivity of antibiotics to pathogenic bacteria, but also changes the physiological and biochemical characteristics of bacteria, and causes the pathogenic bacteria to generate the original unavailable characteristics, such as drug permeability disorder, generation of drug inactivating enzyme, formation of biofilm, and the like, thereby reducing the effect of antibiotics. Currently, antibiotic resistance has become a serious public health problem worldwide.
In recent years, the bacterial Quorum Sensing (QS) system has become an important target for the study of novel drug-resistant bacterial drugs. 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.
Pathogenicity of pathogenic bacteria is regulated by QS, which system mediates the expression of pathogenic genes to achieve its pathogenicity. When the density of the pathogenic bacteria reaches a certain degree, the pathogenic bacteria synthesize and release certain signal molecules, and can start the expression of related genes and regulate and control various biological behaviors of the pathogenic bacteria, such as bioluminescence, toxin generation, biofilm formation, antibiotic generation and the like.
Therefore, the search for drugs that inhibit the quorum sensing system of bacteria is a problem that researchers in the field are in urgent need to solve.
Disclosure of Invention
In view of the above, the present invention provides an application of a compound in preparing a drug for inhibiting a bacterial quorum sensing system, and the compound is used for providing the drug for inhibiting the bacterial quorum sensing system, so that the toxicity of pathogenic bacteria can be weakened on the premise of not inhibiting the growth of pathogenic bacteria.
The specific technical scheme of the invention is as follows:
application of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde in preparing medicine for inhibiting bacterial quorum sensing system.
The experimental result shows that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde can obviously inhibit the strains lasB-gfp, pqsA-gfp and rhlA-gfp in the logarithmic growth phase of the report strain, and presents a dose-effect relationship, and the higher the concentration is, the stronger the inhibition of the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the strains lasB-gfp, pqsA-gfp and rhlA-gfp is; the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde can generate an inhibiting effect on the secretion of elastase, pyocyanin and rhamnolipid of pseudomonas aeruginosa and has an inhibiting effect on a biological membrane of the pseudomonas aeruginosa. The 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde can inhibit three signal paths of a pseudomonas aeruginosa quorum sensing system pqsA, lasB and rhlA under the condition of not inhibiting the growth of the pseudomonas aeruginosa, inhibit the activity of the pseudomonas aeruginosa quorum sensing system, further reduce the pathogenicity and the virulence of bacteria without inhibiting the growth of the bacteria, and slow down the generation of multiple drug resistance of the bacteria.
The structural formula of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde is as follows:
Figure BDA0002591840960000021
use of preferably 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde for the preparation of a medicament for inhibiting the pqsA, lasB and/or rhlA pathway.
The experimental result shows that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde can inhibit the expression of the genes of the pqsA, the lasB and the rhlA of the pseudomonas aeruginosa.
An authoritative survey issued by the national institutes of health reports that over 80% of human microbial infections are mediated by bacterial biofilms. Biofilm acts as a bacterial population, and its differentiation and development are closely related to bacterial quorum sensing. Bacteria with an intact bacterial quorum sensing system can form a biofilm that develops and differentiates normally and is typically resistant to antimicrobials, while bacteria with a defective bacterial quorum sensing system cannot form a typical biofilm, have a significantly reduced resistance to antibiotics, are easily washed away, and are sensitive to antimicrobials. The pseudomonas aeruginosa has strong capability of forming a biofilm on the surface of a tissue, and the formation and the diffusion of the biofilm are also an important mechanism for causing the multiple drug resistance of the pseudomonas aeruginosa.
Use of preferably, 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde for the preparation of a medicament for reducing the formation of bacterial biofilms.
Pseudomonas aeruginosa (p.aeruginosa), also known as pseudomonas aeruginosa, is a gram-negative bacterium, is also an important opportunistic bacterium, often causes nosocomial infections such as respiratory tract infection, pneumonia, urinary tract infection and the like, is considered as the third most pathogenic bacterium causing infections in hospital for patients, and seriously harms the health and life of human beings. The pseudomonas aeruginosa mostly shows strong drug resistance, and the drug resistance mechanism mainly comprises the formation of a biological membrane, the generation of antibiotics to inactivate enzymes and the inhibition of the permeability of drugs. The pseudomonas aeruginosa quorum sensing system comprises a las system, an rhl system and a pqs system, and signal molecules coded by the pseudomonas aeruginosa quorum sensing system can jointly participate in regulating the generation of secondary metabolites such as rhamnolipid, hemolysin, chitinase and cyanide; in addition, each subsystem has a cascade regulation mechanism, and the main control factors of the las system can regulate the expression of other system genes, and the pqs system is also the junction of the las system and the rhl system. The Las system of the pseudomonas aeruginosa dominates the growth and maturation process of the biofilm, the formation of the biofilm can be effectively inhibited by inhibiting the Las system, the Rhl system plays an important role in the formation of the biofilm, the Rhl system can regulate the production of rhamnolipid, plays a role in maintaining the opening and fixing structure of a biofilm channel and the like, and shows that the production of the biofilm is closely related to the induction of bacterial groups, so that a drug which inhibits or destroys the communication among bacteria and does not apply selective pressure to the bacteria becomes an important choice for preventing the production of the biofilm of pathogenic bacteria and the formation of drug resistance. The high intrinsic drug resistance of the pseudomonas aeruginosa is inseparable from a quorum sensing system of the pseudomonas aeruginosa, and the quorum sensing system controls the expression of pathogenic factors such as biofilm, exotoxin, elastase, hemolysin, pyocyancin and the like, and the pathogenic factors determine the pathogenic capability of the pseudomonas aeruginosa on a host.
Preferably, the bacteria are pseudomonas aeruginosa and/or drug-resistant pseudomonas aeruginosa.
Preferably, the use of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde for the manufacture of a medicament for inhibiting the secretion of elastase, pyocyanin and/or rhamnolipid.
Preferably, 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde is obtained by extracting plumula Nelumbinis. Lotus plumule (Plumula nelumbinis), also known as lotus seed of Job's tears, seed of bitter Job's tears and lotus plumule, was first found in Tang's powder, "edible herbal medicine", is a dry embryo in mature seed of perennial aquatic plant lotus of Nymphaeaceae, and its production place is mainly distributed in Hunan, Hubei, Fujian, Jiangsu, Zhejiang and Jiangxi provinces of China. The lotus plumule is cold in nature and bitter in taste, enters heart and kidney channels, has the effects of clearing heart fire and soothing nerves, communicating heart and kidney and arresting seminal emission and stopping bleeding, is used for treating diseases such as heat entering pericardium, coma and delirium, heart and kidney imbalance, insomnia and spermatorrhea, blood heat and hematemesis and the like, and is one of the commonly used traditional Chinese medicines with the effects of clearing heat and removing toxicity.
In the invention, the extraction of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde comprises the following steps:
a) extracting plumula Nelumbinis with solvent under reflux, and removing insoluble substances to obtain first extract;
b) sequentially extracting the first extract by using petroleum ether, ethyl acetate and n-butanol, and taking ethyl acetate extract to obtain an ethyl acetate extract;
c) separating the ethyl acetate extract by chromatography to obtain 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde.
In the step a), the mass ratio of the lotus plumule to the solvent is 1: 10-15, wherein the solvent is selected from water, methanol, ethanol, acetone or ethyl acetate, insoluble substances are removed by filtration or centrifugation, the reflux extraction temperature is 60-150 ℃, and the reflux extraction time is 0.5-80 h.
After removing insoluble matter, before obtaining the first extract, further comprising: drying under reduced pressure.
In the step b), before the first extract is sequentially extracted by petroleum ether, ethyl acetate and n-butanol, the method further comprises the following steps: dispersing the first extract in an equal volume of water;
after the ethyl acetate extract is taken, before the ethyl acetate extract is obtained, the method further comprises the following steps: vacuum drying under reduced pressure.
In step c), the chromatography is selected from normal phase chromatography, reverse phase chromatography or gel chromatography.
It should be noted that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention can be obtained commercially.
The invention also provides a medicine for inhibiting a bacterial quorum sensing system, which comprises 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde and pharmaceutically acceptable auxiliary materials.
The experimental result shows that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde inhibits the expression of the lasB-gfp, pqsA-gfp and rhlA-gfp reporter genes under the condition of not inhibiting the growth of bacteria, has a good inhibiting effect on three main signal paths which play a role in controlling a pseudomonas aeruginosa quorum sensing system, the Las system, the pqs system and the rhl system are related to the production of virulence factors such as elastase, pyocyanin and rhamnolipid, and the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has the effect of inhibiting the virulence of pseudomonas aeruginosa. Moreover, the experimental result shows that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has an inhibiting effect on the biological membrane of the pseudomonas aeruginosa. The medicament for inhibiting the bacterial quorum sensing system is beneficial to effectively solving the problem of antibiotic resistance from the root.
Preferably, the mass ratio of the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde to the pharmaceutically acceptable auxiliary materials is (1-9): (1-9).
Preferably, the medicament is an oral formulation.
Preferably, the oral preparation is a capsule, a tablet or a granule.
In conclusion, the invention provides the application of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde in the preparation of drugs for inhibiting a bacterial quorum sensing system, and experimental results show that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde can inhibit three signal pathways of pqsA, lasB and rhlA of the pseudomonas aeruginosa quorum sensing system under the condition of not inhibiting the growth of the pseudomonas aeruginosa, so that the activity of the pseudomonas aeruginosa quorum sensing system is inhibited, the pathogenicity and the toxicity of bacteria are further reduced without inhibiting the growth of the bacteria, and the generation of bacterial multi-drug resistance is slowed down.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum (600MHz) of a target compound extracted in example 1 of the present invention;
FIG. 2 is a nuclear magnetic resonance carbon spectrum (600MHz) of the target compound extracted in example 1 of the present invention;
FIG. 3 is a graph showing the inhibitory effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the expression of lasB-gfp in example 2 of the present invention;
FIG. 4 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the growth of the PAO1-lasB-gfp strain in example 2 of the present invention;
FIG. 5 is a graph showing the inhibitory effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the expression of pqsA-gfp in example 3 of the present invention;
FIG. 6 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the growth of the PAO1-pqsA-gfp strain in example 3 of the present invention;
FIG. 7 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the inhibition of rhlA-gfp expression in example 4 of the present invention;
FIG. 8 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the growth of the PAO1-rhlA-gfp strain in example 4 of the present invention;
FIG. 9 is a graph showing the inhibitory effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on pyocin secretion in example 5 of the present invention;
FIG. 10 is a graph showing the inhibitory effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on elastase secretion in example 6 of the present invention;
FIG. 11 is a graph showing the inhibitory effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on rhamnolipid secretion in example 7 of the present invention;
FIG. 12 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on biofilm inhibition in example 8 of the present invention;
wherein, in FIGS. 3 to 8, "C25" represents a group of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde, "Positive" represents a group of compounds Iberin, and "Bacteria" represents a control group of Bacteria containing only a culture in which the strain PAO1-lasB-gfp greps at 37 ℃ for 12 to 16 hours in LB medium at 200 rpm; in FIGS. 9 and 11, "C25" represents the group of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde, "Ery" represents the group of erythromycin, "control" represents the blank control group containing only medium, and "DMSO + control" represents the DMSO solvent control group; in FIG. 10, "C25" indicates the group of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde, "Fur" indicates the group of furanones, "control" indicates the blank control containing only medium, and "DMSO + control" indicates the DMSO solvent control; in FIG. 12, "C25" represents the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde group, "AQ" represents the azithromycin positive control group, and "DMSO + control" represents the 0.2% DMSO solvent control group.
Detailed Description
The invention provides application of a compound in preparing a medicament for inhibiting a bacterial quorum sensing system, which is used for providing the medicament for inhibiting the bacterial quorum sensing system so as to weaken the toxicity of pathogenic bacteria on the premise of not inhibiting the growth of pathogenic bacteria.
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 examples of the invention are all commercially or self-made, wherein the PAO1-lasB-gfp green fluorescent protein reporter strain, the PAO1-pqsA-gfp green fluorescent protein reporter strain, the PAO1-rhlA-gfp green fluorescent protein reporter strain and the Pseudomonas aeruginosa PAO1 are all from the university of Nanyang Physician.
EXAMPLE 12 extraction of- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde
This example carried out the extraction of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde, comprising the following steps:
(1) soaking 10kg plumula Nelumbinis in 80% (v/v) ethanol for 12 hr, heating under reflux for 3 times at specific temperature for 2 hr each time, vacuum filtering to remove insoluble substances, and drying the filtrate under reduced pressure to obtain the first extract. Wherein the mass ratio of the lotus plumule to the ethanol is 1: 12.
(2) Sequentially extracting the first extract with petroleum ether, ethyl acetate and n-butanol of equal volume for 3 times, collecting ethyl acetate extractive solution, and vacuum drying under reduced pressure to obtain ethyl acetate extract 4.5 g;
(3) separating the ethyl acetate extract by repeated silica gel column chromatography, open ODS column chromatography, Sephadex LH-20 column chromatography and preparative high performance liquid chromatography to obtain the target compound.
The target compound is yellow amorphous powder with molecular formula of C14H10O5. Referring to fig. 1 and fig. 2, a nuclear magnetic resonance hydrogen spectrum and a nuclear magnetic resonance carbon spectrum (600MHz) of the target compound extracted in example 1 of the present invention are shown, respectively, and the spectral data of the target compound are as follows: ESI-MS M/z 257.2[ M-H ]]-，281.3[M+Na]+；1H-NMR(CD3OD，500MHz)δ:5.20(1H，s，H-2)，7.31(1H，d，J＝1.6Hz)，7.30(1H，dd，J＝1.6，6.4Hz)，6.91(1H，dd，J＝2.5，6.0Hz)，9.67(1H，s，H-10)，6.85(1H，d，J＝1.0Hz)，6.73(1H，d，J＝1.2Hz，H-5’)，6.73(1H，d，J＝1.2Hz，H-6’)；13C-NMR(CD3OD, 125MHz) delta 104.8(C-2), 114.8(C-4), l30.8(C-5), 126.4(C-6), 116.2(C-7), 147.1(C-8), 153.7(C-9), 193.1(C-10), 146.6(C-1'), 115.4(C-2'), 146.1(C-3'), 131.1(C-4'), 115.8(C-5'), 119.4 (C-6'). The above data indicate that the target compound is 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde.
Example the Effect of 22- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the PAO1-lasB pathway
Test compounds: the compound 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention was prepared into 200mM stock solution with 100% DMSO, and isothiocyanate compound Iberin (10. mu.M) was used as a positive control, and 0.2% DMSO was used as a solvent control.
The experimental method comprises the following steps: the compounds of the invention were mixed with ABTGC medium in 96-well microtiter plates and mixed at two-fold dilution to give 100 μ L of drug-containing ABTGC medium per well. The culture of PAO1-lasB-gfp strain grown for 12-16 h in LB medium at 37 ℃ and 200rpm was diluted to 600nm (OD)600) Has a final optical density of 0.02 (2.5X 10)8CFU/mL). Next, 100. mu.L of the bacterial suspension was added to each well of a 96-well microtiter plate to give a final concentration of the compound of the invention in each well of 200, 100, 50, 25, 12.5, 6.25, 3.125, 1.5625. mu.M. And an Iberin positive control, a 0.2% DMSO solvent control, and 200. mu.L of a bacterial control, all of which are the PAO1-lasB-gfp strain, were placed on the same 96-well plate. The 96-well microtiter plates were incubated at 37 ℃ in a Tecan Infinate 200Pro plate reader for at least 16 hours, with the following parameters measured every 15 minutes: OD600GFP fluorescence signal (excitation 485nm, emission 535 nm). Inhibition assays for all test compounds and controls were performed in triplicate.
The experimental results are as follows: FIG. 3 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the inhibition of lasB-gfp expression in example 2 of the present invention. FIG. 3 shows that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has an inhibitory effect on the expression of the lasB-gfp reporter gene. After 4h of incubation, the expression level of lasB-gfp in the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde group began to increase until the incubation time reached 8h and the level of lasB-gfp in each concentration of the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde group began to stabilize; in 6-8h of log growth period of the strain, 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has obvious inhibition effect on the fluorescence of the strain lasB-gfp, and presents a dose-effect relationship, and the higher the concentration is, the stronger the inhibition effect of the compound on the fluorescence of the strain lasB-gfp is.
FIG. 4 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the growth of the strain PAO1-lasB-gfp in example 2 of the present invention. FIG. 4 shows that the concentrations of the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde group PAO1-lasB-gfp strains were almost identical except for the positive control Iberin group, and were almost unchanged by the concentration of the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde. The 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has an inhibition effect on the lasB pathway of a bacterial quorum sensing system under the condition that the growth of the report strain PAO1-lasB-gfp is not influenced.
Example 3: effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the PAO1-pqsA pathway
Test compounds: the compound 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention was prepared into 200mM stock solution with 100% DMSO, and isothiocyanate compound Iberin was used as a positive control and 0.2% DMSO was used as a solvent control.
The experimental method comprises the following steps: the experimental method steps of example 2 are repeated by taking the overnight cultured PAO1-pqsA-gfp green fluorescent protein reporter strain, and the influence of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the pqsA signal path of the pseudomonas aeruginosa quorum sensing system is detected.
The experimental results are as follows: FIG. 5 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the expression of pqsA-gfp in example 3 of the present invention. FIG. 5 shows that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has an inhibitory effect on the expression of the pqsA-gfp reporter gene, and the expression level of the pqsA-gfp in the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde group shows a tendency of increasing and then decreasing and then gradually stabilizing with the increase of culture time; the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonylenecarbonyl-5-aldehyde has an obvious inhibition effect on the fluorescence of the strain pqsA-gfp in 4-8h of the logarithmic growth phase of the strain, and presents a dose-effect relationship, and the higher the concentration is, the stronger the inhibition effect of the compound on the fluorescence of the strain pqsA-gfp is.
FIG. 6 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the growth of the PAO1-pqsA-gfp strain in example 3 of the present invention. FIG. 6 shows that the concentrations of the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde group PAO1-pqsA-gfp strains grew similarly and were independent of the concentration of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde, indicating that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention could inhibit the pqsA pathway of the bacterial quorum sensing system without affecting the growth of the reported PAO1-pqsA-gfp strain.
Example 4: effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the PAO1-rhlA pathway
Test compounds: the compound 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention was prepared into 200mM stock solution with 100% DMSO, and isothiocyanate compound Iberin (10. mu.M) was used as a positive control, and 0.2% DMSO was used as a solvent control.
The experimental method comprises the following steps: the procedure of the experimental procedure of example 2 was repeated using overnight-cultured PAO1-rhlA-gfp green fluorescent protein reporter strain.
The experimental results are as follows: FIG. 7 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the inhibition of rhlA-gfp expression in example 4 of the present invention. FIG. 7 shows that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has an inhibitory effect on the expression of the rhlA-gfp reporter gene, and the expression level of rhlA-gfp in the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde group increases with culture time and shows a gentle rising trend; in the 5-8h of log growth phase of the strain, 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has obvious inhibition effect on the fluorescence of the strain rhlA-gfp and presents a dose-effect relationship, and the higher the concentration is, the stronger the inhibition effect of the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the fluorescence of the strain rhlA-gfp is.
Please refer to FIG. 8, which is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the growth of the PAO1-rhlA-gfp strain in example 4 of the present invention. FIG. 8 shows that each of the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde groups PAO1-rhlA-gfp strains grew in a similar manner and were not affected by the change in the concentration of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde, indicating that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention has an inhibitory effect on the rhlA pathway of the bacterial quorum sensing system without affecting the growth of the reporter strain PAO 1-rhlA-gfp.
Example 5: inhibition of pyocins by 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde
Test compounds: the compound 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention was prepared as a 200mM stock solution in 100% DMSO, with erythromycin (10. mu.M) as a positive control and 0.2% DMSO as a solvent control.
Bacterial pretreatment: the cultured Pseudomonas aeruginosa was taken out and cultured in a 100mL Erlenmeyer flask containing 50mL of sterilized LB medium, to which the corresponding compound was added to a desired concentration, and the overnight bacteria was calibrated at OD600 ═ 0.01 and added to the Erlenmeyer flask, and cultured in a shaker at 37 ℃ for 24 hours at 200 r/min. After 24 hours of bacterial growth, all were mixed and OD600 was measured.
The determination method comprises the following steps: the bacteria in the Erlenmeyer flask were transferred to a 50mL centrifuge tube, centrifuged at 10000rpm/min at 4 ℃ for 10 min. After centrifugation, 40mL of the supernatant was extracted with 3mL of chloroform, and the chloroform layer (lower layer) was transferred to a new tube, 0.2M HCl (0.3 times the amount of chloroform) was added thereto, and after centrifugation, the upper layer was collected and tested for OD 520.
FIG. 9 is a graph showing the inhibitory effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the secretion of pyocin in example 5 of the present invention. FIG. 9 shows that the secretion level of Pseudomonas aeruginosa in the group of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl ring-5-aldehyde was lower than that in the control group and DMSO group, but higher than that in the erythromycin group, indicating that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl ring-5-aldehyde acts to inhibit the secretion of Pseudomonas aeruginosa pyocin.
Example 6: inhibition of Pseudomonas aeruginosa elastase secretion by 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde
Test compounds: the compound 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention was prepared as a 200mM stock solution in 100% DMSO with furanone (10. mu.M) as a positive control and 0.2% DMSO as a solvent control.
The determination method comprises the following steps: the pretreatment step of the pseudomonas aeruginosa PAO1 is the same as the example 5, after the bacteria are cultured for 24 hours, 5mL of bacterial liquid is taken, 10000rpm/min is carried out, and the centrifugal separation is carried out for 10min at 4 ℃. Filtering the mixture once by using a 0.22 mu m filter, configuring the concentration of the elastin (which is noticed to be dark and can not be kept for a long time at room temperature) to 50 mu g/mL by using 1 × reaction buffer according to the operating steps of an EnzChekfi Protease Assay Kit E6638 of a Kit, adding 100 mu L of each of the bacterial supernatant and the prepared substrate, slightly mixing the bacterial supernatant and the prepared substrate, immediately putting the bacterial supernatant and the prepared substrate into an enzyme-linked immunosorbent Assay, and continuously measuring fluorescence (excitation wavelength is 400nm and emission wavelength is 450nm) for 4 hours at intervals of 10min, wherein the height of the fluorescence represents the content of the elastase.
FIG. 10 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the inhibition of elastase secretion in example 6 of the present invention. FIG. 10 shows that the level of elastase in each experimental group gradually increases with time, but the inhibitory effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on elastase secretion is much stronger than that of the control group and the DMSO group, and that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has a certain inhibitory effect on the secretion of Pseudomonas aeruginosa elastase.
Example 7: secretion inhibition of pseudomonas aeruginosa rhamnolipid by 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde
Test compounds: the compound 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention was prepared as a 200mM stock solution in 100% DMSO, with erythromycin (10. mu.M) as a positive control and 0.2% DMSO as a solvent control.
The determination method comprises the following steps: the bacterial pretreatment step was the same as in example 5 above, and after culturing the bacteria for 24 hours, 5mL of the bacterial solution was centrifuged at 10000rpm/min at 4 ℃ for 10 min. 2mL of the supernatant was placed in a 10mL EP tube, and 4mL of diethyl ether was added thereto and shaken well to extract. The ether layer was taken 1mL in a 1.5mL EP tube and placed in a fume hood, and the ether was allowed to evaporate naturally. Dissolving the extracted rhamnolipid with 40 μ L of ultrapure water, adding 360 μ L of 0.9% orcinol solution prepared with 50% concentrated sulfuric acid, mixing, and decocting in 80 deg.C water bath for 30 min. After cooling, 200. mu.L of the suspension was placed in a 96-well plate and measured for OD 421.
FIG. 11 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the inhibition of rhamnolipid secretion in example 7 of the present invention. FIG. 11 shows that the secretion level of Pseudomonas aeruginosa in the group of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl ring-5-aldehyde is lower than that of the control group and DMSO group, even slightly lower than that of erythromycin group, and that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl ring-5-aldehyde has a strong inhibitory effect on the secretion of rhamnolipid of Pseudomonas aeruginosa, and the inhibitory effect is similar to that of erythromycin.
Example 8: biofilm inhibition assay for 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde
Test compounds: the compound 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde of the present invention was prepared into 200mM stock solution with 100% DMSO, azithromycin (10. mu.M) as a positive control, and 0.2% DMSO as a solvent control.
The experimental method comprises the following steps: 100 mul of the prepared sample to be tested is added into the pore plate respectively, and 100 mul of pseudomonas aeruginosa PAO1 bacterial liquid is inoculated. A 0.2% DMSO solvent control and an azithromycin (10 μ M) positive control were set. 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.
FIG. 12 is a graph showing the effect of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde on the inhibition of biofilm in example 8 of the present invention. Experimental data show that the 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde has a good inhibition effect on a biofilm of pseudomonas aeruginosa, and the effect of inhibiting the formation of a bacterial biofilm and not easily generating bacterial drug resistance can be achieved by inhibiting a quorum sensing system of bacteria.
Example 9: anti-pseudomonas aeruginosa quorum sensing granules
Figure BDA0002591840960000121
The preparation method of the pseudomonas aeruginosa quorum sensing resistant granules comprises the following steps:
(1) firstly, 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde is uniformly mixed with lactose, mannitol and CMS-Na;
(2) then adding the prepared 10% starch slurry into the mixture, and sieving the mixture by a 16-mesh sieve to prepare a soft material;
(3) drying at 60 ℃ in a vacuum drying oven, and finishing granules to obtain the anti-pseudomonas aeruginosa quorum sensing granules.
Example 10: anti-pseudomonas aeruginosa quorum sensing capsule
Figure BDA0002591840960000122
The preparation method of the pseudomonas aeruginosa resistant quorum sensing capsule comprises the following steps:
(1) mixing 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde with lactose for 10-15 min;
(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 anti-pseudomonas aeruginosa quorum sensing capsule.
Example 11: anti-pseudomonas aeruginosa quorum sensing tablet
Figure BDA0002591840960000131
The preparation steps of the pseudomonas aeruginosa quorum sensing tablet are as follows:
(1) mixing 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde with lactose for 10-15 min;
(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 tabletting after uniformly mixing to obtain the anti-pseudomonas aeruginosa quorum sensing tablet.
The foregoing is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, various modifications and decorations can be made without departing from the principle of the present invention, and these modifications and decorations should also be regarded as the protection scope of the present invention.

Claims (5)

  1. Use of 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde in the manufacture of a medicament for inhibiting the quorum sensing system of pseudomonas aeruginosa and/or drug-resistant pseudomonas aeruginosa.
  2. 2. Use according to claim 1, characterized in that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde is used for the preparation of a medicament for inhibiting the pqsA, lasB and/or rhlA pathway.
  3. 3. Use according to claim 1, characterized in that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde is used for the preparation of a medicament for reducing the formation of bacterial biofilms.
  4. 4. Use according to claim 1, characterized in that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde is used for the preparation of a medicament for inhibiting the secretion of elastase, pyocyanin and/or rhamnolipid.
  5. 5. Use according to claim 1, characterized in that 2- (3 ', 4' -dihydroxyphenyl) -1, 3-piperonyl-5-aldehyde is obtained by extraction of lotus plumule.
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