CN116509848B - Application of A Ji Ruige in preparation of medicine for resisting gram-positive bacterial infection - Google Patents
Application of A Ji Ruige in preparation of medicine for resisting gram-positive bacterial infection Download PDFInfo
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- CN116509848B CN116509848B CN202310502295.1A CN202310502295A CN116509848B CN 116509848 B CN116509848 B CN 116509848B CN 202310502295 A CN202310502295 A CN 202310502295A CN 116509848 B CN116509848 B CN 116509848B
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- Prior art keywords
- ruige
- staphylococcus aureus
- gram
- bacteria
- bacterial infection
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Classifications
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/4164—1,3-Diazoles
- A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N43/00—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds
- A01N43/48—Biocides, pest repellants or attractants, or plant growth regulators containing heterocyclic compounds having rings with two nitrogen atoms as the only ring hetero atoms
- A01N43/50—1,3-Diazoles; Hydrogenated 1,3-diazoles
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/08—Materials for coatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
- A61L31/14—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
- A61L31/16—Biologically active materials, e.g. therapeutic substances
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/20—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials
- A61L2300/204—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices containing or releasing organic materials with nitrogen-containing functional groups, e.g. aminoxides, nitriles, guanidines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/60—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a special physical form
- A61L2300/606—Coatings
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Wood Science & Technology (AREA)
- Vascular Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Surgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Environmental Sciences (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Zoology (AREA)
- Pharmacology & Pharmacy (AREA)
- Dentistry (AREA)
- Communicable Diseases (AREA)
- Agronomy & Crop Science (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Biomedical Technology (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
Abstract
The invention provides an application of A Ji Ruige in preparing medicines for resisting gram-positive bacterial infection, wherein the A Ji Ruige is provided with CAS number 603148-36-3. The technical scheme of the invention discloses a novel medical application of the A Ji Ruige, wherein the A Ji Ruige has better antibacterial activity on staphylococcus aureus, can obviously inhibit the formation of a biological film, penetrates through a mature biological film and effectively kills bacteria in the mature biological film; and shows more remarkable bactericidal activity than vancomycin. In addition, the A Ji Ruige has strong inhibition effect on clinical drug-resistant bacteria such as MRSA, MSSA, enterococcus faecalis and the like. Furthermore, the hemolysis test result shows that the A Ji Ruige does not inhibit the hemolysis of staphylococcus aureus.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of A Ji Ruige in preparation of medicines for resisting gram-positive bacterial infection.
Background
Gram positive bacteria (including staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis, enterococcus faecium, etc.) are common pathogens for community and nosocomial infections. Gram-positive bacteria exhibit inherent and acquired resistance to antibiotics, and with the widespread use of antibacterial agents, recent reports of gram-positive bacteria resistance to top antibiotics (including vancomycin, linezolid, daptomycin, etc.) have been increasing, which presents serious challenges for clinical anti-infective therapy. For example, the detection rate of methicillin-resistant staphylococcus aureus (MRSA) is continuously rising, and is in high priority in the list of antibiotics resistant to 'important pathogens' of the world health organization. In addition, another difficulty in common gram-positive bacterial treatment is that a higher proportion is prone to forming biofilm, which is one of the important reasons for poor clinical treatment effect of gram-positive bacterial infection. Biofilm formation can reduce sensitivity to antibacterial agents and evade attack and phagocytosis by host immune cells, and when antibiotic concentrations decrease, bacteria proliferate to refill the biofilm and shed into surrounding tissues and blood, resulting in recurrence, chronic infection and persistent disunion. Therefore, development of a novel anti-staphylococcus aureus infection drug capable of inhibiting both bacterial growth and biofilm formation has become one of the current research hot spot directions.
Disclosure of Invention
Aiming at the technical problems, the invention discloses application of Azeliragon (Azeliragon) in preparing medicines for resisting gram-positive bacterial infection, wherein A Ji Ruige has high-efficiency activity for resisting gram-positive bacterial growth and biofilm.
In this regard, the invention adopts the following technical scheme:
use of a Ji Ruige for the manufacture of a medicament for combating a gram positive bacterial infection, said a Ji Ruige, CAS No. 603148-36-3; the A Ji Ruige has the effect of inhibiting the growth of gram-positive bacteria and biofilm formation.
Wherein the structural formula of the A Ji Ruige is shown in the formula (1):
a Ji Ruige, a bioavailable advanced glycation end product Receptor (RAGE) inhibitor, inhibits the binding of hyperactivated RAGE to aβ in the brain, reduces neuroinflammation, delays neurodegenerative disease, reduces damage to the nervous system, and crosses the Blood Brain Barrier (BBB). The advanced glycation end product Receptor (RAGE) is an immunoglobulin on the cell membrane, belongs to a pattern recognition receptor, and has been shown to be closely associated with the occurrence and progression of many chronic diseases such as tumors, inflammation, alzheimer's Disease (AD), and the like. The mechanism of action of a Ji Ruige (Azeliragon) was elucidated to reduce the three neuronal damage of aβ accumulation, tau protein and chronic inflammation, which is currently known to be the most effective drug for the combined effects of RAGE, but clinical trial results indicate that it lacks effectiveness. However, no report on antibacterial aspects of the compound of a Ji Ruige has been found so far. A number of experimental studies have found that a wide range of growth inhibitory effects are exhibited by a number of gram positive bacteria by aj Ji Ruige (Azeliragon).
As a further improvement of the present invention, the gram positive bacterium is at least one of staphylococcus aureus, enterococcus faecalis, enterococcus faecium, staphylococcus epidermidis or streptococcus pneumoniae.
As a further improvement of the present invention, the concentration of the a Ji Ruige in the treatment system is not less than 6.25 μm.
As a further improvement of the present invention, the medicament is a pharmaceutical composition or formulation. Further, the medicine is injection, tablet, pill, capsule, suspending agent, granule, spray or emulsion.
The invention also discloses application of the A Ji Ruige to preparation of a coating for inhibiting gram-positive bacteria, wherein the coating is used for the surface of a medical instrument, the CAS number of the A Ji Ruige is 603148-36-3, and the structural formula is shown as formula (1); the A Ji Ruige has the effect of inhibiting the growth of gram-positive bacteria and biofilm formation.
As a further improvement of the present invention, the concentration of the a Ji Ruige in the coating is not less than 6.25 μm.
The invention also discloses application of the A Ji Ruige to preparation of an antibacterial agent for resisting gram-positive bacteria, wherein the CAS number of the A Ji Ruige is 603148-36-3, and the structural formula is shown as formula (1); the A Ji Ruige has the effect of inhibiting the growth of gram-positive bacteria and biofilm formation.
Compared with the prior art, the invention has the beneficial effects that:
the technical scheme of the invention discloses a novel medical application of the A Ji Ruige, wherein the A Ji Ruige has better antibacterial activity on staphylococcus aureus, and the MIC of the A Ji Ruige is between 6.25 mu M and 12.5 mu M, so that the A/D has the advantages of remarkably inhibiting the formation of a biological film, penetrating through the mature biological film, effectively killing bacteria in the mature biological film, and achieving antibacterial effect by changing the cell membrane permeability of the staphylococcus aureus and inducing peroxidation stress; and shows more remarkable bactericidal activity than vancomycin. In addition, the A Ji Ruige has strong inhibition effect on clinical drug-resistant bacteria such as MRSA, MSSA, enterococcus faecalis and the like. Furthermore, the hemolysis experiment result shows that the A Ji Ruige has no effect of inhibiting the hemolysis of staphylococcus aureus.
Drawings
FIG. 1 is a graph showing the results of the inhibition of growth of Staphylococcus aureus and enterococcus faecalis planktonic bacteria by example A Ji Ruige of the present invention; wherein A-C are Staphylococcus aureus ATCC29213, SA113 and YUSA139, respectively, and D-F are enterococcus faecalis 16C166, 16C51 and OG1RF, respectively.
FIG. 2 is a graph showing the results of the growth inhibition of Staphylococcus aureus and enterococcus faecalis by example A Ji Ruige of the present invention; wherein a is an a Ji Ruige versus CHS101 (MSSA) 24 hour sterilization curve; b is the 6 hour sterilization curve of a Ji Ruige versus CHS101 (MSSA); c is the 6 hour sterilization curve of A Ji Ruige versus YUSA145 (MRSA); d is a 24 hour sterilization curve for a Ji Ruige versus 16C 51.
FIG. 3 is a graph of experimental results of the inhibition of the formation of a fecal Staphylococcus aureus biofilm by A Ji Ruige of the present invention; wherein, A is the OD600 value of MRSA after being treated by the A Ji Ruige with different concentrations, B is the OD600 value of MRSA after being treated by the A Ji Ruige with different concentrations, C is the OD570 value after being dyed by 1% crystal violet of MRSA after being treated by the A Ji Ruige with different concentrations, and D is the OD570 value after being dyed by 1% crystal violet of MSSA after being treated by the A Ji Ruige with different concentrations.
FIG. 4 is a laser confocal plot of 1/2 XMIC of A Ji Ruige versus Staphylococcus aureus according to an embodiment of the invention.
Wherein, a) is a biofilm 3D image formed by staphylococcus aureus YUSA145, b) is a biofilm 3D image formed by 1/2 xMIC A Ji Ruige treated by YUSA145, c) is a biofilm sectional view formed by staphylococcus aureus YUSA145, D) is a biofilm sectional view after 1/2 xMIC A Ji Ruige treated by YUSA 145.
FIG. 5 shows the result of the slow gradient of the PI fluorescence value of A Ji Ruige with drug concentration.
Figure 6 is a graph showing the gradient hyperpolarization of a Ji Ruige drug concentration as an example of the present invention increases.
FIG. 7 shows the results of analysis of human erythrocyte hemolytic activity by A Ji Ruige of the examples of the present invention.
Detailed Description
Preferred embodiments of the present invention are described in further detail below.
Example 1
The MIC value of the A Ji Ruige on staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis and enterococcus faecium is determined by a micro-broth dilution method, and the specific steps comprise:
taking overnight culture bacteria liquid, adjusting turbidity to 0.5 McGeranium (bacterial amount about 1.0-1.5X10) 8 cfu/mL). The bacterial liquid and the CAMHB culture medium are diluted 1:100 and then added into a 96-well plate, 10 gradient holes (200,100,50,25,12.5,6.25,3.125,1.56,0.78,0.39 mu M) are arranged in each row of 12 holes, 200uL of the bacterial liquid is added into the 11 th hole to be used as a positive control, and 200uL of the CAMHB culture medium is added into the 12 th hole to be used as a negative control. MIC value determination of each antibacterial agent the culture conditions and time were carried out according to the CLSI guidelines, and after incubation at 37℃for 18 hours, the results were observed and the MIC value was calculated as the concentration of the drug in the well where no sedimentation of the bacterial liquid could be seen with naked eyes.
TABLE 1 minimum inhibitory concentration of A Ji Ruige against gram-positive bacteria
Note that: MRSA: methicillin-resistant staphylococcus aureus; MSSA: methicillin-sensitive staphylococcus aureus; faecalis: enterococcus faecalis; s. epidemic: staphylococcus epidermidis; faitium: enterococcus faecium; n is the number of strains tested.
The MIC values are shown in table 1, and it is seen that a Ji Ruige has better bacteriostatic activity against a variety of gram-positive bacteria, with MIC values mainly ranging from 6.25 μm to 12.5 μm.
Example 2
Experiment of the growth effects of a Ji Ruige on staphylococcus aureus and enterococcus faecalis.
To verify whether a Ji Ruige was able to inhibit the growth of staphylococcus aureus, enterococcus faecalis, we treated different staphylococcus aureus, enterococcus faecalis with different concentrations of a Ji Ruige, respectively, and tested their OD values at different time points. The method comprises the following specific steps: culturing Staphylococcus aureus and enterococcus faecalis overnight, diluting the overnight culture broth with Tryptone Soybean Broth (TSB) culture medium 1000 times, adding into 96-well plate, adding different concentrations (1/16×,1/8×,1/4×,1/2×and1×) of A Ji Ruige, placing into full-automatic growth curve analyzer, measuring absorbance at 600nm (OD) every 1 hr 600 ) Absorbance, to detect planktonic bacteria content in culture supernatant, incubation temperature is 37 ℃, and growth curve is drawn. This example was performed on staphylococcus aureus ATCC29213, SA113 and YUSA139, and enterococcus faecalis 16C166, 16C51 and OG1RF. As shown in fig. 1, a growth curve of a Ji Ruige was found to inhibit the growth of staphylococcus aureus ATCC29213, SA113 and YUSA139, and enterococcus faecalis 16C166, 16C51 and OG1RF, which initially indicated that a Ji Ruige has potential as an anti-gram-positive bacterial infection drug.
Example 3
A Ji Ruige sterilization profile analysis of staphylococcus aureus and enterococcus faecalis.
Log phase (OD) 600 yUSA145 bacteria solution of =0.5) was diluted 100-fold and incubated with (1×,2×,4×MIC) a Ji Ruige, (4 μg/mL) daptomycin, (16 μg/mL) vancomycin, respectively, followed by shaking at 200 rpm. Samples were then taken at 0, 3, 6, 24 hours respectively, serially diluted with sterile physiological saline, and plated on TSB plates for incubation at 37 ℃ and colony counts after 24 hours. Colony counts are expressed in CFU/mL. The CHS101 bacterial liquid was treated in the same manner.
Log phase (OD) 600 16C51 bacteria solution of=0.5) was diluted 100-fold, and incubated with (2×,4×,8×) a Ji Ruige, (8×) daptomycin, (8×) vancomycin, and then on a shaker at 200rpm, respectively. Subsequently, the first and second heat exchangers are connected,samples were taken at 0, 3, 6, 24 hours respectively, serially diluted with sterile physiological saline, and plated on TSB plates for incubation at 37 ℃ and colony counts after 24 hours. Colony counts are expressed in CFU/mL.
As shown in FIG. 2, the sterilization curve shows that the A Ji Ruige has a sterilization effect on methicillin-sensitive staphylococcus aureus (MSSA) CHS101 at 4 xMIC, has a sterilization effect on methicillin-resistant staphylococcus aureus (MRSA) YUSA145 at 2 xMIC, and has a bacteria count reduced to the detection lower limit within 24 hours, wherein the sterilization effect is stronger than 16 mug/mL vancomycin and 4 mug/mL daptomycin. While a Ji Ruige also shows remarkable bactericidal effect on enterococcus faecalis clinical strain 16C51 at 2 XMIC.
Example 4
Experiment of the effect of a Ji Ruige on the biofilm formation of staphylococcus aureus.
Biofilm formation is a difficulty in anti-infective therapy, and therefore, assessing the effectiveness of a drug must monitor its ability to inhibit biofilm. In this example, the change in the amount of the biofilm was detected by crystal violet staining, repeated 3 times, 3 duplicate wells were formed each time, and the average value was taken as the final detection result. The method comprises the following specific steps: taking overnight bacterial liquid, diluting the bacterial liquid with TSBG culture medium containing 2% glucose in 1000 times of 96-well plates, adding different sub-bacteriostatic concentrations of A Ji Ruige into each group of 3 compound wells, taking a blank culture medium without bacterial liquid as a negative control, and taking a solvent DMSO as a positive control. After incubation for 24 hours in an incubator at 37℃the absorbance at 600nm was measured with a microplate reader. The culture was gently aspirated, rinsed 3 times with sterile PBS and dried at room temperature. Methanol is fixed for 15 minutes, 1% crystal violet dye is used for dyeing for 15 minutes, sterile water is used for washing for 3 times until the control hole is colorless, and the control hole is dried at room temperature. 200 mu L of absolute ethyl alcohol is added into each hole to be dissolved, and the mixture is shaken for 1 minute to measure the absorbance at 570nm by an enzyme-labeled instrument.
As shown in fig. 3, it was found that the inhibitory effect of a Ji Ruige on planktonic bacteria of staphylococcus aureus strain was not significant, whereas the inhibitory effect on biofilm formation of staphylococcus aureus strain was significant when a Ji Ruige was 1/2×mic.
The effect of a Ji Ruige on mature biofilms was further observed with a laser confocal microscope as follows: the method adopts a glass plate method to construct a biological film, and the living bacteria change in the biological film is observed by a laser confocal microscope, and the steps are briefly described as follows: the clinical MSSA strain SA113 of staphylococcus aureus is inoculated in a culture dish with glass inlaid at the bottom, then the culture dish is put into a tin foil box to be wrapped, and is kept static at 37 ℃ for culture for 24 hours, after the culture dish is washed 3 times by using sterile 0.9% NaCl, TSBG culture mediums containing different concentrations of A Ji Ruige are added for continuous culture for 24 hours, after the culture dish is washed by using sterile PBS, live/read fluorescent dye is added, and the culture dish is kept static at room temperature for 30 minutes, and then observation and photographing are carried out under a laser confocal microscope. LIVE/DEAD fluorescent dyes contain two different nucleic acid dyes that can rapidly distinguish plasma membrane-intact LIVE bacteria from plasma membrane-incomplete DEAD bacteria. Wherein the SYTO9 green fluorescent nucleic acid dye is capable of staining both live and dead bacteria, and the fluorescence intensity increases to appear red when Propidium Iodide (PI) enters the bacteria through the destroyed cell membrane only and binds to the nucleic acid. As a result, SYTO9 and PI stained green and red for living and dead cells, respectively, as shown in FIG. 4. At a concentration of 1/2×mic for a Ji Ruige, a significant increase in the proportion of dead cells (red) compared to the control group suggests that a Ji Ruige may reduce the number of bacteria in the mature biofilm. As a result, a Ji Ruige has a better anti-biofilm activity.
Example 5
Membrane permeability assays and cytoplasmic membrane potential assay experiments.
Logarithmic phase of staphylococcus aureus SA113 cells to OD 600 =0.05, incubated with PI solution. The suspensions were treated with different concentrations of a Ji Ruige (final concentrations of 1×,2×and4×mic) and (4 μg/mL,8 μg/mL) vancomycin, and fluorescence intensity was continuously monitored (excitation wavelength 504nm, emission wavelength 523 nm) with 0.1% dmso and 0.1% Triton as controls. Reference to measurement of membrane potential was previously reported [10] Logarithmic phase staphylococcus aureus CHS101 cells were adjusted to OD 600 =0.05 suspensions were treated with different concentrations of a Ji Ruige (final concentrations of 1×,2×and4×mic) and daptomycin (2 μg/mL), the above suspension logarithm was taken as a control with 0.1% dmso and 0.1% tritonCells and 2. Mu. MDiBAC4 (3) were suspended for 5 min. The fluorescence intensity was monitored at an excitation wavelength of 622nm and an emission wavelength of 670nm after treatment with different concentrations of a Ji Ruige, and the results are shown in fig. 5 and 6.
The PI dye is a cell nucleus staining reagent capable of staining DNA, is commonly used for apoptosis detection, is an analogue of ethidium bromide, and releases red fluorescence after being embedded into double-stranded DNA. Although it cannot pass through living cell membranes, it can pass through broken cell membranes to stain nuclei, so that it can detect late apoptotic and necrotic cells (the distinguishing index of early apoptotic cells and necrotic cells is membrane permeability) and increase membrane permeability, so that it can make the nucleic acid chromosome (PI) unable to enter living cells have the opportunity to enter cells to bind with DNA. As can be seen from fig. 5, the PI fluorescence value of a Ji Ruige increased in gradient with the drug concentration, but the increase was not significant.
DiBAC4 (3) is a lipophilic anionic fluorescent dye for detecting cell membrane potential, which is non-fluorescent in itself and emits fluorescence when entering cells to bind to proteins in the cytoplasm. DiBAC4 (3) enters the cell, and an increase in intracellular fluorescence intensity, i.e. an increase in membrane potential, indicates depolarization of the cell; conversely, a decrease in intracellular fluorescence intensity, i.e., a decrease in membrane potential, is indicative of cell hyperpolarization. As shown in fig. 6, methicillin-sensitive staphylococcus aureus (MSSA) CHS101 was subjected to a gradient hyperpolarization of DiBAC4 (3) with increasing drug concentration after treatment with a Ji Ruige.
As can be seen from the data of this example, a Ji Ruige achieves bacteriostatic effects by altering the cell membrane permeability of staphylococcus aureus and inducing peroxidic stress.
Example 6
A Ji Ruige hemolysis assay for erythrocytes.
Fresh human Red Blood Cells (RBCs) were washed with PBS, then resuspended in 4% PBS, and 100 ml was added to a round bottom 96 well polystyrene microtiter plate. Then, with Triton X-100 as a positive control, the concentration of A Ji Ruige was serially diluted 2-fold starting from 400. Mu.g/mL. Then, the mixture was cultured at 37℃for 1 hour with shaking at 60 rpm. After incubation, 96-well plates were centrifuged at 1000g for 3 min, 100 μl of supernatant was pipetted into each well and transferred to a new 96-well plate. Absorbance was measured at a 450.
As shown in FIG. 7, a concentration of 400. Mu.g/mL or less of A Ji Ruige did not cause hemolysis in human erythrocytes, indicating that A Ji Ruige was safe.
Experiments of the above examples all use GraphPad prism8.0 software for data processing and image rendering. P <0.05 was considered statistically different.
The emergence of resistant staphylococcus aureus strains results in failure of traditional antibiotic treatment, which presents a serious challenge for the clinical treatment of staphylococcus aureus infections. Therefore, there is an urgent need to explore novel efficient antibacterial agents with novel antibacterial mechanisms that break bacterial resistance barriers. During the screening of clinical compound libraries for antibacterial activity, we found that a Ji Ruige (Azeliragon) exhibited growth inhibitory effects on staphylococcus aureus.
The results of the influence of the A Ji Ruige on the growth curve, the sterilization curve and the proton motive force of the plasma membrane of staphylococcus aureus show that the A Ji Ruige has a certain antibacterial activity on the clinically separated staphylococcus aureus, and the MIC of the A Ji Ruige is between 6.25 mu M and 12.5 mu M. In addition, the A Ji Ruige has strong inhibition effect on clinical drug-resistant bacteria such as MRSA, MSSA, enterococcus faecalis and the like. The bactericidal activity is an important determinant for predicting the outcome of clinical antibacterial treatments, and a Ji Ruige exhibits more pronounced bactericidal activity than vancomycin, particularly against MRSA. In addition, the formation of a staphylococcus aureus biofilm is an important virulence factor leading to chronic infections, and only a few of the traditional antibiotics are effective against biofilms. The A Ji Ruige has strong inhibition effect on the formation of staphylococcus aureus biological film, and more importantly, the A Ji Ruige can penetrate through the mature biological film and kill staphylococcus aureus in the mature biological film, and the results show that the A Ji Ruige has potential application value in clinical staphylococcus aureus anti-infection treatment.
The foregoing is a further detailed description of the invention in connection with the preferred embodiments, and it is not intended that the invention be limited to the specific embodiments described. It will be apparent to those skilled in the art that several simple deductions or substitutions may be made without departing from the spirit of the invention, and these should be considered to be within the scope of the invention.
Claims (4)
1. Use of a Ji Ruige for the manufacture of a medicament for combating a gram positive bacterial infection, characterised in that: the A Ji Ruige and CAS number is 603148-36-3; the gram positive bacteria are at least one of staphylococcus aureus, enterococcus faecalis, enterococcus faecium and staphylococcus epidermidis.
2. Use of a Ji Ruige according to claim 1 for the preparation of a medicament against gram-positive bacterial infection, characterized in that: the medicine is injection, tablet, pill, capsule, suspending agent, granule, spray or emulsion.
3. Use of a Ji Ruige for the preparation of a gram-positive bacteria inhibiting coating, characterized in that: the coating is used for the surface of a medical instrument, wherein the CAS number of the A Ji Ruige is 603148-36-3, and the gram positive bacteria are at least one of staphylococcus aureus, enterococcus faecalis, enterococcus faecium and staphylococcus epidermidis.
4. Use of a Ji Ruige for the preparation of a disinfectant against gram-positive bacteria, characterized in that: the CAS number of the A Ji Ruige is 603148-36-3, and the gram positive bacteria are at least one of staphylococcus aureus, enterococcus faecalis, enterococcus faecium and staphylococcus epidermidis.
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| CA3147702A1 (en) * | 2019-07-22 | 2021-01-28 | Humanitas Mirasole S.P.A. | Inhibitors of chi3l1 and their uses |
| CN115594642A (en) * | 2021-06-28 | 2023-01-13 | 广西医科大学（Cn） | Az Ji Ruige triazole derivative and application thereof in resisting breast cancer |
| WO2023075400A1 (en) * | 2021-10-27 | 2023-05-04 | 서울대학교산학협력단 | Pharmaceutical composition for treating tauopathy-related diseases |
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| CA3147702A1 (en) * | 2019-07-22 | 2021-01-28 | Humanitas Mirasole S.P.A. | Inhibitors of chi3l1 and their uses |
| CN115594642A (en) * | 2021-06-28 | 2023-01-13 | 广西医科大学（Cn） | Az Ji Ruige triazole derivative and application thereof in resisting breast cancer |
| WO2023075400A1 (en) * | 2021-10-27 | 2023-05-04 | 서울대학교산학협력단 | Pharmaceutical composition for treating tauopathy-related diseases |
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