CN115337296B - Composite material for inhibiting drug-resistant plasmid horizontal transfer and preparation method and application thereof - Google Patents
Composite material for inhibiting drug-resistant plasmid horizontal transfer and preparation method and application thereof Download PDFInfo
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- CN115337296B CN115337296B CN202210766494.9A CN202210766494A CN115337296B CN 115337296 B CN115337296 B CN 115337296B CN 202210766494 A CN202210766494 A CN 202210766494A CN 115337296 B CN115337296 B CN 115337296B
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Classifications
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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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/201—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having one or two double bonds, e.g. oleic, linoleic acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Dispersion Chemistry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Inorganic Chemistry (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention belongs to the technical field of biological materials, and particularly discloses a composite material for inhibiting drug-resistant plasmid horizontal transfer, and a preparation method and application thereof. The invention provides a composite material for inhibiting drug-resistant plasmid horizontal transfer, which can be used as a drug-resistant plasmid conjugation inhibitor, and the preparation steps of the composite material are as follows: s1, stirring and mixing castor oil and isophorone diisocyanate, sequentially adding piperazine and a catalyst, stirring and reacting, adding N-methyldiethanolamine, adding butanone when a solution is difficult to flow, cooling after the reaction, and neutralizing; s2, adding linoleic acid into the reaction system obtained in the step S1, adding water for emulsification, stirring, and purifying to obtain the composite material. The composite material has pH response characteristics, can be used for targeting colon and cecum administration of animals, and can remarkably inhibit conjugation transfer of drug-resistant plasmids among bacteria in intestinal tracts; can be used as a novel effective plasmid inhibitor, and provides a novel method for preventing and controlling the level transmission of plasmid-mediated drug-resistant genes.
Description
Technical Field
The invention relates to the technical field of biological materials, in particular to a composite material for inhibiting drug-resistant plasmid horizontal transfer, a preparation method and application thereof.
Background
Antibiotic resistance is spreading rapidly worldwide, and drug resistance gene transmission is mainly due to plasmid-mediated horizontal gene transmission, and many of the most troublesome drug resistance problems today existAre all related to plasmid mediation of drug resistance genes. For example, a variety of important drug resistance genes (bla NDM Mcr-1, tet (X4), etc.) are both plasmid-mediated, and are accompanied by a broad spread of plasmids. The animal knots and ceca are important sites for drug-resistant gene level transfer; preventing and controlling the horizontal transmission of drug-resistant genes in the intestinal tract becomes a difficult problem.
Plasmid conjugation is a common mechanism for the transfer of bacterial drug resistance genes, and inhibition of plasmid conjugation is considered as one of the means for controlling bacterial drug resistance gene transmission. It has been found that unsaturated fatty acids are considered to be effective plasmid inhibitors (oleic acid, linoleic acid, 2-hexadecynoic and tanzawaic acids) and therefore the development and use of novel plasmid inhibitors can be a new solution. The conjugation inhibitor will be used with an antibiotic, or alone, to prevent resistance to or transmission within the pathogen. However, the research and development of the plasmid conjugation inhibitor are mostly carried out under in vitro experimental conditions, and the report of substances capable of inhibiting the propagation of drug-resistant plasmids in animal intestinal tracts is insufficient, so that the application of the plasmid conjugation inhibitor in clinical prevention and control of bacterial drug resistance is limited.
The aqueous Polyurethane (PU) has excellent adjustable performance and is widely applied to industries such as coating, adhesive, medical dressing and the like. Polyurethanes have been widely used in the medical community for drug responsive delivery systems for targeted drug release. The pH response polyurethane has wide application, can target tumors to realize accurate drug delivery, improves the treatment effect of the drug and reduces the toxic and side effects of the drug, but has no corresponding report on the propagation of bacterial drug resistance.
Disclosure of Invention
The invention aims at solving the problems and provides a composite material for inhibiting drug-resistant plasmid horizontal transfer, and a preparation method and application thereof.
It is a first object of the present invention to provide a composite material that inhibits drug-resistant plasmid level metastasis.
A second object of the present invention is to provide an application of the above composite material in preparing drug-resistant plasmid conjugation-inhibiting drugs;
the composite material is prepared by the following steps:
s1, stirring and mixing Castor Oil (CO) and isophorone diisocyanate (IPDI), sequentially adding piperazine and a catalyst, continuously stirring, then adding N-Methyldiethanolamine (MDEA), reacting until a solution is difficult to flow, adding butanone, continuously reacting, cooling, and then neutralizing;
s2, adding Linoleic Acid (LA) into the system obtained in the step S1, adding water for emulsification, stirring, and then steaming the product in a rotary way to obtain the composite material PULA (cationic polyurethane linoleic acid emulsion).
As a preferred embodiment of the present invention, the castor oil in step S1: piperazine: the molar ratio of N-methyldiethanolamine is 1:0.25: (0.89-1.19).
As a preferable technical scheme of the invention, the catalyst in the step S1 is dibutyl tin dilaurate (DBTDL) with the dosage of 0.01-0.1%.
As a preferable technical scheme of the invention, the mass fraction of the linoleic acid in the step S1 is 3.33% -3.39%.
As a preferable technical scheme of the invention, the step S1 is cooled and then acetic acid is added for neutralization.
Preferably, the composite material in the above application is capable of inhibiting the in vivo conjugative transfer of drug resistant plasmids.
Preferably, the drug-resistant plasmid conjugation inhibiting drug in the above application can be used for controlling bacterial resistance.
Compared with the prior art, the invention has the beneficial effects that:
(1) The invention provides a novel polyurethane linoleic acid composite material PULA, which is simple in preparation, high in biological safety, has pH response characteristics, and can target animal knot and cecum administration, thereby achieving the aim of accurate treatment.
(2) The application of the PULA composite material as the drug-resistant plasmid conjugation inhibitor can obviously inhibit the conjugation and transfer of the IncX4 plasmid in vivo, and provides a new thought and method for overcoming the drug resistance of bacteria.
Drawings
FIG. 1 is a schematic diagram of the synthesis of a PULA material prepared in accordance with the present invention.
FIG. 2 is a graph showing the particle size of PULA prepared in the example of the present invention, FIG. 2A is a graph showing the result of transmission microscopy of the particle size of PULA, and FIG. 2B is a graph showing the result of measurement of zeta sizer Nano-ZSE.
FIG. 3 is a graph showing the pH response release profile of PULA prepared in the experimental example of the present invention.
FIG. 4 is a chart showing HE staining of tissue sections of the PULA group and the control group prepared in example 2 of the present invention.
FIG. 5 is a graph showing the result of the fusion transfer of drug-resistant plasmids in mice inhibited by PULA prepared in example 2 of the present invention.
Detailed Description
The technical solutions of the present invention will be clearly and completely described in conjunction with the embodiments of the present invention, and it is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The experimental methods used in the embodiment of the invention are all conventional methods unless specified otherwise; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
The invention relates to a material source: LA from Shanghai Yi En chemical technologies, CO from Guangzhou New commercial Co, hep from Shanghai Aldine Biochemical technologies, MDEA from Shanghai Yi En chemical technologies, IPDI from Guangdong Weng Jiang chemical reagents, DBTDL from Shanghai Aldine Biochemical technologies, PBS from Beijing blue Jie Chemicals.
Example 1
A composite material for inhibiting drug-resistant plasmid horizontal transfer is prepared by the following steps:
5.02g of Castor Oil (CO) and 4.42g of isophorone diisocyanate (IPDI) are weighed out in an oil bath at 78℃for 10min using an electric stirrer (rotation speed 130-170 r/min) and 0.4g of piperazine (Hep) are added. Then 0.01% (10. Mu.L) of the catalyst dibutyltin dilaurate (DBTDL) was added and stirring was continued for 10min. A certain amount of N-Methyldiethanolamine (MDEA) was added, and the reaction was continued with stirring until the solution was almost stationary, 30ml of butanone was added, and stirring was continued at 60-80℃for 2 hours. Stopping heating, cooling to room temperature, adding appropriate amount of acetic acid for neutralization, and stirring for 30min. After 2.35g of Linoleic Acid (LA) was added to the reaction system and the reaction system was turned to 300r/min, 90ml of deionized water was added to emulsify the mixture, and the mixture was stirred for 2 hours. Transferring the product to a single-neck round-bottom flask, and spin-steaming at 40 ℃ for 30min to obtain the cationic novel polyurethane linoleic acid emulsion. Wherein, the mol ratio of CO, hep, MDEA is 1:0.25:0.89.
example 2
A composite material for inhibiting drug-resistant plasmid horizontal transfer is prepared by the following steps:
5.02g of Castor Oil (CO) and 4.42g of isophorone diisocyanate (IPDI) are weighed out in an oil bath at 78℃for 10min using an electric stirrer (rotation speed 130-170 r/min) and 0.4g of piperazine (Hep) are added. Then 0.01% (10. Mu.L) of the catalyst dibutyltin dilaurate (DBTDL) was added and stirring was continued for 10min. An appropriate amount of N-Methyldiethanolamine (MDEA) was added, and the reaction was continued with stirring until the solution was almost stationary, 30ml of butanone was added, and stirring was continued at 60-80℃for 2 hours. Stopping heating, cooling to room temperature, adding appropriate amount of acetic acid for neutralization, and stirring for 30min. After 2.35g of Linoleic Acid (LA) was added to the reaction system and the reaction system was turned to 300r/min, 90ml of deionized water was added to emulsify the mixture, and the mixture was stirred for 2 hours. Transferring the product to a single-neck round-bottom flask, and spin-steaming at 40 ℃ for 30min to obtain the cationic novel polyurethane linoleic acid emulsion. CO, hep, MDEA is 1:0.25:0.99.
example 3
A composite material for inhibiting drug-resistant plasmid horizontal transfer is prepared by the following steps:
5.02g of Castor Oil (CO) and 4.42g of isophorone diisocyanate (IPDI) are weighed out in an oil bath at 78℃for 10min using an electric stirrer (rotation speed 130-170 r/min) and 0.4g of piperazine (Hep) are added. Then 0.01% (10. Mu.L) of the catalyst dibutyltin dilaurate (DBTDL) was added and stirring was continued for 10min. An appropriate amount of N-Methyldiethanolamine (MDEA) was added, and the reaction was continued with stirring until the solution was almost stationary, 30ml of butanone was added, and stirring was continued at 60-80℃for 2 hours. Stopping heating, cooling to room temperature, adding appropriate amount of acetic acid for neutralization, and stirring for 30min. After 2.35g of Linoleic Acid (LA) was added to the reaction system and the reaction system was turned to 300r/min, 90ml of deionized water was added to emulsify the mixture, and the mixture was stirred for 2 hours. Transferring the product to a single-neck round-bottom flask, and spin-steaming at 40 ℃ for 30min to obtain the cationic novel polyurethane linoleic acid emulsion. CO, hep, MDEA is 1:0.25:1.09.
example 4
A composite material for inhibiting drug-resistant plasmid horizontal transfer is prepared by the following steps:
5.02g of Castor Oil (CO) and 4.42g of isophorone diisocyanate (IPDI) are weighed out in an oil bath at 78℃for 10min using an electric stirrer (rotation speed 130-170 r/min) and 0.4g of piperazine (Hep) are added. Then 0.01% (10. Mu.L) of the catalyst dibutyltin dilaurate (DBTDL) was added and stirring was continued for 10min. An appropriate amount of N-Methyldiethanolamine (MDEA) was added, and the reaction was continued with stirring until the solution was almost stationary, 30ml of butanone was added, and stirring was continued at 60-80℃for 2 hours. Stopping heating, cooling to room temperature, adding appropriate amount of acetic acid for neutralization, and stirring for 30min. After 2.35g of Linoleic Acid (LA) was added to the reaction system and the reaction system was turned to 300r/min, 90ml of deionized water was added to emulsify the mixture, and the mixture was stirred for 2 hours. Transferring the product to a single-neck round-bottom flask, and spin-steaming at 40 ℃ for 30min to obtain the cationic novel polyurethane linoleic acid emulsion. CO, hep, MDEA is 1:0.25:1.19.
experimental example 1
Determination of the entrapment Properties of the composite PULA prepared in examples 1 to 4 of the present invention
The method for measuring the drug loading and encapsulation efficiency comprises the following steps: taking a certain amount of polyurethane emulsion, filtering out non-entrapped insoluble linoleic acid through a syringe filter of 0.22 mu M, freeze-drying the emulsion, adding acetonitrile into a certain amount of freeze-dried polyurethane (M) for ultrasonic dissolution for 30-60min, centrifuging, and testing the concentration of the supernatant by utilizing HPLC to obtain the entrapped linoleic acid content (M). The actual dosage of the aqueous polyurethane emulsion is m 0 Drug Loading (LC) and Encapsulation Efficiency (EE) were calculated by the following formulas:
drug Loading (LC)% =m/mx100%
Encapsulation Efficiency (EE)% =m/m 0 ×100％
Analysis of results:
the solids content, drug loading and encapsulation efficiency of the composite materials prepared in examples 1-4 of the present invention are shown in Table 1. Wherein PU 0.99 The solid content, drug loading and encapsulation efficiency of LA are higher.
TABLE 1
Experimental example 2
Determination of particle size and Zeta potential of composite PULA prepared in examples 1-4 of the present invention
The testing method comprises the following steps: the particle size and zeta potential of the aqueous polyurethane emulsion were characterized using a zeta sizer Nano-ZSE (malvern instrument) and the emulsion was diluted to about 0.01wt% with distilled water prior to testing. The structure and particle size of the samples were further characterized using transmission electron microscopy.
Analysis of results:
the Zeta potential results are shown in Table 2, and indicate that the 4 PULAs are cationic compounds and have positive charges. The transmission microscope imaging result (see FIG. 2A) and the zeta sizer Nano-ZSE measurement result (see FIG. 2B) show that the particle sizes of the 4 PULAs are 50-500 nm, so that the 4 PULAs synthesized by the invention are all Nano-scale materials.
TABLE 2
Experimental example 3
In vitro Release test of the composite PULA prepared in examples 1-4 of the present invention under different pH conditions
The testing method comprises the following steps: solutions were prepared at pH 2,5.8,7.4. 100mL of PBS buffer was placed in a capped jar and 3 replicates were made for each concentration gradient. About 0.05g of each of the above-mentioned materials was placed in a dialysis bag of 2.5 cm. Times.5 cm, and the two ends were clamped by clamps, and placed in a PBS solution (containing 0) of 2,5.8,7.2% Tween-80), the experiment was performed on a shaker at a temperature of 37℃and a rotational speed of 120 rpm/min. 2mL of buffer solution is taken at 0h,0.5,1,2,4,6,8, 10, 12 and 24 respectively, and 2mL of Na with corresponding concentration is added after each taking 2 S, solution, keeping the volume of the solution unchanged. The samples were taken out each time and stored in a-20℃refrigerator. And after all the samples are taken out, carrying out pretreatment, and carrying out content test by using high performance liquid chromatography.
HPLC detection: and (3) building standard curve by using an LA standard substance, measuring LA response polyurethane and in-vitro release, and determining the drug concentration according to the peak area of the standard curve.
Analysis of results:
as shown in fig. 3, all four polyurethane materials have pH-responsive release characteristics, wherein PU 0.99 -LA、PU 1.09 -LA、PU 1.19 LA response release is better. The emulsion has complete structure under acidic condition (pH 2.0), and the outer membrane structure is destroyed under neutral and alkaline condition (pH 7.4) to release LA. The colon and the cecum of the animal are in a weak acidic neutral environment (pH is 6.0-7.0), so that the PULA provided by the invention can release LA in the colon and the cecum of the animal, and provides a basis for inhibiting drug-resistant plasmid conjugation and transfer.
Experimental example 4
Evaluation of cytotoxicity of composite Material PULA prepared in example 2 of the present invention
Respectively taking experimental groups and PU 0.99 Liver, kidney, spleen, stomach, duodenum, colon tissue of mice of group LA are of appropriate size and are stored in vials containing fixative.
The resulting tissue slices were sent to Bio-Inc. for tissue slice preparation and HE staining.
Analysis of results:
as shown in fig. 4, PU 0.99 Compared with the results of HE staining of tissue sections of the LA group and the control group, the liver, kidney, spleen, stomach, duodenum and colon tissues have no obvious lesions, which shows that the PU-LA has less influence on cell tissues.
Experimental example 5
Animal experiment: the composite material PULA prepared in example 2 of the present invention was selected and tested in inhibiting in vivo joint transfer.
The method comprises the following specific steps:
1. preparation of bacterial suspension
Donor bacteria E.coli MQCSZ4GFP and E.coli C600-lux were grown to log phase (OD 600 About 0.3).
2. Animal experiment flow
The invention provides a drug-resistant plasmid joint transfer model in the intestinal tract of a mouse:
the invention takes 6-8 week old C57B6/7 mice as a study object, and causes the intestinal flora disturbance of the mice by continuously lavaging 200 mu L/day streptomycin (the concentration is 5 g/L). The mice were fasted with streptomycin removed at night 4 days after streptomycin administration. Mice were filled with 200 μl of a suspension of donor and recipient bacteria and diets and drinking were restored 1h after challenge. 0.1g of mouse feces/mouse were collected 1, 3, 5 and 7 days after the challenge, the feces were pretreated and plated on selective medium by double dilution, and placed at 37℃for stationary culture for 18-24 hours, and the numbers of donor bacteria and recipient bacteria were counted and the conjugation transfer frequency was calculated.
Frequency of zygote transfer = number of zygotes/number of recipient bacteria
The donor strain was an E.coli MQCSZ4GFP constructed from this laboratory [ refer to patent CN110129246A ], which carries a conjugatively transferable plasmid of the type IncX4 on which the colistin resistance gene (mcr-1) can be located.
The recipient bacterium E.coli C600-lux is a strain which can bioluminescence and is constructed in the early stage of the study [ refer to patent CN110066820A ], carries a streptomycin drug resistance gene rpsl and is highly resistant to streptomycin sulfate.
The fecal pretreatment method is to accurately weigh 0.1g of mouse feces, add the mouse feces into 900 mu L of phosphate buffer solution, and shake and mix the sample uniformly.
The selective culture mediums are respectively wheat Kaka agar culture mediums (containing 2000 mug/mL streptomycin sulfate) and aim to screen and count the number of recipient bacteria; myconKai agar medium (containing 2000. Mu.g/mL streptomycin sulfate+2. Mu.g/mL polymyxin E) was used to screen plasmid conjugates.
The specific experimental operation steps are as follows: purchasing a plurality of mice in sterile conditionThe environment was subjected to adaptive rearing for 7 days, followed by streptomycin treatment (1 mg/day) for 3 days on mice. Feed and purified water were removed on the fourth day, donor and recipient bacterial suspensions were supplied on the fifth day, feed and drinking water were re-supplied, and after 30 minutes mice were supplied with purified water and PU prepared in example 2 of the present invention, respectively 0.99 LA emulsion and continuous administration for seven days, as control and test groups (8 each), 0.1g of mouse faeces/each day was collected, dissolved in 900 μl of PBS solution, subjected to gradient dilution, and the dilutions were spread on medium containing 2000 μg/mL streptomycin sulfate, and the number of recipient bacteria was selected and counted; plasmid conjugates were screened by plating with a medium containing 2000. Mu.g/mL streptomycin sulfate+2. Mu.g/mL polymyxin E MAKAI agar (see FIG. 5B).
Analysis of results:
as shown in fig. 5, control 8 mice detected plasmid zygotes in the feces of the first two days after challenge, with only plasmid conjugative transfer events occurring on day 5 after challenge. The following day after challenge, plasmid conjugation transfer events were found in 2 mice. In contrast, no plasmid conjugative transfer event was found in the PULA group (see fig. 5A), indicating that PULA inhibits the occurrence of plasmid conjugative transfer (see fig. 5C).
It is apparent that the above examples of the present invention are only for clearly illustrating the technical solution of the present invention, and are not limited to the specific embodiments of the present invention. Any modification, equivalent replacement, improvement, etc. that comes within the spirit and principle of the claims of the present invention should be included in the protection scope of the claims of the present invention.
Claims (2)
1. The application of the composite material in preparing the medicine for preventing and treating bacterial drug resistance is characterized in that the composite material is prepared by the following steps:
s1, stirring and mixing castor oil and isophorone diisocyanate, sequentially adding diethylene glycol piperazine and a catalyst, stirring and reacting, then adding N-methyldiethanolamine, adding butanone when the solution is difficult to flow, continuing the reaction, cooling, and then neutralizing;
s2, adding linoleic acid into the reaction system obtained in the step S1, adding water for emulsification, and purifying the product after stirring;
castor oil described in step S1: diethylene glycol piperazine: the molar ratio of N-methyldiethanolamine is 1:0.25: (0.89-1.19);
the catalyst in the step S1 is dibutyl tin dilaurate, and the dosage is 0.01-0.1%;
the mass fraction of the linoleic acid in the step S2 is 3.33% -3.39%;
the drug prevents and controls bacterial resistance by inhibiting the conjugal transfer of the IncX4 plasmid in vivo.
2. The use according to claim 1, wherein step S1 is performed by cooling and then neutralizing with acetic acid.
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