CN109568494B - Application of bletilla striata alcohol extract in preparation of polymyxin antibacterial synergist - Google Patents
Application of bletilla striata alcohol extract in preparation of polymyxin antibacterial synergist Download PDFInfo
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- CN109568494B CN109568494B CN201910056283.4A CN201910056283A CN109568494B CN 109568494 B CN109568494 B CN 109568494B CN 201910056283 A CN201910056283 A CN 201910056283A CN 109568494 B CN109568494 B CN 109568494B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
- A61K36/898—Orchidaceae (Orchid family)
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
- A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/30—Extraction of the material
- A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
- A61K2236/50—Methods involving additional extraction steps
- A61K2236/55—Liquid-liquid separation; Phase separation
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- 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
Abstract
The invention discloses an application of a bletilla striata alcohol extract in preparation of a polymyxin antibacterial synergist, wherein the synergist is prepared by mixing the bletilla striata alcohol extract and polymyxin B, and the mass ratio of the bletilla striata alcohol extract to the polymyxin B is 1-256: 1. The bletilla striata alcohol extract provided by the invention has weak inhibition effect on escherichia coli when being used alone, but can obviously enhance the antibacterial activity of polymyxin B after being combined with the polymyxin B, and particularly can enhance the antibacterial activity of polymyxin B on drug-resistant escherichia coli by 2-4 times.
Description
(I) technical field
The invention relates to a bletilla striata alcohol extract, in particular to an application of the bletilla striata alcohol extract in preparation of a polymyxin antibacterial synergist.
(II) background of the invention
Escherichia coli (Escherichia coli) is commonly known as Escherichia coli and is a normal flora in the intestinal tract of humans and animals. However, some serotypes of E.coli often cause a variety of intestinal and parenteral diseases, such as diarrhea, hemorrhagic enteritis, neonatal pyogenic meningitis, urinary tract infections, and even sepsis. With the increasing severe infections caused by multi-drug resistant escherichia coli and the lack of novel antibiotics capable of resisting the infections, polymyxin has become the last line of defense for treating escherichia coli at present. Although the polymyxin has low drug resistance probability according to previous reports, the polymyxin is caused by gene mutation on bacterial chromosome and cannot be transmitted among different bacteria. However, the detection of the plasmid-mediated super drug resistance gene mcr-1 in E.coli isolated from animals and patients, which has recently been found at home and abroad, not only allows E.coli to develop polymyxin resistance, but also allows it to be horizontally transmitted among different strains. Therefore, the clinical treatment of the Escherichia coli infection becomes very complicated and difficult, and even the situation of no medicine is available is approached. Therefore, it has become urgent to explore new strategies and methods.
Bletilla striata is a precious medicinal variety in the genus bletilla of the family Orchidaceae, has a long history of use, and is recorded in Shen nong Ben Cao Jing, and then recorded in traditional Chinese medical ancient books such as Ben Cao Yi Xue (readability of materia Medica) and Ben Cao gang mu (compendium of materia Medica). Rhizoma Bletillae enters lung meridian and is mainly used for treating hemoptysis, carbuncle, swelling and sore; it is also the principal drug used by physicians of all generations for treating pulmonary tuberculosis. Modern pharmacological studies show that the bletilla striata is rich in antibacterial active ingredients, such as phenanthrene compounds and bibenzyl compounds. The invention adopts the bletilla striata extract as a synergist of colistin resistance, and lays a foundation for the research and development of novel antibacterial traditional Chinese medicines.
Disclosure of the invention
The invention aims to solve the problem of increasingly serious escherichia coli drug resistance, and provides a bletilla striata alcohol extract and application thereof as an antibacterial synergist of polymyxin.
The technical scheme adopted by the invention is as follows:
the invention provides an application of a bletilla striata alcohol extract in preparation of a polymyxin antibacterial synergist, wherein the synergist is prepared by mixing the bletilla striata alcohol extract and polymyxin B, and the mass ratio of the bletilla striata alcohol extract to the polymyxin B is 1-256: 1. The synergist is antibacterial synergist for colibacillus sensitive to polymyxin and colibacillus resistant to polymyxin, wherein multiple strains of clinical isolates carry plasmid-mediated super drug-resistant gene mcr-1.
In the synergist, the concentration of the alcohol extract of bletilla striata is 1-256 mug/mL, the concentration of polymyxin B is 0.5-4 mug/mL, and the concentration of escherichia coli is 106cfu/ml。
The bletilla striata alcohol extract is prepared by the following method: drying and crushing rhizoma bletillae, performing reflux extraction with an ethanol water solution with the volume concentration of 95%, concentrating the filtrate under reduced pressure (preferably to the volume of 1/3-1/20 times), performing polyamide column chromatography, eluting with deionized water to be colorless, eluting with an ethanol water solution with the volume concentration of 20-60%, collecting an elution peak of a target component (preferably to the elution of the ethanol water solution with the volume concentration of 60%), and concentrating under reduced pressure to be dry to obtain the rhizoma bletillae alcohol extract.
Further, the drying and crushing of the bletilla striata refers to drying the root of the bletilla striata in the sun or drying the root of the bletilla striata in an oven at the temperature of 30-80 ℃, crushing and sieving with a sieve of 10-100 meshes.
Furthermore, the volume dosage of the ethanol water solution is 3-10ml/g calculated by the weight of the bletilla striata powder.
Further, the reflux extraction is preferably performed 3 times, each for 30-120 min.
Further, the polyamide column chromatography method comprises the following steps: adding the concentrated solution after the filtrate is concentrated into polyamide (preferably 200-300 mesh), stirring uniformly, and then putting into a chromatographic column added with polyamide for column chromatography.
Preferably, the rhizoma bletillae ethanol extract is obtained by eluting with 60% ethanol water solution, collecting 60% ethanol elution peak, and concentrating under reduced pressure to dryness.
Compared with the prior art, the invention has the following beneficial effects: the bletilla striata alcohol extract provided by the invention has weak inhibition effect on escherichia coli when being used alone, but can obviously enhance the antibacterial activity of polymyxin B after being combined with the polymyxin B (see table 1), and particularly can enhance the antibacterial activity of polymyxin B on drug-resistant escherichia coli by 2-4 times.
(IV) description of the drawings
FIG. 1 HPLC analysis of bletilla striata alcohol extract (EF 60).
FIG. 2 the effect of combination of bletilla striata alcohol extract (EF60) and polymyxin on growth of polymyxin-resistant E.coli MCR1_ NJ (A) and E.coli ATCC25922 (B);
FIG. 3 time-kill curves for E.coli MCR1_ NJ (A) and E.coli ATCC25922 (B).
(V) detailed description of the preferred embodiments
The invention will be further described with reference to specific examples, but the scope of the invention is not limited thereto:
the bletilla striata is collected and prepared according to the 'Chinese pharmacopoeia' 2015 edition.
Example 1 preparation of bletilla striata alcohol extract
Drying rhizoma bletillae in an oven at 60 ℃, crushing, sieving with a 40-mesh sieve, taking 1kg of dry powder according to a material ratio of 1 kg: reflux-extracting 4L with 95% ethanol water solution for 3 times, each for 90 min. Mixing filtrates, concentrating under reduced pressure to obtain 110g ethanol extract, adding 100g polyamide (200-300 mesh), stirring, transferring to chromatographic column (10cm X40 cm) filled with 600g polyamide, eluting with deionized water until colorless, washing with 20% ethanol water solution, eluting with 60% ethanol water solution for 5 column volumes, collecting 60% ethanol elution peak, concentrating under reduced pressure to dryness to obtain rhizoma bletilla ethanol extract (EF60) 15g, which is rich in phenanthrene compounds, and has HPLC chromatogram shown in FIG. 1.
Example 2 drug susceptibility test
The experimental example is to study the minimum inhibitory concentrations of the rhizoma bletillae alcohol extracts EF60 and polymyxin on different escherichia coli.
The test bacteria in table 1 were inoculated on MH plates, cultured in an incubator at 37 ℃ for 48 hours, a single colony was selected from the plates, inoculated on MH slant, and cultured at 37 ℃ for 24 hours for further use.
Selecting one ring of test bacteria from activated slant to 5ml MH liquid culture medium, shake culturing at 37 deg.C and 160rpm overnight, and diluting with MH liquid culture medium to bacteria concentration of 106cfu/ml, as test bacterial liquid. The minimum bacteriostatic concentration is determined by adopting a double dilution method, and the operation is completely carried out in a super clean bench. Diluting the compound to be tested with MH culture medium to different final concentrations (64 μ g/mL EF60, 1 μ g/mL polymyxin B, 64 μ g/mL EF60+1 μ g/mL polymyxin B), adding 100 μ L each into 96-well plate, adding 100 μ L test bacterial liquid into each well, mixing, culturing at 37 deg.C for 20 hr, and measuring OD600Values were also determined by visual observation using the lowest concentration that completely inhibited the growth of indicator bacteria as the minimum inhibitory concentration, and the MICs of EF60 and polymyxin B alone and in combination were recorded.
MH flat plate quality composition: 0.2% of beef powder, 0.15% of soluble starch, 1.75% of acid hydrolyzed casein, 1.0% of agar, deionized water as a solvent, and natural pH value.
MH liquid culture medium comprises the following components in mass: 0.2% of beef powder, 0.15% of soluble starch, 1.75% of acid hydrolyzed casein, deionized water as a solvent, and natural pH value.
The results are shown in Table 1, when the extract is used alone, the MIC of the bletilla striata alcohol extract EF60 to all escherichia coli is more than or equal to 256 mug/mL, and the antibacterial effect is weak; polymyxin B showed sensitivity (MIC 1) to ATCC25922 and zd01 strains, but resistance (MIC 4 μ g/mL) to other strains. When the two strains are combined, the sensitivity of the two strains to EF60 is improved by at least 4 times, and the MIC of the polymyxin-resistant Escherichia coli to polymyxin B is reduced from 4 to 1, namely, the polymyxin B is converted from drug resistance to sensitivity.
TABLE 1 EF60 MIC and FICI for alone and in combination with polymyxin B
Experimental example 3 growth inhibition Curve
The experimental example is to study the inhibition effect of the combination of the bletilla striata alcohol extract EF60 and polymyxin with sub-bacteriostatic concentration on the growth of escherichia coli.
Inoculating Escherichia coli MCR1_ NJ to MH plate, culturing in 37 deg.C incubator for 48h, selecting a single colony from the plate, inoculating to MH slant, and culturing at 37 deg.C for 24 h. Selecting one ring of test bacteria from activated slant to 5ml MH liquid culture medium, shake culturing at 37 deg.C and 160rpm overnight, and diluting with MH culture medium to bacteria concentration of 106cfu/ml, and obtaining Escherichia coli MCR1_ NJ bacterial liquid.
EF60 and polymyxin B prepared in example 1 were diluted with MH medium to different concentrations (1. mu.g/mL polymyxin B, 0.5. mu.g/mL polymyxin B, 1. mu.g/mL polymyxin B + 64. mu.g/mL EF60, 0.5. mu.g/mL polymyxin B + 64. mu.g/mL EF60, 64. mu.g/mL EF60), 100. mu.L of each was added to a 96-well plate, 100. mu.L of E.coli MCR1_ NJ was added to each well, and mixed well in culture medium at 37 ℃Culturing in a box for 20 hours, and measuring OD600Values were also taken with MH medium containing 5% DMSO by volume as a no-drug control, and the results are shown in fig. 2, panel a.
Preparation of 10 under the same conditions using E.coli ATCC25922 instead of E.coli MCR1_ NJ6cfu/mL E.coli ATCC25922 bacterial solution, EF60 and polymyxin B prepared in example 1 were diluted with MH medium to different concentrations (0.5. mu.g/mL polymyxin B, 0.25. mu.g/mL polymyxin B, 0.5. mu.g/mL polymyxin B + 16. mu.g/mL EF60, 0.25. mu.g/mL polymyxin B + 16. mu.g/mL EF60, 16. mu.g/mL EF60), 100. mu.L of each was added to a 96-well plate, then 100. mu.L of E.coli ATCC25922 bacterial solution was added to each well, mixed and cultured in an incubator at 37 ℃ for 20 hours, and OD was measured600Values, while using MH medium with 5% DMSO as a no-drug control, are shown in fig. 2, panel B.
As shown in FIG. 2, 64. mu.g/mL (1/4 XMIC) EF60 alone had substantially no inhibitory effect on E.coli MCR 1-NJ. When the derivative is combined with polymyxin B of 0.5 mu g/mL (1/8 multiplied by MIC), the derivative has more obvious inhibition effect on the growth of MCR1_ NJ within 0-4 h; and when combined with 1. mu.g/mL (1/4MIC) polymyxin B, completely inhibited the growth of the drug resistant strain. Similarly, 16. mu.g/mL EF60 in combination with 0.25. mu.g/mL (1/4 × MIC) polymyxin B had some inhibitory effect on the early growth of E.coli ATCC25922, but over time, the cells grew rapidly again; when polymyxin B was increased to 0.5. mu.g/mL (1/2 XMIC), the combination of the two could completely inhibit the growth of E.coli ATCC 25922. The above results further confirm that the combination of EF60 and polymyxin B has a synergistic bacteriostatic effect on escherichia coli MCR1 — NJ, while having only an additive antibacterial effect on escherichia coli ATCC 25922.
Experimental example 4 time-Sterilization Curve
The experimental example is to study the bactericidal effect of the combination of the bletilla striata alcohol extract EF60 and polymyxin on escherichia coli.
Inoculating Escherichia coli MCR1_ NJ to MH plate, culturing in 37 deg.C incubator for 48h, selecting a single colony from the plate, inoculating to MH slant, and culturing at 37 deg.C for 24 h. Selecting a ring of test bacteria from the activated slant to 5ml MH liquid culture medium, shaking at 37 deg.C and 160rpmIncubated overnight, diluted with medium to a bacterial concentration of about 106cfu/ml, and obtaining Escherichia coli MCR1_ NJ bacterial liquid.
EF60 and polymyxin B prepared in example 1 were diluted with MH medium to different concentrations (1. mu.g/mL polymyxin B, 4. mu.g/mL polymyxin B, 1. mu.g/mL polymyxin B + 64. mu.g/mL EF60, 4. mu.g/mL polymyxin B + 64. mu.g/mL EF60, 64. mu.g/mL EF60), 100. mu.L of each was added to a 96-well plate, 100. mu.L of E.coli MCR1_ NJ bacterial solution was added to each well, mixed and cultured in an incubator at 37 ℃ for 20 hours, and OD was measured600Values, while using MH medium with 5% DMSO as a no-drug control, are shown in fig. 3, panel a.
Preparation of 10 under the same conditions using E.coli ATCC25922 instead of E.coli MCR1_ NJ6cfu/mL E.coli ATCC25922 bacterial solution, EF60 and polymyxin B prepared in example 1 were diluted with MH medium to different concentrations (0.5. mu.g/mL polymyxin B, 1. mu.g/mL polymyxin B, 0.5. mu.g/mL polymyxin B + 16. mu.g/mL EF60, 1. mu.g/mL polymyxin B + 16. mu.g/mL EF60, 16. mu.g/mL EF60), 100. mu.L each was added to a 96-well plate, 100. mu.L of E.coli ATCC25922 bacterial solution was added to each well, mixed and cultured in an incubator at 37 ℃ for 20 hours, and OD was measured600Values, while using MH medium with 5% DMSO as a no-drug control, are shown in fig. 3, panel B.
As shown in figure 3, 64 mug/mL EF60 and 1 mug/mL polymyxin B have no inhibition effect on Escherichia coli MCR1_ NJ when used alone, and can completely inhibit the growth of the bacteria but have no sterilization effect when used together; when 64. mu.g/mLEF 60 and 4. mu.g/mL (1 × MIC) polymyxin B were used in combination, it was seen that EF60 enhanced the rate of sterilization of E.coli MCR 1-NJ by polymyxin B. The bactericidal effect of this enhanced polymyxin B was more fully exhibited on escherichia coli ATCC 25922. For example, 1. mu.g/mL (1 × MIC) polymyxin B alone, had essentially no bactericidal effect on ATCC 25922; however, when used in combination with EF60 at 16. mu.g/mL, ATCC25922 showed almost no viable colonies detected after 3h treatment.
Experimental example 5 mouse protection experiment
Taking 70 ICR mice, male, with a weight of 18-22g, randomly dividing into a control group and a large intestine rodBacteria group, rhizoma bletillae alcohol extract EF60 group, polymyxin B group, and rhizoma bletillae alcohol extract EF60+ polymyxin B group. Each group contained 10 animals. Control was given no agent; coli group, intraperitoneal injection 2X 107/kg Escherichia coli MCR1_ NJ (1% yeast physiological saline suspension (w/v) dilution); rhizoma bletillae ethanol extract EF60 group, intraperitoneal injection 2X 107Intraperitoneal injection of 60mg/kg of bletilla striata alcohol extract (prepared from 0.2% sodium carboxymethylcellulose and 0.01% Tween 80) is carried out half an hour after the viable Escherichia coli MCR1_ NJ is obtained; polymyxin B group, i.p. 2X 107After half an hour for the live Escherichia coli MCR1_ NJ, 0.5mg/kg polymyxin B (prepared by normal saline) is injected into tail vein; rhizoma bletilla alcohol extract EF60+ polymyxin B group, respectively administered 2X 107After half an hour after each hour, 0.5mg/kg polymyxin B was injected into the caudal vein of viable Escherichia coli MCR1_ NJ, followed by intraperitoneal injection of 10, 30, 60mg/kg and rhizoma bletilla alcohol extract EF60 for 3 days, once a day. After the administration, normal diet and drinking water were given, and the general condition and mortality of the mice were observed within 14 days (table 2). The result shows that the combination of the bletilla striata alcohol extract and the polymyxin B can obviously reduce the death rate of mice infected with drug-resistant escherichia coli, and the combination of the bletilla striata alcohol extract and the polymyxin B has a synergistic protection effect.
TABLE 2 Effect of combination of alcohol extracts of bletilla striata and polymyxin on mortality of E.coli infected mice
Note: x2Test,. P<0.001 (compared with E.coli group)
Claims (5)
1. An application of a bletilla striata alcohol extract in preparation of a polymyxin antibacterial synergist is characterized in that the synergist is formed by mixing the bletilla striata alcohol extract and polymyxin B, wherein the mass ratio of the bletilla striata alcohol extract to the polymyxin B is 1-256: 1; the bletilla striata alcohol extract is prepared by the following method: drying and crushing rhizoma bletillae, performing reflux extraction by using an ethanol water solution with the volume concentration of 95%, performing reduced pressure concentration on the filtrate, performing polyamide column chromatography, eluting by using deionized water to colorless, then eluting by using an ethanol water solution with the volume concentration of 60%, collecting elution peaks of target components, and performing reduced pressure concentration to dryness to obtain an alcohol extract of the rhizoma bletillae; the synergist is an escherichia coli antibacterial synergist, and the escherichia coli is a polymyxin sensitive type or a drug-resistant type; the concentration of the bletilla striata alcohol extract in the synergist is 16-256 mug/mL.
2. Use according to claim 1, characterized in that the E.coli carries a gene with super resistance to drugsmcr-1。
3. The application of claim 1, wherein the drying and pulverizing of rhizoma bletillae is carried out by sun-drying rhizoma bletillae root or oven-drying at 30-80 ℃, pulverizing, and sieving with 10-100 mesh sieve.
4. The use according to claim 1, wherein the volume of the ethanol aqueous solution is 3-10ml/g calculated by the weight of the bletilla striata powder.
5. The use according to claim 1, characterized in that the reflux extraction is carried out 3 times, each time for 30-120 min.
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| KR20160044768A (en) * | 2014-10-16 | 2016-04-26 | 한국생명공학연구원 | Antimicrobial method by synergistic effect of ciclopirox and polymyxin B against gram-negative bacteria |
| WO2018162551A1 (en) * | 2017-03-08 | 2018-09-13 | Università Degli Studi Di Siena | Pharmaceutical composition comprising resveratrol and polymyxins for use as antibacterial agent |
| CN108743801A (en) * | 2018-06-29 | 2018-11-06 | 浙江中医药大学 | A kind of Pseudobulbus Bletillae (Rhizoma Bletillae) extract and its application |
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| CN109512998A (en) * | 2016-03-04 | 2019-03-26 | 广州英赛特生物技术有限公司 | The application of synergetic effect additive of the esterification derivative of oxygen-containing hydrocarbon derivative as polymyxins |
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| KR20160044768A (en) * | 2014-10-16 | 2016-04-26 | 한국생명공학연구원 | Antimicrobial method by synergistic effect of ciclopirox and polymyxin B against gram-negative bacteria |
| WO2018162551A1 (en) * | 2017-03-08 | 2018-09-13 | Università Degli Studi Di Siena | Pharmaceutical composition comprising resveratrol and polymyxins for use as antibacterial agent |
| CN108743801A (en) * | 2018-06-29 | 2018-11-06 | 浙江中医药大学 | A kind of Pseudobulbus Bletillae (Rhizoma Bletillae) extract and its application |
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