CN107961233B - Application of trichloro-substituted II-type halogenated polyketone compounds - Google Patents
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Abstract
The patent discloses the application of trichloro-substituted II-type halogenated polyketone compounds, and the structural formula of the trichloro-substituted II-type halogenated polyketone compounds is as follows:
the invention obtains more trichloro compounds by improving the preparation method, and in addition, the antibacterial activity of the compound is screened, and the result shows that the compound has broad-spectrum antibacterial activity, the activities of resisting gram-positive bacteria such as staphylococcus aureus (MRSA) and drug-resistant bacteria thereof, staphylococcus epidermidis and bacillus subtilis, the activities of resisting gram-negative bacteria such as escherichia coli (ESBL) generating ultra-broad-spectrum β -lactamase, proteus and brucella, and the activities of resisting fungi such as candida albicans.
Description
Technical Field
The invention relates to the technical field of microorganisms, in particular to application of a trichloro-substituted II-type halogenated polyketone compound, and especially relates to application of a trichloro-substituted halogenated II-type polyketone compound, namely zunyiminycin C.
Background
Natural products from streptomyces often have good biological activity and drug-forming potential, and are important sources of antibiotics. However, with the abuse of antibiotics, the appearance of a plurality of 'super bacteria' brings huge challenges to the treatment of diseases such as pathogenic bacteria infection and the like in clinic, and some super bacteria have the phenomenon of no medicine and no medical treatment. In view of the current increasingly severe antibacterial situation, the research and development of antibiotics is increased, and the exploration and research of new antibiotics become urgent matters, and are also effective ways for solving the problem of antibiotic resistance.
The halogenated natural product from streptomycete has the characteristics of novel structure, good activity and the like. Such as: chlorinated polyketone neocarzillin a having antileukemic activity; BE-19412A and its methylation product with inhibitory effect on mouse tumor cells; polyketone chinikomicins A with inhibition effect on different tumor cells of human body; chlorophenazine having bactericidal action against multi-drug resistant mycobacterium tuberculosis. In addition, the clinical anti-infective vancomycin, teicoplanin and new antibiotic drugs dalbavancin, oritavancin and tedizolid which are approved to be marketed by the FDA in the U.S. in 2014 and are all halogenated natural products.
The applicant separates and identifies a strain named Streptomyces sp. FJS31-2 (the strain preservation number is CGMCC4.7321) from soil of Sanjing mountain of special habitat Vaskrita of Guizhou at earlier stage, and separates and identifies compounds of the novel chlorinated polyketone series, such as a halogenated II type polyketone antibiotic compound disclosed in Chinese patent CN106167495A, a preparation method and application thereof, wherein the halogenated II type polyketone antibiotic compound is the compound of the Zunyimycin C,
however, due to the defects of the preparation method, the obtained yield is small, the yield is low, and the yield is small (about 7mg of each compound), so that only the activity of the drug-resistant staphylococcus aureus is performed, and in order to further obtain other antibacterial activities, the applicant researches the preparation method, finally obtains a preparation method with high biomass, and researches other antibacterial activities.
Disclosure of Invention
The invention aims to provide a research on other antibacterial activities of trichloro-substituted II-type halogenated polyketone compounds.
The application of trichloro-substituted II-type halogenated polyketone compounds has the structural formula:
the compounds are useful for anti-gram-positive, anti-gram-negative or anti-fungal activity.
The preparation method of the trichloro-substituted II-type halogenated polyketone compound comprises the following steps: step one, activating a strain: the classification names stored in the refrigerator at-80 ℃ are: streptomyces sp.FJS31-2 strain, the preservation number of the strain is CGMCC NO.4.7321, the preservation date is 2016, 6 and 2 days, the preservation unit is the common microorganism center of China Committee for culture preservation and management, the preservation address is the microorganism research institute of China academy of sciences No. 3, West Lu No. 1 Hospital, North Jing China, the rising area, when activated: digging spores of the strains by using an aseptic inoculating loop, cross-streaking and inoculating the spores on a flat plate of a basic culture medium, standing and culturing for 3d at 28 ℃, selecting single colonies, subculturing to the third generation, and then carrying out amplification culture;
step two, fermentation culture of fermentation products: selecting an improved GYD solid culture medium for fermentation culture, adding agar powder into the culture medium, standing at 28 ℃ for 17d, mashing the thallus together with the culture medium, adding ethyl acetate for extraction twice, combining the extract, and concentrating under reduced pressure to obtain a fermentation product;
step three, purification and separation of fermentation products: a. dissolving the fermentation product with acetone solvent, mixing with silica gel powder, and purifying with chloroform-acetone; 30: 1; 15: 1; 10: 1; 5: 1; 2: 1; pure acetone, sequentially carrying out 7 gradient elutions and collecting eluent, carrying out rotary evaporation and reduced pressure recovery on the eluent, developing the eluent by using a developing agent, combining points with 365nm fluorescence yellow-green color, 8% sulfuric acid ethanol yellow color and 0.5 migration value (Rf), and weighing to obtain F5;
b. f5 is separated by normal phase silica gel column chromatography, after the component F5 is dissolved in acetone solvent, the mixture is mixed with silica gel powder according to the ratio of 6:1 by adopting petroleum ether-acetone; 4: 1; sequentially eluting 3 gradient eluates in sequence at ratio of 2:1, collecting eluting solvent, performing rotary evaporation and reduced pressure recovery of the eluting solvent, developing with developing agent, mixing 365nm fluorescence yellow-green, 8% sulphuric acid ethanol yellow, migration value (Rf) at 0.5, mixing, and weighing to obtain F5-3;
c. dissolving F5-3 in acetone, scraping silica gel powder showing yellow-green fluorescence under 365nm fluorescence by adopting a thin-layer chromatography method, uniformly grinding the scraped silica gel powder, filling the ground silica gel powder into a separation column, eluting by adopting acetone, and recovering an acetone solvent to obtain the zunyiminycin C compound.
The formula of the improved GYD culture medium is as follows: 4g/L of glucose, 4g/L of malt extract, 4g/L of yeast powder, 2g/L of calcium carbonate, 0.5mL of trace element premix, 10g/L of absolute ethyl alcohol, humic acid B soaked for 24h, deionized water added for volume determination to 1000mL, and autoclaving at 121 ℃ for 30 min.
The trace element premix liquid: ZnSO
4·7H
2O 2g、FeSO
4·7H
2O 2g、MnCl
2·4H
2O 2g、CuSO
4·5H
2O2g、 Na
2B
4O
4·10H
2O2 g and (NH)
4)
6MO
7·4H
2And O2 g, and the volume is determined to be 1L by double distilled water.
Further, the gram-positive bacteria are staphylococcus epidermidis or bacillus subtilis.
Further, the gram-negative bacteria are proteus, brucella activity or escherichia coli producing extended spectrum β -lactamase.
Further, the fungus is candida albicans.
The invention has the advantages that:
1) the compound Zunyimycin C is a Streptomyces alkaloid, is derived from a secondary metabolite of Streptomyces sp.FJS31-2 strain, and is separated from special environment-free Vanjatu mountain in Guizhou. At present, the strain is preserved outside the laboratory and also preserved in China general culture Collection (preservation number: CGMCC 4.7321). The compound Zunyimycin C can be obtained by activated culture, so the adopted raw materials are special and easy to obtain, and have no pollution to the environment and no irreversible damage to resources.
2) The compound Zunyimycin C has better antibacterial activity, and experimental researches show that the compound has broad-spectrum antibacterial activity, gram-positive bacteria resistance, gram-negative bacteria resistance or antifungal activity. The preparation, separation and identification of the compound provide a compound source for the research and development of antibiotics and also provide a primer for the synthesis of other compounds with biological activity.
Drawings
FIG. 1 is a flow chart of Zunyimycin C isolation;
FIG. 2 is a graph of Zunyimycin C anti-S.epidermidis activity;
FIG. 3 is a graph showing the activity of Zunyimycin C against Bacillus proteus;
FIG. 4 is a graph of Zunyimycin C activity against Brucella;
FIG. 5 is a graph of Zunyimycin C activity against Candida albicans;
FIG. 6 is a graph of Zunyimycin C activity against Bacillus subtilis;
FIG. 7 is a graph of Zunyimycin C anti-MRSA activity;
FIG. 8 is a graph of Zunyimycin C anti-ESBL activity.
Detailed Description
The present invention will be described in further detail below by way of specific embodiments:
1. activation of Streptomyces sp.FJS31-2 strain
Taking out the strain preserved on the glycerol slant from a refrigerator at minus 80 ℃, digging spores of 1-ring strain Streptomyces sp, FJS31-2 by using an aseptic inoculating loop, cross-streaking and inoculating the spores to a basal medium plate with the diameter of 11cm, standing and culturing for 3d at 28 ℃, and picking single bacterial colony to pass to the third generation for amplified culture.
2. Fermentation culture of fermentation product
Streptomyces sp.FJS31-2 strain is cultured by fermentation in an improved GYD solid culture medium, 150mL of fermentation culture medium is bottled in 500 mL triangular flask, and agar powder is added into each flask according to the mass of the agar powder and 1.8% of the volume of the fermentation culture medium. Inoculating the activated strain with the amount of 1 × 1cm2 on the culture plate per bottle, standing at 28 deg.C for 17d, mashing the strain and culture medium, extracting with ethyl acetate twice at 130rpm for 24 hr, mixing extractive solutions, and concentrating at 40 deg.C under reduced pressure to obtain fermented product. The above operations were repeated, and a total of 38g of fermentation product was obtained by combining 100L of fermentation culture.
The formula of the improved GYD culture medium is as follows: 4g/L of glucose, 4g/L of malt extract, 4g/L of yeast powder, 2g/L of calcium carbonate, 0.5mL of trace element premix, 10g/L of absolute ethyl alcohol, soaking humic acid B for 24h, adding deionized water to reach the constant volume of 1000mL, and carrying out autoclaving at 121 ℃ for 30 min.
The trace element premix liquid: ZnSO
4·7H
2O 2g、FeSO
4·7H
2O 2g、MnCl
2·4H
2O 2g、CuSO
4·5H
2O2g、 Na
2B
4O
4·10H
2O2 g and (NH)
4)
6MO
7·4H
2And O2 g, and the volume is determined to be 1L by double distilled water.
3. Purification and separation of fermentation product
(1) Dissolving 32g of fermentation product by using acetone solvent, uniformly mixing the fermentation product with silica gel according to the mass ratio of about 1:1.5 (namely adding 48g of 100-200-mesh silica gel powder into 32g of fermentation product), and volatilizing the solvent to obtain a river sand-shaped sample which is used as a sample for loading on a column; weighing 1200g of 100-200-mesh silica gel powder, uniformly mixing with a chloroform solvent (bubbles cannot be generated in the process), putting into a separation column with the length of 975mm and the inner diameter of 120mm, slowly sinking the silica gel powder until the silica gel powder does not sink, adding an upper column sample, and adopting chloroform-acetone [ pure chloroform ]; 30: 1; 15: 1; 10: 1; 5: 1; 2: 1; acetone ], sequentially eluting by 7 gradients, wherein each gradient elutes 3-4 (about 7.2L-9.6L of elution solvent per column volume), collecting 80 parts of elution solvent per 1000mL, after each part is recovered by a rotary evaporator under reduced pressure, adding 10mL of acetone to dissolve, transferring to a penicillin bottle with the specification of 20mL, performing thin layer chromatography (TCL) spotting, and performing petroleum ether: acetone ═ 2:1, chloroform: acetone ═ 5:1 or chloroform: methanol 10:1, developing with a developing agent, observing whether the fluorescence is 254nm or 365nm under a conventional ultraviolet visible light analyzer, and developing with a coloring agent developing with 8% sulfuric acid ethanol; the 365nm fluorescence yellow-green color and the 8% sulfuric acid ethanol yellow color were combined, and the mobility value (Rf) was at 0.5 point, and after combining, F53.124g was obtained by weighing.
(2) F53.124g is further purified and separated by normal phase silica gel column chromatography. Uniformly mixing 3.124g of dissolved components of the acetone solvent and silica gel according to the mass ratio of about 1:1.5 (namely 3.124g of fermentation product is added with 4.7g of 100-200-mesh silica gel powder), and obtaining a river sand-shaped sample after the solvent is volatilized, wherein the sample is used as a sample for loading on a column; weighing 140 g of 100-one 200-mesh silica gel powder and petroleum ether: acetone (6: 1) (no bubbles generated during the process) is loaded into a separation column with a length of 975mm and an inner diameter of 50mm, silica gel powder is slowly sunk until no more sinking, and a sample is loaded into the column, and petroleum ether-acetone [6: 1; 4: 1; 2:1], sequentially eluting by 3 gradients, wherein each gradient elutes 4-5 (about 1L-1.2L of elution solvent per column volume) columns, collecting 40 parts of elution solvent per 100mL, adding 10mL of acetone after decompression and recovery of each part by a rotary evaporator, dissolving, transferring into a penicillin bottle with the specification of 20mL, performing thin layer chromatography (TCL) spotting, and performing petroleum ether: acetone ═ 2:1, chloroform: acetone ═ 5:1 or chloroform: methanol 10:1, developing with a developing agent, observing whether the fluorescence is 254nm or 365nm under a conventional ultraviolet visible light analyzer, and developing with a coloring agent developing with 8% sulfuric acid ethanol; the 365nm fluorescence was combined to give a yellowish green color, the 8% ethanol sulfate was combined to give a yellow color, and the mobility value (Rf) was at a point of 0.5, and after combining, F5-391 mg was weighed.
(3) Dissolving F5-391 mg of component in acetone, and dispensing (plate specification: 20 cm. times.20 cm) thin layer chromatography plate with sample loading of 45 mg/block by thin layer chromatography (TCL) method to prepare chloroform: acetone: and (2) dropping 140mL of developing agent in a ratio of formic acid to 1:1, pouring the developing agent into a developing cylinder, putting a thin-layer chromatography plate into the developing cylinder, taking out the plate when the solvent is about 0.5cm away from the edge of the plate, volatilizing the solvent, observing under 365nm fluorescence, scraping off silica gel powder with Rf value of 0.25 and yellow-green fluorescence under 365nm fluorescence, uniformly grinding the scraped silica gel, filling into a separation column, eluting with acetone, and recovering an acetone solvent machine to obtain 14mg of the zunyimycin C compound.
4. Application of Zunyimycin C antibacterial activity
(1) The test strains are staphylococcus aureus (MRSA), bacillus subtilis, brucella, staphylococcus epidermidis, proteus, escherichia coli (ESBL) generating broad-spectrum β -lactamase and candida albicans.
(2) Culture medium: MH (A) culture medium, weighing MH (A) culture medium 36.5g and distilled water 1L, mixing well, and autoclaving at 121 deg.C for 15 min. The medium was poured into plates in a clean bench, approximately 20mL each. The culture dish is placed in an oven at 30 ℃ for 24h, whether bacteria grow or not is observed, and the culture dish can be used in an aseptic mode.
(3) Strain activation: taking out the test strains preserved on the glycerol inclined plane from a refrigerator at the temperature of minus 80 ℃, digging 1 ring of each test strain by using a sterile inoculating loop, cross-streaking and inoculating the test strains on an MH (A) culture medium plate with the diameter of 11cm, standing and culturing for 1d at the temperature of 37 ℃, and picking single colonies and subculturing to a third generation.
(4) Preparation of a solution of compound Zunyimycin C: zunyimycin C3 mg was weighed out and dissolved in 1mL DMSO solution to make the solution clear without turbidity.
(4) The antibacterial activity was measured by the agar diffusion method: firstly, preparing a suspension of test bacteria with the concentration of 10-6 or 10-7 by using distilled water; secondly, the suspension is poured into MH (A) culture medium to ensure that the surface coating is uniform; thirdly, punching a plurality of small holes with the diameter of 8mm on MH (A) culture medium coated with test bacteria, and respectively inoculating 100uL of Zunyimycin C solution and a control in the small holes; fourthly, putting the culture dish into an incubation thermostat at 37 ℃ for culturing for 24 hours, and taking out the culture dish to measure the diameter of the inhibition zone.
Examples of the applications
The result shows that Zunyimycin C has better inhibiting effect on staphylococcus aureus (MRSA), bacillus subtilis, brucella, staphylococcus epidermidis, proteus, escherichia coli (ESBL) producing ultra-broad spectrum β -lactamase, candida albicans and the like, the inhibition zone of the Zunyimycin C is larger than 15mm, and the result is detailed in table 1 and figures 2 to 8.
Table 1: zunyimycin C antibacterial activity detection result
The foregoing is merely an example of the present invention, and common general knowledge in the field of known specific structures and characteristics of the embodiments has not been described in detail, so that a person of ordinary skill in the art can understand all the common technical knowledge in the field of the invention before the application date or the priority date, can know all the prior art in the field, and have the ability to apply routine experimentation before the application date. It should be noted that, for those skilled in the art, without departing from the structure of the present invention, several changes and modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of the claims of the present application shall be determined by the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
Claims (1)
1. The application of trichloro-substituted II-type halogenated polyketone compounds is characterized in that: the structural formula of the trichloro-substituted II-type halogenated polyketone compound is as follows:
the compound is used as the only active component in the preparation of medicines or compositions with anti-staphylococcus epidermidis, anti-gram-negative bacteria or anti-fungal activity, wherein the gram-negative bacteria are proteus, brucella or escherichia coli which can generate β -lactamase with extended spectrum, and the fungi are candida albicans.
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| CN115054597B (en) * | 2022-06-30 | 2023-08-25 | 延安大学 | Application of halogenated type II polyketide in intervention of Alzheimer's disease |
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| CN106167495A (en) * | 2016-06-03 | 2016-11-30 | 遵义医学院 | A kind of halogenation II type polyketide compound, preparation method and applications |
| CN106432262A (en) * | 2016-06-03 | 2017-02-22 | 遵义医学院 | Streptomyces-derived halogenated polyketide compound, preparation method and application |
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| CN106167495A (en) * | 2016-06-03 | 2016-11-30 | 遵义医学院 | A kind of halogenation II type polyketide compound, preparation method and applications |
| CN106432262A (en) * | 2016-06-03 | 2017-02-22 | 遵义医学院 | Streptomyces-derived halogenated polyketide compound, preparation method and application |
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