CN115490753A - Cyclic lipopeptide compound and preparation method and application thereof - Google Patents

Cyclic lipopeptide compound and preparation method and application thereof Download PDF

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CN115490753A
CN115490753A CN202210733329.3A CN202210733329A CN115490753A CN 115490753 A CN115490753 A CN 115490753A CN 202210733329 A CN202210733329 A CN 202210733329A CN 115490753 A CN115490753 A CN 115490753A
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cyclic lipopeptide
ethyl acetate
preparation
compound
methanol
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何山
丁立建
林思晓
石煜彤
王潇
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Ningbo University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/12—Cyclic peptides with only normal peptide bonds in the ring
    • C07K5/126—Tetrapeptides
    • 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
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    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12P21/00—Preparation of peptides or proteins
    • C12P21/02—Preparation of peptides or proteins having a known sequence of two or more amino acids, e.g. glutathione
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    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract

The invention discloses a cyclic lipopeptide compound and a preparation method and application thereof, and is characterized in that the structural formula of the cyclic lipopeptide compound is shown as I, the preparation method comprises the steps of obtaining a fermentation product of the cyclic lipopeptide compound by fermenting and culturing bacillus with the preservation number of CGMCC No.6554 through microorganisms, then soaking the fermentation product with ethyl acetate to extract a crude extract, and separating and purifying the crude extract through reduced pressure column chromatography, normal phase medium pressure column chromatography, reverse phase medium pressure column chromatography and reverse phase semi-preparative high performance liquid chromatography.

Description

Cyclic lipopeptide compound and preparation method and application thereof
Technical Field
The invention relates to a cyclic lipopeptide compound, in particular to a novel antibacterial cyclic lipopeptide compound extracted from marine bacillus and a preparation method and application thereof.
Background
Although the existing antibiotics such as vancomycin and daptomycin largely alleviate the problem of treating methicillin-resistant staphylococcus aureus (MRSA), staphylococcus aureus and other pathogenic bacteria infections, the search for new antibacterial drugs is imminent due to the abuse of antibiotics and the increasing resistance of pathogenic bacterial strains. The bacillus is used as an important resource library for new drug discovery, mainly produces lipopeptide compounds, shows various biological activities including antibacterial, anti-inflammatory, antitumor, antiviral and antiplatelet properties, and has wide research potential.
The inventor optimizes the culture medium condition of a strain of marine bacillus and obtains the optimal strain culture condition through antibacterial activity and chemical screening. Subsequent chemical composition studies of ethyl acetate extracts under extensive fermentation of the strains under optimal culture conditions revealed a novel natural product of cyclic lipopeptides, which were subsequently evaluated for bacteriostatic activity. At present, the chemical structure and the bacteriostatic activity of the compound are not reported, so that the related medicines are not found in the market.
Disclosure of Invention
The invention aims to solve the technical problem of providing a cyclic lipopeptide compound which has obvious inhibition effect on methicillin-resistant staphylococcus aureus (MRSA), staphylococcus aureus, vibrio alginolyticus and vibrio haemolyticus, and a preparation method and application thereof.
The technical scheme adopted by the invention for solving the technical problems is as follows: a cyclic lipopeptide compound is characterized in that the structural formula of the cyclic lipopeptide compound is shown as (I);
Figure 425437DEST_PATH_IMAGE001
（I）。
the preparation method of the cyclic lipopeptide compound comprises the following steps:
(1) Fermentation production
Activating bacillus amyloliquefaciens with the collection number of CGMCC No.6554 on a culture dish containing Gao's I, culturing for 7 days at the constant temperature of 28 ℃, inoculating the bacillus amyloliquefaciens into a liquid culture medium A, culturing for 3 days at the rotating speed of 150 rpm/min at the rotating table of 28 ℃ to obtain seed liquid, inoculating the seed liquid into YSP culture medium which is sterilized in advance according to the inoculation amount of 10 percent of the volume ratio, and culturing for 7 days at the rotating speed of 150rpm on the table of 28 ℃ to finally obtain a fermentation product;
(2) Extract extraction
Adding ethyl acetate with the same volume as the fermented product into the fermented product obtained in the step (1), repeatedly extracting for 3 times, evaporating the ethyl acetate leaching liquor under reduced pressure, adding mixed liquor of ethyl acetate and water with the same volume as the fermented product, repeatedly extracting for 3 times, combining ethyl acetate extraction liquor obtained by three times of extraction, concentrating under reduced pressure, and evaporating to obtain a crude extract;
(3) Isolation preparation of compounds
Dissolving the crude extract obtained in the step (2) by using a methanol solvent, performing primary separation by using a reduced pressure column chromatography (VLC), performing gradient elution by using petroleum ether/ethyl acetate with a volume ratio of 20, 1, 2, 0; subjecting the collected 3 rd component to normal phase medium pressure chromatography, and performing gradient elution by petroleum ether/ethyl acetate at a volume ratio of 1,4; separating the collected component 3 by reversed phase medium pressure column chromatography, collecting 50 tubes, wherein the adopted eluent is methanol and water, the volume percentage of the methanol is 30-100%, the elution time is 120 min; taking a 28 th tube for semi-preparative reverse phase high performance liquid chromatography separation, adopting a mixed solution of acetonitrile and water according to a volume ratio of 65:
Figure 779058DEST_PATH_IMAGE001
（I）。
the preparation method of the A liquid culture medium in the step (1) comprises the following steps: 20 g of starch, 2g of peptone, 6g of yeast crude extract 3 1 g，KBr 100 mg，Fe 2 (SO 4 ) 3 •4H 2 0 40mg of the extract is dissolved in 1L of seawater.
The preparation method of the YSP culture medium in the step (1) is as follows: 10 g of peptone, 5 g of yeast extract powder, 20 g of sucrose and 35 g of sea salt are dissolved in 1000 ml of distilled water.
The gradient eluent in the reversed phase medium pressure column chromatography in the step (3) is methanol and water, the volume percentage of the methanol is from 30 to 60 percent, and the elution time is 0 to 45 min; the volume percentage of the methanol is 83-100%, and the elution time is 46-120 min.
The flow rate for the isolation preparation of the compound by semi-preparative reverse phase high performance liquid chromatography described in step (3) was 2.0 mL/min.
The cyclic lipopeptide compound is used for preparing at least one of a methicillin-resistant staphylococcus aureus (MRSA) inhibiting medicament, a staphylococcus aureus inhibiting medicament, a vibrio alginolyticus inhibiting medicament and a vibrio hemolyticus inhibiting medicament.
Compared with the prior art, the invention has the advantages that: the invention relates to a cyclic lipopeptide compound and a preparation method and application thereof, wherein the preparation method comprises the steps of carrying out microbial fermentation culture on bacillus with the preservation number of CGMCC NO.6554 to obtain a fermentation product of the cyclic lipopeptide compound, then soaking the fermentation product in ethyl acetate to extract a crude extract, separating and purifying the crude extract by virtue of reduced pressure column chromatography, normal phase medium pressure column chromatography, reversed phase medium pressure column chromatography and reversed phase semi-preparative high performance liquid chromatography, and screening antibacterial activity to discover that the compound has strong inhibition activity against methicillin-resistant staphylococcus aureus (MRSA), staphylococcus aureus, vibrio alginolyticus and vibrio hemolyticus, so that the compound can be used for developing and utilizing lead medicaments for inhibiting related diseases and infection caused by various pathogenic bacteria.
The above Bacillus amyloliquefaciens (Bacillus amyloliquefaciens) The strain is an ESB-2 strain, the preservation number is CGMCC No.6554, the strain is preserved in China general microbiological culture Collection center on 11 months at 09 and 2012, and the preservation address is No. 3 of Xilu No. 1 Beichen of the rising area of Beijing.
Detailed Description
The present invention will be described in further detail with reference to examples.
Example 1
A cyclic lipopeptide compound, the structural formula of which is shown as (I):
Figure 780512DEST_PATH_IMAGE001
（I）。
example 2
The method for separating and preparing the cyclic lipopeptide compound shown in the structural formula (I) in the embodiment 1 specifically comprises the following steps:
(1) Fermentation production
Activating Bacillus amyloliquefaciens with preservation number of CGMCC No.6554 on a culture dish containing Gao's I, culturing at 28 deg.C for 7 days, inoculating to A liquid culture medium (starch 20 g, peptone 2g, yeast crude extract 6g, caCO) 3 1 g，KBr 100 mg，Fez(SO 4 ) 3 4H 2 0 40mg,1L seawater), culturing at 150 rpm/min for 3 days with a rotary shaker at 28 deg.C to obtain seed solution, inoculating 10% (about 20 ml) of the seed solution into sterilized 300 bottles of YSP culture medium (containing 350 ml), and culturing at 150rpm on shaker at 28 deg.C to obtain 7% seed solutionDay, finally obtaining a fermentation product; the preparation method of the YSP culture medium comprises the following steps: dissolving 10 g of peptone, 5 g of yeast extract powder, 20 g of sucrose and 35 g of sea salt in 1000 ml of distilled water, and then sterilizing at 120 ℃ for 15min in a sterilization pot;
(2) Extract extraction
Adding the fermented product into ethyl acetate with the same volume as the fermented product, repeatedly extracting for 3 times, then evaporating the ethyl acetate leaching liquor under reduced pressure, then adding mixed liquor of ethyl acetate with the same volume as the fermented product and water with the same volume, repeatedly extracting for 3 times, combining ethyl acetate phase extraction liquor obtained by three times of extraction, concentrating under reduced pressure and evaporating to obtain a crude extract;
(3) Isolation preparation of compounds
The crude extract was dissolved in a methanol solvent and subjected to preliminary separation by reduced pressure column chromatography VLC (6 × 15 cm,200-300 mesh), and gradient elution was performed with a solvent ratio of petroleum ether/ethyl acetate (20, 1, 2, 0. After HPLC detection and activity tracking, the active ingredient is mainly concentrated in Fr.2 and Fr.3 components, and therefore, the two components are further separated and purified. Normal phase medium pressure chromatography was first performed on component fr.3 (120 g) with the elution solvent and system being petroleum ether: ethyl acetate =1,4; after activity screening, the component Fr.3.3 is subjected to reversed phase medium pressure column chromatography at a flow rate of 20 mL/min and a gradient elution range (MeOH: H) 2 30-60% of O, 46-120 min of 0-45 min and 83-100%) of the waste water; and (3) performing HPLC reversed phase semi-preparation in a 28 th tube (120 mg), wherein an eluent is formed by mixing acetonitrile and water according to a volume ratio of 65:
Figure 884472DEST_PATH_IMAGE002
（I）。
the compound I of the invention is white powderThe high resolution mass spectrum (HR-ESI-MS) in the ion mode gives the peak of the quasi-molecular ionm/z 607.7442 [M + Na] + . Bonding of 13 C NMR spectrum to determine its molecular formula as C 32 H 48 N 4 O 6 Of the compound 1 H and 13 the C NMR spectrum and the two-dimensional spectrum data are shown in Table 1:
TABLE 1D and 2D NMR data for Compound I (600, 150 MHz, DMSO-d 6 )
Figure 350089DEST_PATH_IMAGE003
Note 1: the signal attribution of the meter is based on DEPT, 1 H- 1 And analyzing the H COSY, the HMBC and the HSQC. 2: s-singlet, d-doublet, t-triplet, m-multiplet. 3: 1 h was obtained by 600 MHz NMR; 13 c was obtained by 150 MHz NMR.
Example 3
Cyclic lipopeptide compounds of example 1 activity and uses
(1) Experimental sample
Preparing a solution of a sample to be detected: the test sample is the pure compound I separated and purified in the above example 1, an appropriate amount of sample is precisely weighed, a solution with a required concentration is prepared by DMSO for testing the antibacterial activity, and the initial concentration of a positive control (vancomycin hydrochloride) is 2.5 mug/mL. The indicator bacteria used in this experiment were methicillin-resistant staphylococcus aureus (MRSA), staphylococcus aureus (s.a), vibrio alginolyticus and vibrio haemolyticus. The indicator used in this experiment was an Alamar blue indicator.
(2) Experimental methods
The 96-well plate antibacterial test method comprises the following steps: in a 96-well plate, mueller-Hinton broth with a final volume of 200. Mu.L/well was used as a minimal medium, wherein the concentration of the compound was diluted to a concentration of 128 to 0.5. Mu.g/mL in a two-fold broth dilution method and 1X 10 5 Bacterial cultures were added at turbidity of CFU/mL. Incubate the plates in the dark at 37 ℃ for 8 hours, after incubation is complete, add 15 μ L Alamar blue indicator (indicator diluted to 0.02% with sterile water) to each well,after 1 hour of incubation, the solution was observed for changes. Vancomycin hydrochloride was used as a positive control, and when bacteria grew, alamar blue was reduced to change from bluish blue to pink. The final concentration of the wells closest to red and remaining blue was called the Minimum Inhibitory Concentration (MIC) determining activity.
(3) Results of the experiment
In a 96-well plate antibacterial assay, the MIC values of compound i for each pathogen were as follows:
TABLE 2 evaluation of antibacterial Activity of Compound I
Figure 749977DEST_PATH_IMAGE004
。
As can be seen from Table 2, the compound has strong activity of inhibiting methicillin-resistant Staphylococcus aureus (MRSA), staphylococcus aureus, vibrio alginolyticus and Vibrio haemolyticus, and thus can be used for development and utilization of lead drugs for inhibiting related diseases and infections caused by various pathogenic bacteria.
The above description is not intended to limit the present invention, and the present invention is not limited to the above examples. Those skilled in the art should also appreciate that they may make various changes, modifications, additions and substitutions within the spirit and scope of the invention.

Claims (7)

1. A cyclic lipopeptide compound is characterized in that the structural formula of the cyclic lipopeptide compound is shown as (I);
Figure 80415DEST_PATH_IMAGE001
（I）。
2. a method for preparing the cyclic lipopeptide compound of claim 1, comprising the steps of:
(1) Fermentation production
Activating bacillus amyloliquefaciens with the preservation number of CGMCC No.6554 on a culture dish containing Gao's I, culturing at the constant temperature of 28 ℃ for 7 days, inoculating the bacillus amyloliquefaciens into a liquid culture medium A, rotating a shaking table at 28 ℃, culturing at the rotating speed of 150 rpm/min for 3 days to obtain a seed solution, inoculating the seed solution into a YSP culture medium which is sterilized in advance according to the inoculation amount of 10 percent of the volume ratio, and culturing at the temperature of 28 ℃ and 150rpm on the shaking table for 7 days to finally obtain a fermented product;
(2) Extract extraction
Adding ethyl acetate with the same volume as the fermented product into the fermented product obtained in the step (1), repeatedly extracting for 3 times, evaporating the ethyl acetate leaching liquor under reduced pressure, adding mixed liquor of ethyl acetate and water with the same volume as the fermented product, repeatedly extracting for 3 times, combining ethyl acetate extraction liquor obtained by three times of extraction, concentrating under reduced pressure, and evaporating to obtain a crude extract;
(3) Isolation preparation of compounds
Dissolving the crude extract obtained in the step (2) by using a methanol solvent, performing primary separation by using a reduced pressure column chromatography (VLC), performing gradient elution by using petroleum ether/ethyl acetate with a volume ratio of 20, 1, 2, 0; subjecting the collected 3 rd component to normal-phase medium pressure chromatography, performing gradient elution with petroleum ether/ethyl acetate at a volume ratio of 1,4; performing reversed-phase medium-pressure column chromatography separation on the collected component 3, wherein the adopted eluent is methanol and water, the volume percentage of the methanol is 30-100%, the elution time is 120 min, and 50 tubes are collected in total; taking a 28 th tube for semi-preparative reverse phase high performance liquid chromatography separation, adopting a mixed solution of acetonitrile and water according to a volume ratio of 65:
Figure 759789DEST_PATH_IMAGE001
（I）。
3. the method for preparing cyclic lipopeptide compound according to claim 2The preparation method of the liquid culture medium A in the step (1) is characterized by comprising the following steps: 20 g of starch, 2g of peptone, 6g of yeast crude extract 3 1 g，KBr 100 mg，Fe 2 (SO 4 ) 3 •4H 2 0 40mg of the extract is dissolved in 1L of seawater.
4. The method for preparing cyclic lipopeptide compounds according to claim 2, characterized in that the preparation method of the YSP culture medium is as follows: 10 g of peptone, 5 g of yeast extract powder, 20 g of sucrose and 35 g of sea salt are dissolved in 1000 ml of distilled water.
5. The method for preparing cyclic lipopeptide compounds according to claim 2, wherein the gradient eluent in the reversed-phase medium-pressure column chromatography in step (3) is methanol and water, the volume percentage of methanol is 30-60%, and the elution time is 0-45 min; the volume percentage of the methanol is from 83 percent to 100 percent, and the elution time is 46 to 120 min.
6. The method of claim 2, wherein the cyclic lipopeptide compound is prepared by the following steps: the flow rate for the isolation preparation of the compound by semi-preparative reverse phase high performance liquid chromatography described in step (3) was 2.0 mL/min.
7. Use of the cyclic lipopeptide compound of any one of claims 1-6 in the preparation of a medicament for inhibiting at least one of methicillin-resistant staphylococcus aureus, vibrio alginolyticus and vibrio haemolyticus.
CN202210733329.3A 2022-06-27 2022-06-27 Cyclic lipopeptide compound and preparation method and application thereof Pending CN115490753A (en)

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