CN118146275A - Glycolipid compound and preparation method and application thereof - Google Patents

Glycolipid compound and preparation method and application thereof Download PDF

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CN118146275A
CN118146275A CN202410275372.9A CN202410275372A CN118146275A CN 118146275 A CN118146275 A CN 118146275A CN 202410275372 A CN202410275372 A CN 202410275372A CN 118146275 A CN118146275 A CN 118146275A
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formula
compound
glycolipid
compounds according
strain
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王乂
杨立远
张庆庆
于登
朱伟明
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Ocean University of China
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Ocean University of China
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Abstract

The invention discloses a glycolipid compound, a preparation method and application thereof, and belongs to the technical field of marine organisms and medicines. The glycolipid compounds of the invention include compounds of formula I, and stereoisomers or pharmaceutically acceptable salts thereof. The compound shown in the formula I is extracted and separated from Pseudogymnoascus sp.OUCMDZ-4032 strain from Antarctic marine sediment, and proved by experiments, the compound can be combined with antibiotics (such as ciprofloxacin) to greatly enhance the antibacterial activity of the antibiotics on gram-negative bacteria, and can be used for developing antibiotic auxiliary agents.

Description

Glycolipid compound and preparation method and application thereof
Technical Field
The invention relates to the technical field of marine organisms and medicines, in particular to a glycolipid compound extracted and separated from a microbial fermentation culture derived from Antarctic marine sediment and application of the glycolipid compound as a biosurfactant and combined with ciprofloxacin to enhance the activity of the glycolipid compound on inhibiting gram-negative bacteria.
Background
Antarctic regions are subjected to low temperature, drought (cold desert), frequent freeze thawing cycles, strong wind, high sublimation, evaporation, nutrient starvation and strong ultraviolet radiation for a long time. Thus, microorganisms that survive for long periods of time in such extreme environments may metabolically and physiologically evolve various strategies to accommodate such harsh environments, creating special physiological metabolic features and chemical defense mechanisms. And in particular psychrophilic fungi, have become an important source for the discovery of new bioactive secondary metabolites. Therefore, the research on psychrophilic bacteria and bioactive secondary metabolites has important significance in the biotechnology and pharmaceutical fields.
Multidrug-resistance (MDR) is one of the most serious global public health threats in this century. Among them, most of the bacteria resistant to antibiotics are gram-negative pathogenic bacteria. Due to its unique structure, gram-negative bacteria have stronger resistance than gram-positive bacteria, causing serious drug-resistant infections worldwide. However, for decades, the development of new antibiotics capable of overcoming drug resistance has been stopped, and in order to solve the problem of drug resistance of antibiotics and the emergence of multi-drug resistant strains, a current method is to combine a biosurfactant with an antibiotic to improve the therapeutic effect thereof. In recent years, nanoparticles have been attracting attention as antibiotic adjuvants for synergistic bacteriostasis. However, the related natural products are relatively few. Therefore, strategies to develop new adjuvants to restore drug sensitivity to super-resistant bacteria are highly desirable.
Glycolipid compounds, which are composed of carbohydrate molecules linked to fatty acids, are characterized by a high degree of structural diversity and have the ability to reduce surface tension and interfacial tension at the interface and thus have biosurfactant activity. Recently, there has been an increasing interest in biosurfactants because of their unique properties such as low toxicity, high biodegradability, high foaming capacity, antimicrobial activity, and selectivity and specificity at extreme temperatures, pH and salinity. These properties are considered to be more advantageous than other chemical surfactants, and glycolipid compounds are therefore considered to be a good alternative for use in the environmental, petroleum, food and pharmaceutical industries, such as glycolipids as food additives and food preservatives, in the development of antibiotic adjuvants for clinical antimicrobial applications.
Disclosure of Invention
A first object of the present invention is to provide glycolipid compounds isolated from microorganisms derived from Antarctic marine sediments, including but not limited to the glycolipid compounds of formula i and all the stereoconfigurations thereof or pharmaceutically acceptable salts thereof:
（I）。
The positions where the configuration of the compounds of formula I may be altered include C-6 and C-12 steric configurations, cis-trans isomerism of double bonds and sugar configurations.
The glycolipid compound shown in the formula I is obtained by extracting, separating and purifying Pseudogymnoascus sp, OUCMDZ-4032 strain from Antarctic ocean sediment.
The Pseudogymnoascus sp.OUCMDZ-4032 strain is preserved in China general microbiological culture Collection center (CHINA GENERAL Microbiological Culture Collection Center, CGMCC) with a preservation number of CGMCC No. 21946 in 4-7 of 2021.
A second object of the present invention is to provide a process for the preparation of glycolipid compounds of formula I, which are isolated from fermentation cultures of Pseudogymnoascus sp.
The specific preparation method of the compound shown in the formula I comprises the following steps:
(1) Fermenting Pseudogymnoascus sp.
(2) Subjecting the obtained total crude extract to normal phase silica gel pressure reduction column chromatography, gradient eluting with petroleum ether/dichloromethane and dichloromethane/methanol as eluent, vacuum concentrating the eluted components, and performing LC-MS analysis to obtain 12 components Fr.1-Fr.12;
(3) Subjecting the component Fr. to reversed phase silica gel pressure column chromatography, and separating to obtain 15 components Fr. -1-Fr. -10-15 by using methanol/water as eluent;
(4) Components Fr. -14 were purified by HPLC to give compounds of formula I.
The elution gradient in the step (2) is petroleum ether/dichloromethane=100:0, 50:1, 10:1, 1:1, 0:100 in sequence; dichloromethane/methanol=100:1, 50:1, 20:1, 10:1, 5:1, 2:1, 1:1, 0:100.
The volume ratio of methanol/water in the step (3) is 10:90-0:100.
It is a third object of the present invention to provide the use of a compound of formula I in combination with an antibiotic (e.g. ciprofloxacin) to enhance the inhibitory activity of the antibiotic against gram-negative bacteria.
The invention has the technical effects that: the glycolipid compound shown in the formula I is obtained by extracting and separating a fungal fermentation culture from Antarctic ocean sediment; the compound can be used in combination with antibiotics to greatly enhance the antibacterial activity of antibiotics to gram-negative bacteria, and can be used for developing antibiotic auxiliary agents. The invention adopts a 96-well plate method to measure the minimum inhibitory concentration (Minimal inhibit concentration, MIC) of the compound of the formula I on 5 strains of bacteria, and on the basis, adopts a chessboard method to evaluate the bacteriostatic activity of the compound of the formula I and ciprofloxacin combined drug on 3 strains of gram-negative bacteria, and the result shows that: 32. the combined administration of the mug/mL compound shown in the formula I and ciprofloxacin can effectively enhance the antibacterial activity of the ciprofloxacin, and can respectively reduce the MIC of pseudomonas aeruginosa, escherichia coli and paratyphoid bacillus by 1024 times, 256 times and 256 times.
Drawings
FIG. 1 is a strain morphology map of Pseudogymnoascus sp.
FIG. 2 is a nuclear magnetic resonance hydrogen spectrum (DMSO-d 6, 400 MHz) of a compound of formula I.
FIG. 3 is a nuclear magnetic resonance carbon spectrum (DMSO-d 6, 100 MHz) of a compound of formula I.
FIG. 4 is a plot of the LR-ESI-MS analysis of the compound of formula I (positive ion mode, [ M+H ] +).
Fig. 5 is a graph of the results of a drop collapse experiment for the compound of formula I.
Detailed Description
The following specific examples are offered to further illustrate, but not to limit the invention.
The experimental methods of the following specific examples are all conventional methods unless otherwise specified; the experimental reagents used in the following examples are commercially available unless otherwise specified.
Example 1: isolation and purification and identification of strains
1. Sample collection
The sample is a Antarctic ocean sediment sample, and is immediately placed into a sterile sealing bag after being collected, is frozen for preservation and transportation to a laboratory, and is preserved in a refrigerator at the temperature of minus 20 ℃.
2. Sample processing
The marine sediment sample is separated by adopting a gradient dilution method, namely a sample 1g is weighed in a sterile environment, firstly 75% ethanol is used for surface sterilization, then sterilized seawater is used for flushing the sample for multiple times, finally the sample is placed in a mortar for grinding into homogenate, and the supernatant is diluted into three gradients of 0.1 g/mL, 0.01 g/mL and 0.001 g/mL by using the sterilized seawater.
3. Isolation and purification of strains
The microorganisms were isolated and cultured using PDA medium (natural pH). First, 0.2 mL was pipetted using a sterile pipette
The sample solutions with different dilution ratios are dripped into PDA solid culture medium (200 g of cooked potato, 20g of glucose, 15 to 20g of agar and natural pH are added into each liter of water), and then a sterilization coating rod is used for coating uniformly, after bacterial solution permeates into the culture medium, the bacterial solution is placed into a constant temperature incubator at 28 ℃ for inversion culture for 4 to 7 days. Purifying the strain by adopting a plate streaking method, observing the growth condition of the plate strain, and carrying out streaking culture when single colony appears. The specific method for scribing the flat plate comprises the following steps: the inoculating loop is burnt by adopting the outer flame of the alcohol lamp, after the inoculating loop is fully cooled, a single colony is scraped from the flat plate, the inoculating loop is held on the agar flat plate to carry out zigzag scribing, and the operation is required to be carried out in a sterile area near the flame of the alcohol lamp. After the inoculation is completed, the serial numbers, names and dates of the strains are marked on the bottom of a culture dish, and then the culture dish is placed in a constant temperature incubator at 28 ℃ for inverted culture. If the primary streaking fails to purify the strain, a secondary streaking operation is required until the strain is completely purified.
4. The preservation method of the strain comprises the following steps:
And (3) slope preservation: the purified strains are inoculated in a slant PDA culture medium by adopting a zigzag streaking method, and after the strains grow to be mature, the strains are placed in a refrigerator at 4 ℃ for storage, and 3 strains are arranged in parallel.
Freezing and storing glycerol pipes: the purified strain was frozen using PDA liquid medium (20% glycerol added) as the frozen stock. Taking 1 mL frozen stock solution, placing in a frozen stock tube, and sterilizing. After cooling, a proper amount of mycelium of the strain on the agar plate is scraped and placed in a freezing tube and preserved in a refrigerator at the temperature of minus 80 ℃.
5. Identification of strains
The strain is identified by a method combining morphology and molecular biology. The external phenotype characteristics of the strain were photographed and archived, and the morphological photographs of the strain are shown in fig. 1. The strain has the following morphological characteristics: the aerial hypha is short and white; microscopic morphology of the insert piece is observed under a 400-fold mirror, which shows that aerial hyphae are broken into spores, and the spores are spherical and smooth. The ITS DNA sequence of the strain was amplified using the primer sequences ITS1 (5'-TCCGTAGGTGAACCTGCGG-3') and ITS4 (5'-TCCTCCGCTT ATTGATATGC-3'). The extracted total DNA of the strain is used as a template, PCR amplification is carried out, and the ITS DNA sequence length of the strain is 521 bp (shown as a sequence table SEQ No. 1). The strain is identified as Pseudogymnoascus sp, OUCMDZ-4032 and has a preservation number of CGMCC No. 21946 by ITS sequence comparison.
Example 2: separation, purification and structural identification of the compound of formula I
1. Preparation of total crude extract
Selecting a proper amount of mycelium of a target strain, inoculating the mycelium into a fungus 3# culture medium, and fermenting for 5 days in a shaking table at 16 ℃ and 180 r/min to obtain seed liquid of the strain. The seed solution is inoculated into a fermentation medium, namely a rice solid medium (80 g rice+120 mL seawater) according to the proportion of 5 percent by volume, and is fermented, and 200 bags are fermented altogether. Standing in a shaking table at 16 ℃ and fermenting for 30 days to obtain a strain culture.
The fungal 3# medium includes: 200 g of cooked potatoes, 10 g of monosodium glutamate, 20g of mannitol, 20g of maltose, 10 g of glucose, 0.3 g of MgSO 4 ·7H2 O, 3 g of yeast extract and seawater are added into each liter of water to prepare the natural pH.
Crushing Pseudogymnoascus sp.OUCMDZ-4032 culture, adding 3 times volume of ethyl acetate into fermentation culture, extracting for three times, ultrasonic treating each time for 0.5 h, filtering ethyl acetate extract, and vacuum concentrating to obtain oily total crude extract 75 g.
2. Separation and purification of compounds
And (3) carrying out normal phase silica gel decompression column chromatography separation on the oily total crude extract 75 g obtained by strain fermentation. Setting elution gradient of petroleum ether/dichloromethane 100:0, 50:1, 10:1, 1:1, 0:100; dichloromethane/methanol 100:1, 50:1, 20:1, 10:1, 5:1, 2:1, 1:1, 0:100, and the eluted fractions were concentrated in vacuo and subjected to LC-MS analysis, which was divided into 12 fractions Fr.1-12.
The component Fr. is subjected to reversed-phase silica gel pressure column chromatography (methanol: water: 10: 90-0: 100) to obtain 15 components (Fr. 10-1-Fr. 10-15). Purification of components Fr. -14 by HPLC（25 min ACN-H2O,0 min：10% ACN+90% H2O,15 min 100% ACN, 20 min–25 min 10% ACN+90% H2O） afforded compound of formula I (18.6 mg, t R =16.5 min).
3. Structure identification of Compounds
The structure of the compound separated and purified by the invention is determined as shown in the formula I by adopting Nuclear Magnetic Resonance (NMR), ultraviolet (UV) spectrum, high resolution mass spectrum (HRESIMS) and other spectrum technologies.
The characteristics of the compounds of formula I: yellow brown oily solids ; [α]28 D +89.28(c 1, MeOH),ECD (0.80 mM, MeOH) λmax (Δ ε) 231 (+15.56), 231(-18.38) nm; UV (MeOH) λ max (log ε) 230 (2.83), 271 (3.13) nm; IR (KBr) ν max 3365, 2951, 2930, 2869, 1681, 1556, 1456, 1383 ,1205, 1147, 1078, 993 cm-1; 1H and 13 CNMR (DMSO, dimethyl sulfoxide-d 6) are detailed in Table 1; positive ion high resolution mass spectrum HRESIMS: M/z 629.3515 [ M+H ] + (C32H53O12 calcd 629.3532), molecular formula is C 32H52O12. The structure identification related patterns of the compound of the formula I are shown in figures 2-4.
TABLE 1 Nuclear magnetic data sheet for Compounds of formula I (1H 400 MHz, 13C 100 MHz, NMR, DMSO-d6, TMS, delta ppm)
Example 3: surface Activity test of Compounds of formula I
The structure of the compound of the formula I consists of a hydrophobic fatty chain and a hydrophilic glycosyl group, so that the compound is supposed to have good surface activity, and the surface activity of the compound of the formula I is qualitatively tested by adopting a water drop collapse experiment. Ultrapure water was dyed with 0.01% crystal violet and made into 10. Mu.L drops, which were placed on the paraffin sealing film. Staining water and water stained with 10% MeOH were used as negative controls. These droplets have only a small contact point with the hydrophobic surface and form a sphere shape. Staining water containing 10% MeOH and 0.1% Tween 20 was used as positive control. Due to its lower water tension, the water droplets collapse and spread to the hydrophobic surface. The compound of formula I was tested at a concentration of 1mM in staining water containing 10% MeOH and the experimental results are shown in figure 5. The degree of collapse of the drops after addition of the compound of formula I was comparable to, even slightly greater than, the positive control. The compound shown as the formula I has good biological surface activity.
Example 4: evaluation of antibacterial Activity of Compounds of formula I
1. Evaluation of bacteriostatic Activity
The antibacterial activity of the compound of the formula I on 5 strains of bacteria including pseudomonas aeruginosa (Pseudomonas aeruginosa ATCC 10145), escherichia coli (ESCHERICHIA COLI ATCC 11775), paratyphoid bacillus (Salmonella PARATYPHI ATCC 9150), bacillus subtilis (Bacillus subtilis ATCC 6051) and Methicillin-resistant staphylococcus aureus (Methicillin-RESISTANT STAPHYLOCOCCUS AUREUS ATCC 43300) is preliminarily evaluated by adopting a 96-well plate method, ciprofloxacin is used as a positive control, and a bacterial LB culture medium is used as a negative control; the initial concentration of the compound of the formula I is 64 mug/mL, and the antibacterial activity of the compound is primarily judged by visually observing whether the bottom of a 96-well plate is clear after culture. The results of the bacteriostatic activity are shown in Table 2.
TABLE 2 antibacterial activity preliminary screening of Compounds of formula I
As can be seen from Table 2, the compounds of formula I have weak inhibitory activity against Bacillus subtilis (MIC value 32. Mu.g/mL) and no inhibitory activity against the other four strains (MIC > 64. Mu.g/mL), indicating that the compounds of formula I do not possess good bacteriostatic activity per se.
Example 5: evaluation of antibacterial Activity of Compound of formula I and ciprofloxacin combination
1. Chessboard method antibacterial activity determination
The antibacterial activity of the compound of formula I and ciprofloxacin combined drug against 3 gram-negative bacteria (pseudomonas aeruginosa, escherichia coli and paratyphoid bacillus) was evaluated by using a chessboard method.
Referring to the CLSI M27-A (yeast liquid culture dilution method antifungal drug sensitivity experiment) scheme, the drug stock solution was diluted with LB liquid culture medium (0.5% yeast extract, 0.5% NaCl,1% tryptone) to a 2-fold ratio of the final mass concentration of the drug ranging from 2-0.001953125. Mu.g/mL (Pseudomonas aeruginosa), 0.125-4.8828125X 10 -4 . Mu.g/mL (E.coli), 0.25-0.0009765625. Mu.g/mL (paratyphi). The final concentration of the compound of formula I is 64-1. Mu.g/mL.
Strains were picked from LB plates and inoculated into LB liquid medium at 28℃and 180 rpm to activate strain 12 h.
The operation is carried out according to the following method: taking 50 mu L of ciprofloxacin diluted by a ratio from high concentration to low concentration, and sequentially adding columns 1-12 of a 96-well plate; taking 50 mu L of compound liquid medicine of the formula I diluted by a double ratio from low concentration to high concentration, and sequentially adding the compound liquid medicine into rows B-G of a 96-well plate. 100. Mu.L of the bacterial suspension was added to each well, and a blank (200. Mu.L of LB medium) and a growth control (100. Mu.L of LB medium and 100. Mu.L of bacterial suspension) were additionally added. The results of the incubation at constant temperature and humidity of 28℃for 24 h and visual clarification Kong Pandou were repeated 3 times.
2. Evaluation method for combined action effect of two medicaments
The invention adopts the FICI method to evaluate the results, the method is an nonparametric method model developed based on Loewe Additivity (LA) theory, and the formula is as follows:
FICl is a partial bacteriostasis combination index, wherein MIC A and MIC B are MIC values when two drugs are used singly, and MIC A in combination and MIC B in combination are MIC values when two drugs are combined. The FICI is calculated as a double value of the maximum concentration when the MIC value is higher than the maximum limit of detection. According to example 3, since the compound of formula I has no bacteriostatic activity against three gram-negative bacteria, its MIC is defined as 128. Mu.g/mL. The FICI rule is the most commonly used model for explaining the interaction of antibacterial drugs in the invention, but various standards exist for interpretation of FICI values in different documents, and experimental results are judged by adopting the standards of 'FICI < 0.5 is synergistic effect, FICI < 4 is no interaction, and FICI >4 is antagonistic effect'.
FICl: the partial bacteriostasis joint index is calculated as:
FLCI (Pseudomonas aeruginosa ）= MICA in combination/MICA+MICB in combination/MICB=0.001953125/2+ 32/128=9.765625×10-4+0.25 < 0.5, is therefore judged to be co-bacteriostatic.
FLCI (E.coli ）= MICA in combination/MICA+MICB in combination/MIC B =4.8828125×10-4/0.125+ 32/128=3.90625×10-3+0.25 < 0.5, is thus judged to be a combined bacteriostatic effect).
FLCI (paratyphi ）= MICA in combination/MICA+MICB in combination/MIC B =0.0009765625/0.25+ 32/128=3.90625×10-3+0.25 < 0.5, thus judged to be combined bacteriostatic effects.
As shown in Table 3, the MIC of the compound of formula I with 32 mug/mL and ciprofloxacin can be reduced by 1024 times, 256 times and 256 times respectively.
TABLE 3 evaluation of synergistic antibacterial Activity of the compounds of formula I and ciprofloxacin combinations on three gram-negative strains by FICI
From the results of the examples, it can be concluded that the combined administration of 32 mug/mL of the compound of formula I and ciprofloxacin can effectively improve the synergistic antibacterial effect, and the MIC of the compound on pseudomonas aeruginosa, escherichia coli and paratyphoid bacillus is respectively reduced by 1024 times, 256 times and 256 times.

Claims (8)

1. A glycolipid compound of formula i, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof:
（Ⅰ）。
2. The process for the preparation of glycolipid compounds according to claim 1, wherein said compound of formula i is isolated from a fermentation culture of Pseudogymnoascus sp.oucmdz-4032 strain derived from antarctic marine sediment.
3. The method for producing glycolipid compounds according to claim 2, wherein said Pseudogymnoascus sp. OUCMDZ-4032 strain is deposited in China general microbiological culture collection center with the accession number CGMCC No. 21946, month 4 and 7 of 2021.
4. The method for producing glycolipid compounds according to claim 2, comprising the steps of:
(1) Fermenting Pseudogymnoascus sp.
(2) Subjecting the obtained total crude extract to normal phase silica gel pressure reduction column chromatography, gradient eluting with petroleum ether/dichloromethane and dichloromethane/methanol as eluent, vacuum concentrating the eluted components, and performing LC-MS analysis to obtain 12 components Fr.1-Fr.12;
(3) Subjecting the component Fr.10 to reversed-phase silica gel pressure column chromatography, and separating to obtain 15 components Fr.10-1-Fr.10-15 by using methanol/water as eluent;
(4) Components Fr. -14 were purified by HPLC to give compounds of formula I.
5. The method for producing glycolipid compounds according to claim 4, wherein the elution gradient in the step (2) is petroleum ether/methylene chloride=100:0, 50:1, 10:1, 1:1, 0:100 in this order; dichloromethane/methanol=100:1, 50:1, 20:1, 10:1, 5:1, 2:1, 1:1, 0:100.
6. The method for producing glycolipid compounds according to claim 4, wherein the volume ratio of methanol/water in said step (3) is 10:90 to 0:100.
7. Use of a glycolipid compound according to claim 1 for enhancing the inhibitory activity of an antibiotic against gram-negative bacteria in combination with the antibiotic.
8. The use of glycolipid compounds according to claim 7, wherein the antibiotic is ciprofloxacin.
CN202410275372.9A 2024-03-12 2024-03-12 Glycolipid compound and preparation method and application thereof Pending CN118146275A (en)

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