CN119899237A - Nucleoside antibiotic with anti-tuberculosis activity and preparation method and application thereof - Google Patents
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Abstract
本发明公开了一种具有抗结核杆菌活性的核苷类抗生素及其制备方法和应用；所述核苷类抗生素为从链霉菌Streptomyces sp.NRRL 30475发酵液中提取分离得到的muraymycin D9，其分子式为C38H61N11O15，为首次报道肽链末端缬氨酸与非蛋白源氨基酸epicapreomycidine亚胺脱水环合的muraymycin化合物；经体外抗结核杆菌活性研究表明，本发明提供的核苷类化合物对耻垢分枝杆菌具有很强的抗菌活性，可望开发成新的抗结核杆菌药物。
The invention discloses a nucleoside antibiotic with anti-tuberculosis activity and a preparation method and application thereof; the nucleoside antibiotic is muraymycin D9 extracted and separated from the fermentation broth of Streptomyces sp.NRRL 30475, and the molecular formula thereof is C 38 H 61 N 11 O 15 , which is the first reported muraymycin compound in which the terminal valine of the peptide chain is dehydrated and cyclized with the non-protein amino acid epicapreomycidine imine; in vitro anti-tuberculosis activity studies show that the nucleoside compound provided by the invention has strong antibacterial activity against Mycobacterium smegmatis, and is expected to be developed into a new anti-tuberculosis drug.
Description
Technical Field
The invention relates to a nucleoside antibiotic with anti-tubercle bacillus activity, and also relates to a preparation method and application of the nucleoside antibiotic.
Background
After 12 years of emergence of penicillin as the first antibiotic, the problem of drug-resistant bacteria gradually appears, even becomes super drug-resistant bacteria, and with the wide use of antibiotics, the problem of drug resistance of bacteria is endangering the safety of human health and global public health. Mcdonald et al, 2002, first isolated 22 cells muraymycins in Streptomyces sp.NRRL 30471 fermentation broth (J am. Chem. Soc.2002, 124:10260), and found that they have extremely strong MraY translocase activity, and can effectively inhibit bacterial cell wall biosynthesis processes, thus exhibiting potent antibacterial activity. Muraymycins belongs to nucleoside antibiotics, the structural unit of which mainly comprises valine, L-leucine, non-protein amino acid epicapreomycidine, aminopropane and glycyluridine (GlyU) core parts, the structural variation of leucine residues in polypeptide parts can be divided into A, B, C, D types, the type D is the simplest L-leucine, the type C is (3S) -3-OH-L-leucine, the type B is L-leucine acylated and connected with a saturated fatty acid branched chain, the carbon chain length is 3-10C, the type A is similar to the type B, and the tail end of the fatty acid branched chain is substituted by guanidine groups. Wherein, the A-type antibacterial activity is strongest, the MIC for the escherichia coli mutant (E.coli delta tolC) is less than 0.03 mug/mL, and the ED 50 for mice infected with staphylococcus aureus reaches 1.1mg/kg. Muraymycin in addition to MraY translocase inhibitory activity, 2016 have found that muraymycin D has inhibitory activity against N-acetylglucosamine-1-phosphate transferase (WecA) of Mycobacterium tuberculosis in both replicative and non-replicative states, thus exhibiting superior anti-Mycobacterium tuberculosis activity. However, the yield of fermentation culture muraymycins is low, and the fermentation method needs to be optimized to improve the yield of the compound, or other analogues with novel structures and stronger activity are sought.
Disclosure of Invention
The invention aims to provide a nucleoside antibiotic with anti-tubercle bacillus activity, and also provides a preparation method and application of the nucleoside antibiotic.
The invention discloses a nucleoside antibiotic with anti-tubercle bacillus activity, which has a molecular formula of C 38H61N11O15, is named muraymycin D, and has a structure shown in a formula I:
The nucleoside antibiotics are muraymycin nucleoside antibiotics obtained by dehydrating and cyclizing valine at the tail end of a peptide chain and non-protein amino acid epicapreomycidine imine, screening and optimizing fermentation media of Streptomyces sp.NRRL 30475 and mutant strains thereof, and performing mass fermentation, separation and purification or chemical synthesis.
The preparation method of the nucleoside antibiotics comprises the following steps:
(1) Fermenting, namely taking Streptomyces sp.NRRL 30475 strain, culturing with a BPM23A culture medium to obtain a seed culture solution, and inoculating the seed culture solution into the BPM23A culture medium to culture to obtain a fermentation broth;
(2) Extracting, namely centrifuging the fermentation liquor obtained in the step (1) to obtain mycelia and supernatant, ultrasonically extracting the mycelia by using methanol, concentrating to obtain an extract A, adding nonionic macroporous resin into the supernatant, stirring, filtering, discarding the filtrate, eluting the macroporous resin by using methanol until the macroporous resin is colorless, and recovering the methanol to obtain an extract B;
(3) Separating and purifying the extracts A and B by reverse MCI column chromatography, sephadex LH-20 column chromatography and liquid phase preparation method to obtain nucleoside antibiotic with anti-tubercle bacillus activity.
The method comprises the steps of (1) taking a Streptomyces sp.NRRL 30475 strain purified M2 plate, culturing for 3-5 days at 25-30 ℃ by using a BPM23A culture medium, inoculating the obtained seed culture solution into 10-15L of the BPM23A culture medium, and culturing for 7-10 days at 25-30 ℃ to obtain a fermentation broth.
In the step (2), the mycelium is extracted by methanol ultrasonic for 3-5 times, and the supernatant is added with 1% -4% of nonionic macroporous resin, stirred for 6-8 hours and then filtered.
Wherein, in the step (3), the extract is separated by MCI column chromatography, and eluted sequentially by 20%, 40%, 60%, 80% and 100% methanol, and the total of 19 fractions Fr.1-1-Fr.1-19 are obtained, fr.1-7 is separated by gel column chromatography to obtain 5 fractions Fr.1-7-1-Fr.1-7-5, fr.1-7-2 is eluted by preparative liquid phase MeOH, thus obtaining the nucleoside antibiotics with anti-tubercle bacillus activity.
The invention also discloses a pharmaceutical composition comprising the nucleoside antibiotic with anti-tubercle bacillus activity and a pharmaceutically acceptable carrier.
The nucleoside antibiotics with the anti-tubercle bacillus activity can be applied to the preparation of antibacterial drugs.
Wherein the antibacterial drug is an anti-tubercle bacillus drug.
Wherein the medicament is in the form of tablet, capsule, injection, powder injection, granule, fat emulsion, microcapsule, dripping pill, ointment or transdermal controlled release patch.
The preparation method comprises the steps of mixing muraymycin D and lactose or corn starch as required, adding magnesium stearate as lubricant, uniformly mixing, granulating, tabletting and preparing tablets, mixing muraymycin D and lactose or corn starch as carrier when preparing capsules, granulating and encapsulating, mixing muraymycin D and lactose or corn starch as diluent when preparing granules, granulating, drying and preparing granules, and adding carrier when preparing powder injection and injection, and adding carrier when preparing fat emulsion, ointment or transdermal controlled release patch.
The invention principle is that the nucleoside antibiotic with anti-tubercle bacillus activity is muraymycin nucleoside antibiotic which is obtained by screening and optimizing fermentation conditions of Streptomyces sp.NRRL 30475, adding biosynthesis precursors such as leucine and the like for large-scale fermentation, and adopting modern chromatographic means for separation and purification, and is a compound with novel structure, namely the first reported muraymycin nucleoside antibiotic which is obtained by dehydrating and cyclizing valine at the tail end of a peptide chain with non-protein amino acid epicapreomycidine imine, and is named muraymycin D. The structural framework of the compound is rare and is not easy to obtain through chemical synthesis or transformation, and an activity test result shows that the compound muraymycin D has stronger antibacterial activity on mycobacterium smegmatis.
Compared with the prior art, the nucleoside antibiotic with the anti-tubercle bacillus activity has the following remarkable advantages that the nucleoside compound muraymycin D has stronger antibacterial activity on mycobacterium smegmatis, and the IC 50 is 32 mug/mL, is an excellent novel antibacterial compound and can be developed into a novel antibacterial drug. The medicine is in the form of tablet, capsule, injection, powder for injection, granule, fat emulsion, microcapsule, dripping pill, ointment, transdermal controlled-release patch, etc.
Drawings
FIG. 1 is a schematic diagram of the structure of a nucleoside antibiotic muraymycin D of the present invention;
FIG. 2 is a HRESI-MS diagram of the nucleoside antibiotic muraymycin D of the present invention;
FIG. 3 is a 1 H NMR chart of nucleoside antibiotic muraymycin D of the present invention;
FIG. 4 is a 13 C NMR chart of nucleoside antibiotic muraymycin D of the present invention;
FIG. 5 is a HSQC chart of nucleoside antibiotic muraymycin D of the present invention;
FIG. 6 is a HMBC diagram of nucleoside antibiotic muraymycin D of the present invention;
FIG. 7 is a NOESY diagram of nucleoside antibiotic muraymycin D of the present invention.
Detailed Description
The technical scheme of the invention is further illustrated below in connection with examples, in which the test materials used are all commercially available by conventional means, with Streptomyces sp.NRRL 30475 being commercially available from ARS Culture Collection (https:// nrrl. Ncaur. Usda. Gov /).
Example 1
The preparation method of the nucleoside antibiotic muraymycin D, disclosed by the invention, comprises the following steps of:
(1) Fermenting by taking Streptomyces sp.NRRL 30475 purified strain, culturing in BPM23A culture medium (medium composition: glucose 5.0g/L, HY yeast 441.0 g/L, calcium carbonate 7.0g/L, maltrin m 180.80.0 g/L, L-methionine 1.5g/L, L-leucine 1.5 g/L) at 28deg.C for 3 days, inoculating the obtained seed culture solution into 10L of BPM23A culture medium, and culturing at 28deg.C for 7 days to obtain fermentation liquor;
(2) Extracting, namely centrifuging the obtained fermentation liquor to obtain mycelium and supernatant. Extracting mycelium with methanol directly for 3 times by ultrasonic extraction, concentrating to obtain extract A, adding 1% -4% of nonionic macroporous resin into supernatant, stirring for 6-8 hours, filtering, discarding filtrate, eluting macroporous resin with methanol to colorless, and recovering methanol to obtain extract B;
(3) Separating the extract by MCI column chromatography, eluting with 20%, 40%, 60%, 80% and 100% methanol sequentially, mixing to obtain 19 fractions (Fr.1-1 to Fr.1-19), separating Fr.1-7 by gel column chromatography to obtain 5 fractions (Fr.1-7-1 to Fr.1-7-5), and eluting Fr.1-7-2 by preparative liquid phase (26% MeOH) to obtain compound muraymycin D (yield: 4.6 mg), with structural formula shown in figure 1.
The nucleoside compound muraymycin D of the present invention is white powder, and its molecular formula is deduced to be C 38H61N11O15.1 H and 13 C nuclear magnetic resonance data as shown in Table 1 from electrospray ion mass spectrum signals M/z912.4427[ M+H ] + and M/z 910.3[ M-H ] -.
1 H and 13 C NMR data (D 2 O) of tables 1 and Muraymycin D9
Structural analysis of Muraymycin D A yellow powder was estimated to have a molecular formula of C 38H61N11O15 and an unsaturation degree of 14 based on HRESIMS data (m/z 912.4427[ M+H ] +, calculated as 912.4427, FIG. 2). 1H NMR、13 C NMR and HSQC spectra of muraymycin D were analyzed (FIGS. 3-5) and found to be 7 carbonyl groups, 1 guanidino group, 5 methyl groups, 7 methylene groups, 18 methine groups (including 2 sp 2 hybridized methine groups). Compared with the known compound muraymycin D, the molecular formula of the compound muraymycin D is reduced by 1H 2 O, and the unsaturation degree is increased by 1. C-32 (delta C 157.1)、C-33(δC 175.7) shifts to high field and C-34 (delta C 62.9.9) shifts to low field in the carbon spectrum, and H-27[ delta H 4.82.82 (1H, m) ] of muraymycin D is combined with key HMBC of C-33 (figure 6), so that the planar structure of the compound is determined, and the compound is a first reported muraymycin compound formed by dehydrating and cyclizing carboxyl of terminal valine with non-protein source amino acid epicapreomycidine imine.
The relative configuration of compound muraymycin D was determined by comparing NMR data (table 1) in combination with NOESY related signals (fig. 7) and shared biogenic synthetic pathways as a novel compound as shown in fig. 1.
Example 2
Evaluation of anti-Mycobacterium smegmatis Activity:
Mycobacterium smegmatis strain (Mycobacterium SMEGMATIS MC) is streaked on Middlebrook 7H10 solid medium, placed at 37℃for 2d, then inoculated into sterilized 7H9 liquid medium, and shake-cultured at 37℃for 24H to strain to logarithmic phase, and the subsequent MIC assay is performed. The cultured Mycobacteria were centrifuged at 5000rpm X10 min to collect the pellet, which was washed 2 times with 7H9 medium, resuspended in fresh 7H9 medium, sonicated and M.smegmatis OD 600 was adjusted to 0.02 for use. In a transparent 96-well plate, the medicines to be screened are diluted by adopting a 2-time gradient, 4 compound wells are arranged, and meanwhile, a strain growth control and a culture medium control are arranged. For Mycobacterium smegmatis, the positive control drug is isoniazid, and the specific method comprises the steps of adding 200 mu l/hole of fresh culture medium to column 1 by using a row gun, adding 100 mu l/hole of fresh culture medium to columns 2-11, and adding 200 mu l of each of four EFGH holes of column 12 by using the row gun as a culture medium control. To the wells of the first column, 2. Mu.l of 12.8mg/ml of compound mother liquor formulated in DMSO was added. The solution was diluted by the gradient dilution method to column 11, and 100. Mu.l of the solution was taken out from column 11. Here, the wells of columns 1 to 11 were each 100. Mu.l of a gradient diluted compound mixture. Subsequently, 100 μl of mycobacterium smegmatis with OD 600 =0.02 was added to column 1-11 wells to give a final concentration of 0.01. 200 μl of the bacterial suspension was added to each of the four ABCD wells of column 12 as a bacterial suspension control. To this end, a whole 96-well plate contained 200. Mu.l of liquid per well. Finally, the cells were directly cultured in a 37℃incubator for 2 days, and the bacterial turbidity OD 600 was measured by using an enzyme-labeled instrument.
The results show that muraymycin D has an anti-Mycobacterium smegmatis activity IC 50 of 32 μg/mL and that the compound has inhibitory activity against Mycobacterium smegmatis in vitro. Mycobacterium smegmatis (M.smegmatis) is often used as an alternative model organism in M.tuberculosis research, and although it has a high degree of sequence homology to M.tuberculosis, it is considered to be non-pathogenic to humans and therefore is widely used in the study of Mycobacterium tuberculosis and other in vivo infections, and is often used to evaluate potential therapeutic applications of drugs.
Example 3
Preparation of tablets:
Muraymycin D9 prepared in example 1 is taken, and proper amounts of pharmaceutical excipients such as starch, magnesium stearate and the like are added, fully and uniformly mixed, and then tabletting is carried out to prepare tablets for oral administration.
Example 4
Preparation of capsules:
Taking muraymycin D prepared in the above example 1, adding appropriate amount of starch as pharmaceutical adjuvant, mixing, and making into capsule for oral administration.
Example 5
Preparation of granules:
taking muraymycin D prepared in the above example 1, adding appropriate amount of corn starch as pharmaceutical adjuvant, mixing, granulating, drying, and making into granule for oral administration.
Therefore, the nucleoside antibiotic with anti-tubercle bacillus activity has strong antibacterial activity on mycobacterium smegmatis and is expected to be developed into a novel anti-tubercle bacillus drug.
Claims (10)
1. The nucleoside antibiotic with anti-tubercle bacillus activity is characterized in that the molecular formula of the nucleoside antibiotic is C 38H61N11O15, and the structure is shown as formula I:
2. The nucleoside antibiotic according to claim 1, wherein the nucleoside antibiotic is a muraymycin nucleoside antibiotic in which the valine at the end of the peptide chain is imine-dehydrated with a non-protein source amino acid epicapreomycidine.
3. A process for the preparation of the nucleoside antibiotic of claim 1, comprising the steps of:
(1) Fermenting, namely taking Streptomyces sp.NRRL 30475 strain, culturing with a BPM23A culture medium to obtain a seed culture solution, and inoculating the seed culture solution into the BPM23A culture medium to culture to obtain a fermentation broth;
(2) Extracting, namely centrifuging the fermentation liquor obtained in the step (1) to obtain mycelia and supernatant, ultrasonically extracting the mycelia by using methanol, concentrating to obtain an extract A, adding nonionic macroporous resin into the supernatant, stirring, filtering, discarding the filtrate, eluting the macroporous resin by using methanol until the macroporous resin is colorless, and recovering the methanol to obtain an extract B;
(3) Separating and purifying the extracts A and B by reverse MCI column chromatography, sephadex LH-20 column chromatography and liquid phase preparation method to obtain nucleoside antibiotic with anti-tubercle bacillus activity.
4. The preparation method of the Streptomyces sp.NRRL 30475 strain purification M2 plate, wherein the preparation method is characterized in that the step (1) is characterized in that a Streptomyces sp.NRRL 30475 strain purification M2 plate is adopted, a BPM23A culture medium is used for culturing for 3-5 days at 25-30 ℃, and the obtained seed culture solution is inoculated into 10-15L of the BPM23A culture medium and is cultured for 7-10 days at 25-30 ℃ to obtain a fermentation solution.
5. The preparation method of the composite material of the porous membrane of the invention according to claim 3, wherein in the step (2), the mycelium is extracted by methanol ultrasonic for 3-5 times, and the supernatant is added with 1% -4% of nonionic macroporous resin, stirred for 6-8 hours and filtered.
6. The method according to claim 3, wherein the step (3) comprises separating the extract by MCI column chromatography, eluting with 20%, 40%, 60%, 80% and 100% methanol sequentially, mixing to obtain 19 fractions Fr.1-1 to Fr.1-19, separating Fr.1-7 by gel column chromatography to obtain 5 fractions Fr.1-7-1 to Fr.1-7-5, and eluting Fr.1-7-2 by preparative liquid phase MeOH to obtain the nucleoside antibiotic with anti-tubercle bacillus activity.
7. A pharmaceutical composition, characterized in that, the pharmaceutical composition comprises the nucleoside antibiotic with anti-tubercle bacillus activity of claim 1, and a pharmaceutically acceptable carrier.
8. Use of a nucleoside antibiotic having anti-tubercle bacillus activity according to claim 1 for the preparation of an antibacterial agent.
9. The use according to claim 8, wherein the antibacterial agent is an anti-tubercle bacillus agent.
10. The use according to claim 8, wherein the medicament is in the form of a tablet, capsule, injection, powder for injection, granule, fat emulsion, microcapsule, drop pill, ointment or transdermal controlled release patch.
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