CN109762046A - Cyclic peptide antibiotic and preparation method thereof and the application in preparation Killing Mycobacterium Tuberculosis drug - Google Patents
Cyclic peptide antibiotic and preparation method thereof and the application in preparation Killing Mycobacterium Tuberculosis drug Download PDFInfo
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Abstract
The invention discloses a kind of cyclic peptide compound atratumycin (1) and preparation method thereof and the application in preparation Killing Mycobacterium Tuberculosis drug.The cyclic peptide compound atratumycin (1), structural formula is shown in formula I.The present invention isolated cyclic peptide compound atratumycin (1) from marine actinomycete mutant strain Streptomyces atratus SCSIO ZH16NS fermentation culture medium, cyclic peptide compound atratumycin (1) has significant inhibiting effect to mycobacterium tuberculosis, it can be used for preparing antituberculotic, for treatment lungy, therefore the present invention provides compound candidate to develop new antituberculotic, has great importance to exploitation Chinese Sea drug resource.
Description
Technical field
The invention belongs to natural products technical fields, and in particular to a kind of cyclic peptide compound and preparation method thereof and make
Application in standby Killing Mycobacterium Tuberculosis drug.
Background technique
Microbial natural products are the important sources of drug, wherein non-ribosomal peptides compound (nonribosomal
Peptides, NRPs) because it is with multifarious structure and extensive bioactivity, there is important ground in drug development
Position.So far, the drug in more than 40 cyclic peptide compound sources has been had more than in clinical use, as anti-infectives are mould up to holding in the palm
Element, anti-tumor drug bleomycin, the bacitracin of anti-skin infection, immunosuppressor cyclosporin etc. belong to non-ribosomal peptides
Class compound (Curr.Opin.Struct.Biol.2010,20,234-240；Curr.Opin.Chem.Biol.2017,38,
24-29).The structure of peptides complexity and numerous chiral centres bring huge challenge, bioengineering skill to medicament research and development
The progress of art and biosynthesis technology is synthesis and the structure of modification of complicated non-ribosomal peptides compound, provides
New approaches and methods.
In numerous non-ribosomal peptides, have a kind of multiple containing adjacent benzene alkyl substitution cinnamic acid structural unit, structure novel
It is miscellaneous, the cyclic peptide compound of activity multiplicity.It is different according to the structure of substituent group, this kind of compound can be divided into three classes.First
A skyllamycin analog derivative RP-1776 is isolated from bacterial strain Streptomyces sp.KY11784, activity survey
Test result show its to platelet derived growth factor (PDGF) be combined with inhibiting effect (J.Antibiot.2001,54,
405–414).The compound renames as skyllamycin A, and the like after skyllamycin B again from bacterial strain
Isolated (Chemistry.2014,20,4948-4955 in Streptomyces sp.Acta 2897；
J.antibiot.1992,45,1055–1063).WS9326 series derivates, WS9326A and WS9326C from
It is isolated in Streptomyces sp.9078, active testing as the result is shown its with significant Antiparasitic Activity
(Org.Lett.2012,14,4946–4949).WS9326H is isolated from bacterial strain Streptomyces sp.SNM55
Compound has significant inhibiting effect (Org.Lett.2018,20,1999-2002) to the generation of blood tubule.
Summary of the invention
The first purpose of the invention is to provide one kind to have the active cyclic peptide compound of Killing Mycobacterium Tuberculosis
atratumycin(1)。
Cyclic peptide compound atratumycin (1) of the invention or its pharmaceutical salts, shown in structural formula such as formula (I):
It is described a second object of the present invention is to provide a kind of preparation method of cyclic peptide compound atratumycin (1)
Cyclic peptide compound atratumycin (1) be from marine actinomycete mutant strain Streptomyces atratus SCSIO
Separation is prepared in the fermentation culture medium of ZH16NS.
It is preferred that, the specific steps are as follows:
(a) fermentation culture medium of marine actinomycete mutant strain Streptomyces atratus SCSIO ZH16NS is prepared,
The supernatant of fermentation culture medium is separated with mycelium and macroreticular resin；Mycelium and macroreticular resin mixture use acetone soak
Extraction, obtains acetone leaching liquor, obtains medicinal extract after acetone leaching liquor is concentrated；
(b) medicinal extract for obtaining step (a) crosses silica gel column chromatography, using chloroform-methanol as eluant, eluent, by chloroform: methanol
Volume ratio 100:0,95:5,90:10,85:15,80:20,70:30,60:40,50:50,0:100 successively carry out gradient elution, receive
Integrate chloroform: the fraction Fr.A6 that methanol volume ratio elutes as 70:30, it is purified to obtain cyclic peptide compound atratumycin (1).
The hair of the atratus SCSIO of marine actinomycete mutant strain Streptomyces described in step (a) ZH16NS
Ferment culture is to be prepared by the following method: by marine actinomycete mutant strain Streptomyces atratus SCSIO
ZH16NS is accessed in seed culture medium, and ferment to obtain seed culture fluid, seed culture fluid is linked into fermentation medium, fermentation obtains
Fermentation culture medium；The seed culture medium are as follows: every liter of glycerol containing 20g, 10g fish meal, 5g yeast extract powder, 5g CaCO3, remaining
Amount is water, adjusts pH value to 7.4；The fermentation medium are as follows: every liter of glycerol containing 20g, 10g fish meal, 5g yeast extract powder, 5g
CaCO3, 20g XAD-16 macroreticular resin, surplus is water, adjusts pH value to 7.4.
Third object of the present invention is to provide the cyclic peptide compound atratumycin (1) or its pharmaceutical salts to exist
Prepare the application in anti-mycobacteria drug.It is preferred that the anti-mycobacteria drug is Killing Mycobacterium Tuberculosis drug.
Fourth object of the present invention is to provide a kind of anti-mycobacteria drug, and the anti-mycobacteria drug, which contains, to be had
The cyclic peptide compound atratumycin (1) of effect amount or its pharmaceutical salts are as active constituent.It is preferred that the anti-mycobacteria
Drug also includes that pharmaceutically acceptable carrier, the anti-mycobacteria drug are Killing Mycobacterium Tuberculosis drug.
Fifth object of the present invention is to provide marine actinomycete mutant strain Streptomyces atratus SCSIO
Application of the ZH16NS in preparation cyclic peptide compound atratumycin (1).
Fermentation culture medium of the present invention from marine actinomycete mutant strain Streptomyces atratus SCSIO ZH16NS
In it is isolated have the active cyclic peptide compound atratumycin (1) of Killing Mycobacterium Tuberculosis, tests prove that, the ring
Peptides atratumycin (1) is to mycobacteria M.tuberculosis H37Ra and M.tuberculosis H37RV
The MIC value of inhibition is respectively 3.8 μM and 14.6 μM, has preferably anti-mycobacteria activity, shows that it is controlled in antituberculosis
Treating has important value in drug development.
For marine streptomyces Streptomyces atratus SCSIO ZH16 of the invention in number of patent application
It is 201610806737.1, denomination of invention are as follows: a kind of marine streptomyces and its cyclic peptide compounds are in preparation Killing Mycobacterium Tuberculosis
It is disclosed in the Chinese patent of application in drug.
Marine actinomycete mutant strain Streptomyces atratus SCSIO ZH16NS of the invention has been disclosed in Li,
Y.；Zhang,C.；Liu,C.；Ju,J.；*Ma,J.*Genome sequencing of Streptomyces atratus
SCSIO ZH16and activation production of nocardamine via metabolic
engineering.Front Microbiol.,2018,9:1269,doi:10.3389/fmicb.2018.01269..The bacterial strain
The applicant also holds, and guarantees to provide in 20 years to the public from the applying date.
Detailed description of the invention
Fig. 1 is the high resolution mass spectrum figure of compound a tratumycin (1)；
Fig. 2 is the second order ms structure of compound a tratumycin (1)；
Fig. 3 is the second order ms debris analysis of compound a tratumycin (1)；
Fig. 4 is the single crystal diffraction structure of compound a tratumycin (1).
Specific embodiment
The following examples are further illustrations of the invention, rather than limiting the invention.
The Screening of Media of 1 marine streptomyces mutant strain Streptomyces atratus SCSIO ZH16NS of embodiment
Marine streptomyces Streptomyces atratus SCSIO ZH16 of the present invention is from China's South China Sea
Sediment sample in it is isolated.With frame knock out building Streptomyces atratus SCSIO ZH16NS bacterial strain (Li,
Y.；Zhang,C.；Liu,C.；Ju,J.；*Ma,J.*Genome sequencing of Streptomyces atratus
SCSIO ZH16and activation production of nocardamine via metabolic
engineering.Front Microbiol.,2018,9:1269,doi:10.3389/fmicb.2018.01269).It will growth
Streptomyces atratus SCSIO ZH16NS bacterial strain on ISP2 culture medium is seeded to respectively to be trained containing 50mL difference
In the 250mL triangular flask for supporting base, the fermented and cultured seven days under the conditions of 28 DEG C, 200rpm.Culture medium butanone after fermentation is extracted
It takes and is analyzed with HPLC, as a result, it has been found that fermentation is able to produce compound a tratumycin (1) in FYG culture medium.
Wherein, ISP2 culture medium group becomes as follows: 4.0g/L glucose, 4.0g/L yeast extract powder, and 10g/L malt extracts
Powder, 30g/L sea salt, 20g/L agar powder, solvent are water, adjust pH value to 7.4；FYG culture medium group becomes as follows: 20g/L is sweet
Oil, 10g/L fish meal, 5g/L yeast extract powder, 5g/LCaCO3, solvent is water, adjusts pH value to 7.4.
The separation of 2 compound a tratumycin (1) of embodiment and Structural Identification
1, the fermentation culture medium of marine streptomyces mutant strain Streptomyces atratus SCSIO ZH16NS is prepared
(1) preparation of seed culture medium and fermentation medium:
A) preparation of seed culture medium: in every liter of seed culture medium containing 20g glycerol, 10g fish meal, 5g yeast extract powder,
5g CaCO3, surplus is water, adjusts pH value to 7.4.0.75L seed culture medium is prepared, then average mark is loaded on 15 250mL cones
In shape bottle, every bottle of 50mL, 121 DEG C of sterilizing 30min are spare.
B) preparation of fermentation medium: in every liter of fermentation medium containing 20g glycerol, 10g fish meal, 5g yeast extract powder,
5g CaCO3, 20g XAD-16 macroreticular resin, surplus is water, adjusts pH value to 7.4.10L fermentation medium is prepared, it is then average
It is sub-packed in 50 1L conical flasks, each 200mL, 121 DEG C of sterilizing 30min are spare.
(2) culture of seed:
The marine streptomyces mutant strain Streptomyces atratus SCSIO ZH16NS of activation is linked into and is equipped with
In the 250mL conical flask of 50mL seed culture medium, is cultivated for 24 hours on 28 DEG C, the shaking table of 200rpm, obtain seed culture fluid.
(3) scale fermentation culture:
50mL seed culture fluid in above-mentioned conical flask is transferred in the 1L conical flask equipped with 200mL fermentation medium,
It is cultivated 7 days on 28 DEG C, the shaking table of 200r/min, obtains marine streptomyces mutant strain Streptomyces atratus SCSIO
The fermentation culture medium of ZH16NS.
2, compound in marine streptomyces mutant strain Streptomyces atratus SCSIO ZH16NS fermentation culture medium
The separation of atratumycin (1)
(1) extraction of fermentation culture medium
The fermentation culture medium of marine streptomyces mutant strain Streptomyces atratus SCSIO ZH16NS was carried out
Filter, separates supernatant with mycelium and macroreticular resin；Mycelium and macroreticular resin mixture are extracted using acetone soak, ultrasound
Processing obtains acetone leaching liquor, and acetone leaching liquor obtains medicinal extract after revolving condensation concentration.
(2) separation of compound a tratumycin (1)
The medicinal extract that step (1) is obtained uses chloroform-methanol as mobile phase through normal-phase silica gel column chromatography, with chloroform: methanol
Different volumes ratio (100:0,95:5,90:10,85:15,80:20,70:30,60:40,50:50,0:100) successively carries out gradient
Elution, chloroform: methanol volume ratio is that the fraction that 100:0 volume ratio elutes is denoted as Fr.A1, and chloroform: methanol volume ratio is 95:
The fraction eluted under 5 gradients is denoted as Fr.A2, chloroform: methanol volume ratio is that the fraction eluted under 90:10 gradient is denoted as
Fr.A3, chloroform: methanol volume ratio is that the fraction eluted under 85:15 gradient is denoted as Fr.A4, chloroform: methanol volume ratio is
The fraction eluted under 80:20 gradient is denoted as Fr.A5, chloroform: methanol volume ratio is the fraction eluted under 70:30 gradient
Be denoted as Fr.A6, chloroform: methanol volume ratio is that the fraction eluted under 60:40 gradient is denoted as Fr.A7, chloroform: methanol volume ratio
Fraction to elute under 50:50 gradient is denoted as Fr.A8, chloroform: methanol volume ratio evaporates for what is eluted under 0:100 gradient
Minute mark is Fr.A9.High-efficient liquid phase analysis is carried out to above-mentioned fraction Fr.A1-A9, finds to contain compound in Fr.A6 fraction
atratumycin(1)；The inverted medium pressure liguid chromatograph of Fr.A6 fraction (RP-18 (40-63 μm, Merck), CH3CN/H2O30
~100%v/v linear gradient elution 120min, flow velocity 10mL/min), obtain Fr.B1~B5；By Fr.B4 (CH3CN/H2O60%
V/v elution obtains) high-efficient liquid phase color is partly prepared by reverse phase ODS (YMC-Pack ODS-A column, 250 × 20mm, 5 μm)
Spectrum isolates and purifies (mobile phase CH3CN/H2O 50%v/v elution, flow velocity 3.0mL/min), obtain compound a tratumycin (1)
(retention time 17.1min).
By structural analysis, to of the invention from marine streptomyces mutant strain Streptomyces atratus SCSIO
Compound a tratumycin (1) qualification result prepared in the fermentation culture medium of ZH16NS is as follows:
Compound a tratumycin (1) is clear crystal, molecular formula C68H84N12O16, HR-ESI-MS m/z
1325.6201([M+H]+)；[α]25 D+60(c 0.05,MeOH)；UV(MeOH)λmax(logε)204(4.99),220
(4.86),283(4.46)nm；IR(film):vmax:3289,2955,1755,1693,1628,1516,1443,1277,
1242,1223,1066cm-1.According to the molecular ion peak m/z 1325.6193 ([M+H] in high resolution mass spectrum (Fig. 1)+,calcd
1325.6201), and binding compounds13C-NMR data information can determine the molecular formula of (1) compound atratumycin
C68H84N12O16, show that the degree of unsaturation of compound a tratumycin (1) is 33.The analysis of detailed 1D and 2D-NMR data can be with
Determine threonine (Thr) in compound atratumycin (1), serine (Ser), tryptophan (Trp), asparagine (Asn),
Phenserine (β-OH-Phe), proline (Pro), valine (Val), glycine (Gly), leucine (Leu), tyrosine
(Tyr) presence.Remaining 1013C-NMR signal is 3- (2-methyl in structure according to HMBC and COSY associated home
Phenyl) -2 (E)-propenoic acid group.In HMBC, H-2 and C-1, H-3 and C-2, C-4, C- can be obviously observed
5, H-10 is long-range related to C-4, C-8, C-9's.In COSY spectrum, it can be observed that H-2/H-3, H-5/H-6/H-7/H-8
Coupling.Coupling constant (the J that 2E configuration in structure passes through H-32,3=15.7Hz) it determines.
The order of connection of amino acid is analyzed by MS and is determined.Compound a tratumycin (1) molecule is from m/z 1325.6
([M+H]+) second order ms in, the fragment ion peak at m/z 1098.5 (y9), 1011.5 (y8), 825.4 (y7) is successively
It is by losing -2 (E)-propenoic acid- threonine group of 3- in structure (2-methyl phenyl), serine and color ammonia
What acid groups generated.Fragment ion peak 825.4 (y7) further continuously lose asparagine, Phenserine (β-OH-Phe),
Proline (Pro) obtains fragment ion peak m/z 711.4 (y6), 548.3 (y5) and 451.3 (y4) fragment ion peak y3 (m/
Z 352.2), y2 (m/z 295.2), y1 (m/z 332.2) they are that valine (Val), glycine (Gly) and bright are successively lost by y4
What propylhomoserin generated.The fragment ion peak b1-b9 of compound a tratumycin (1) can also pass through amino acid amide key in structure
Fault interpretation.Therefore, in summary fragment ion peak information can be inferred that in compound a tratumycin (1) structure
The amino acid order of connection (Fig. 2, Fig. 3).A degree of unsaturation having more in compound a tratumycin (1) can pass through cyclic peptide
The presence of structure is explained.The link position of cyclic peptide is explained by the chemical shift variation of H-13 in threonine and C-13.Cause
This, is with the excessively above analysis we conclude that the planar structure of compound a tratumycin (1), this and the X that we obtain below
Optically diffractive structure is consistent (Fig. 4).
The absolute configuration of compound a tratumycin (1) is determined by the analysis of single crystal diffraction data.Single crystal diffraction
Flack (X) constant 0.04 (11) can determine the L-Thr that is configured as, L-Ser, L-Trp, L-Pro, D-Asn, D- of amino acid
Val, D-Leu, D-Tyr and (2S, 3S) -3-OH-Phe, this stereochemical structure determining with Marfey ' s reaction is passed through are consistent.
1 compound a tratumycin's (1) of table1H and13C-NMR data (DMSO-d6)
By the target compound atratumycin (1) that the above method separates, shown in structural formula such as formula (I):
Antibacterial activity test analysis of the 3 compound a tratumycin (1) of embodiment to mycobacteria
Compound a tratumycin (1) is tested to mycobacteria M.tuberculosis using meat soup doubling dilution
H37Ra and M.tuberculosis H37RVInhibitory activity.Compound a tratumycin (1) is measured using doubling dilution
To M.tuberculosis H37Ra and M.tuberculosis H37RVAntibacterial activity test operating procedure briefly describe
It is as follows: 1) by -80 DEG C freeze from main light emission M.tuberculosis H37Ra and M.tuberculosis H37Rv (UAlRa)
Each 2mL is seeded to respectively in the conical flask containing 50mL 7H9 culture medium (containing 0.1%twin80), and culture to OD value reaches
Between 0.3~1.0；2) compound a tratumycin (1) is configured to DMSO the mother liquor of 10mg/mL, according still further to certain proportion
To each diluted chemical compound to 5120-2.5 μ g/mL, with rifampin (RIF, 10ug/mL, 1ug/mL) for positive control, DMSO is yin
Property control, respective compound is added in 96 hole elisa Plates with every 5 μ L of hole, each compound sets three repetitions；3) by bacterium solution
Stoste dilution, taking luminous value to reach the dilution bacterium solution of 3000~5000/200 μ L is detection bacterium solution；4) in 96 hole elisa Plates
The bacterium solution that 195 μ L have diluted is added with the every hole of the volley of rifle fire, so that the final concentration of each compound is followed successively by 128-0.0625 μ g/mL, in 37
Culture in DEG C incubator, and luminous value is detected in 0-7d.Active testing is the results show that compound a tratumycin (1) is right
M.tuberculosis H37Ra and M.tuberculosis H37RVThe MIC value of inhibition is respectively 3.8 μM and 14.6 μM, Li Fu
It puts down to M.tuberculosis H37Ra and M.tuberculosis H37RVThe MIC value of inhibition is 1.0ug/mL, is shown
It has important value in antituberculosis therapy drug development.
The above is only the preferred embodiment of the present invention, it is noted that above-mentioned preferred embodiment is not construed as pair
Limitation of the invention, protection scope of the present invention should be defined by the scope defined by the claims..For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, several improvements and modifications can also be made, these change
It also should be regarded as protection scope of the present invention into retouching.
Claims (10)
1. cyclic peptide compound atratumycin (1) or its pharmaceutical salts, shown in structural formula such as formula (I):
2. a kind of preparation method of cyclic peptide compound atratumycin (1) described in claim 1, which is characterized in that described
Cyclic peptide compound atratumycin (1) be from marine actinomycete mutant strain Streptomyces atratus SCSIO
Separation is prepared in the fermentation culture medium of ZH16NS.
3. preparation method according to claim 2, which comprises the following steps:
(a) fermentation culture medium for preparing marine actinomycete mutant strain Streptomyces atratus SCSIO ZH16NS, will send out
The supernatant of ferment culture is separated with mycelium and macroreticular resin；Mycelium and macroreticular resin mixture are extracted using acetone soak
It takes, obtains acetone leaching liquor, obtain medicinal extract after acetone leaching liquor is concentrated；
(b) medicinal extract for obtaining step (a) crosses silica gel column chromatography, using chloroform-methanol as eluant, eluent, by chloroform: methanol volume
Than 100:0,95:5,90:10,85:15,80:20,70:30,60:40,50:50,0:100 successively carry out gradient elution, collect chlorine
Imitative: methanol volume ratio is the fraction Fr.A6 of 70:30 elution, purified to obtain cyclic peptide compound atratumycin (1).
4. preparation method according to claim 3, which is characterized in that fermentation culture medium described in step (a) is to pass through
Following methods preparation: marine actinomycete mutant strain Streptomyces atratus SCSIO ZH16NS is accessed into seed culture
In base, ferment to obtain seed culture fluid, seed culture fluid is linked into fermentation medium, fermentation obtains fermentation culture medium；Described
Seed culture medium are as follows: every liter of glycerol containing 20g, 10g fish meal, 5g yeast extract powder, 5g CaCO3, surplus is water, adjust pH value to
7.4；The fermentation medium are as follows: every liter of glycerol containing 20g, 10g fish meal, 5g yeast extract powder, 5g CaCO3、20g XAD-16
Macroreticular resin, surplus are water, adjust pH value to 7.4.
5. cyclic peptide compound atratumycin (1) described in claim 1 or its pharmaceutical salts are preparing anti-mycobacteria medicine
Application in object.
6. application according to claim 5, which is characterized in that the anti-mycobacteria drug is Killing Mycobacterium Tuberculosis
Drug.
7. a kind of anti-mycobacteria drug, which is characterized in that contain a effective amount of cyclic peptide compound as shown in formula (I)
Atratumycin (1) or its pharmaceutical salts are as active constituent.
8. anti-mycobacteria drug according to claim 7, which is characterized in that also carried comprising pharmaceutically acceptable
Body.
9. anti-mycobacteria drug according to claim 7 or 8, which is characterized in that the anti-mycobacteria drug is
Killing Mycobacterium Tuberculosis drug.
10. marine actinomycete mutant strain Streptomyces atratus SCSIO ZH16NS is in preparation claim 1 formula (I)
Shown in application in cyclic peptide compound atratumycin (1).
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