CN101153052B - Uridine peptide antibiotic, pharmaceutically acceptable salt, producing method and uses thereof - Google Patents
Uridine peptide antibiotic, pharmaceutically acceptable salt, producing method and uses thereof Download PDFInfo
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Abstract
The present invention provides antibiotics of urinate glucoside peptide category with a structural formula (I) and the acceptable salt in pharmaceutics. The antibiotics can be prepared through fermentation and cultivation of produced fungus. The compound of the present invention is a group of cell-wall peptidoglycan synthesized inhibitor, has anti-tuberculosis activity and pyocyanic fungus, and can be used for preparing anti-infective drugs.
Description
Technical field
The present invention relates to one group of uridine peptide antibiotics and its pharmacy acceptable salt, and its production and use, the microbial fermentation field belonged to.
Background technology
The uridine peptide antibiotics is existing at present reports, as Mureidomycins (U.S. Patent No. 5039663) and pacidamycins (U.S. Patent No. 6228842B), this compounds mainly acts on cell walls, suppress the synthetic of whole cell peptidoglycan, toxicity is very little, and the present medicine that does not act on this target spot clinically, so the research of this compounds is to finding that drug-resistance bacteria medicine has great importance.
Researchist of the present invention has found that in research process a strain can produce the bacterial strain of novel uridine peptide antibiotics SS-1, SS-2 and SS-3, the structure of this microbiotic SS-1, SS-2 and SS-3 is illustrated, different with the known kind of this compounds, and have the activity of anti-mycobacterium tuberculosis and anti Bacillus pyocyaneu Flugge.
Summary of the invention
The purpose of this invention is to provide one group of novel uridine peptide antibiotics, have the active function of anti-mycobacterium tuberculosis and anti Bacillus pyocyaneu Flugge.
Another object of the present invention provides one group of uridine peptide antibiotics at pharmacy acceptable salt.
A further object of the present invention provides one group of uridine peptide antibiotics and at the microbial fermentation production method of pharmacy acceptable salt.
Another object of the present invention provides a kind of streptomyces bacterial strain that can produce novel uridine peptide antibiotics SS-1, SS-2 and SS-3.
Another object of the present invention provide one group of uridine peptide antibiotics and at pharmacy acceptable salt in the purposes of preparation on the anti-infectives.
The invention provides the uridine peptide antibiotics of (I) and formed that has structural formula at pharmacy acceptable salt:
R is in the structural formula (I)
(Met) compound is called for short SS-1, and R is
(Leu) compound is called for short SS-2, and R is
The compound of (Methione sulfoxide) is called for short SS-3.
Described pharmacy acceptable salt is ammonia salt, sodium salt, hydrochloride, vitriol, organic alkali salt or organic acid salt.
With The compounds of this invention has that the microbial product of similar structures reported Mureidomycins (United States Patent (USP) 5039663) and pacidamycins (United States Patent (USP) 6228842B) arranged, but compound of the present invention is different with them, and the C-terminal of Mureidomycins is a m-Tyrosine; And C-terminal of the present invention is a tryptophane, contains L-Ala among the pacidamycins, and contains methionine(Met) among the SS-1 of the present invention, contains leucine among the SS-2, contains first sulphur sulfoxide among the SS-3.
SS-1 of the present invention, SS-2 and SS-3 uridine peptides can adopt the suitable culture base to cultivate earlier and belong to the SS bacterial strain of streptomyces or its change strain; Separate from fermented liquid then and contain crude extract of the present invention, separation and purification goes out SS-1, SS-2 and SS-3 from crude extract again.
The preparation method of uridine peptide antibiotics compound of the present invention comprises fermentation culture, separation, extraction and refining, and the used bacterial strain of fermentation culture is a streptomycete.
Wherein said streptomycete is streptomycete (Sterptomyces sp.) SS CGMCC No.1764.
The present invention utilizes microorganism to obtain to have the material of more excellent pharmacologically active.The present invention isolates multiple microorganism from natural soil, and has carried out the screening of anti-microbial activity, found that streptomcycete strain (Streptomyces SP.) SS bacterial strain can produce and has excellent antibiotic active new compound SS-1, SS-2 and SS-3.
In fact, all can produce the microorganism of streptomyces of SS-1, SS-2 or SS-3 all at the present invention's row.Be used for the present invention preferably microorganism be streptomycete SS.
Described bacterial strain is streptomycete (Sterptomyces sp.) SS, is deposited in China Committee for Culture Collection of Microorganisms common micro-organisms center (CGMCC) on July 20th, 2006, and deposit number is CGMCC No.1764.
Be used for cultivating the substratum of described microorganism, employing can be carbon source, nitrogenous source, inorganic salt, organic salt and can be by the trace nutrition of its utilization by the nutrition source of its utilization, these compositions can add in the substratum in advance once, perhaps intermittently or add in the substratum continuously.
Concerning the used microorganism preferably of the present invention, can adopt following substratum (by weight): glucose 0.4-0.6%; Yeast extract paste 0.4-0.6%; Peptone 0.4-0.6%; Extractum carnis 0.4-0.6%; Corn steep liquor 0.3-0.5%; Soybean cake powder 0.5-1.5%; Starch 1-3%; CaCO
30.3-0.5%; CoCl
26H
2O 0.3-0.5 ‰, all the other are water; The accent pH value is 7.2.
Be preferably: glucose 0.5%; Yeast extract paste 0.5%; Peptone 0.5%; Extractum carnis 0.5%; Corn steep liquor 0.4%; Soybean cake powder 1%; Starch 2%; CaCO
30.4%; CoCl
26H
2O 0.4 ‰, and all the other are water; Transferring pH value is 7.2.
Best cultivation can adopt static cultivation, shaking table cultivation, stir culture, submerged culture or alternate manner, but concerning mass production, preferably submerged culture.
Culture condition (time, temperature, PH etc.) becomes with bacterial classification is different, and also different with the variation of medium component, those skilled in the art can select as the case may be according to the culture process of streptomycete.
Stop cultivating when reaching peak concentration when SS-1, SS-2 and SS-3 accumulate in substratum, from fermented liquid, separate the crude product that contains compound, can adopt the general extraction and separation method of tunning to carry out.For example: can use means such as adsorption chromatography, ion-exchange, molecular sieve individually, also the arbitrary combination more than two kinds can be used.In more detail, according to ordinary method, at first filter or centrifugal, isolate the mycelia and the culturing filtrate of solid shape, compound of the present invention mainly is present in the culturing filtrate, and culturing filtrate is carried out chromatography, concentrates with macroporous resin, collect activeconstituents, organic solvent is removed in underpressure distillation, and the decompression lyophilize promptly obtains the crude product of SS-1, SS-2 and SS-3 material.
For further refining from crude product, can adopt separation, the process for purification of general amphoteric water-soluble material, for example, can use absorption with macroporous adsorbent resin chromatography, ion-exchange, reversed phase chromatography etc.When further refining if necessary, but repeated using aforesaid method or carry out methods such as reversed phase chromatography with the elute soln that contains buffering salt can make highly purified SS-1, SS-2 and SS-3.
Affirmation to SS-1, SS-2 in separation, extraction and the treating process and SS-3 material, can use this material that it is had inhibiting microorganism, as bioassay method or the high-efficient liquid phase technique of Pseudomonas aeruginosa (Pseudomonas aeruginosa), the two also uses better.
Therefore compound of the present invention is an amphoteric substance, and the method for available this area routine converts it into its pharmacy acceptable salt, a kind of as in ammonia salt, sodium salt, hydrochloride, vitriol, organic alkali salt or the organic acid salt.
Uridine peptide antibiotics of the present invention and be the whole cell peptidoglycan synthetic inhibitor at pharmacy acceptable salt has the activity of anti-mycobacterium tuberculosis and Pseudomonas aeruginosa, can be used for preparing anti-infectives, as anti-mycobacterium tuberculosis and charrin's disease medicine.
The present invention can mix SS-1, SS-2 and the SS-3 material that contains effective dose respectively with the carrier that pharmaceutically allows, make medicament.Also can mix with the carrier that pharmaceutically allows, make medicament containing the material of effective doses any two or more among SS-1, SS-2 or the SS-3.
Adopt microbial fermentation processes of the present invention and refining SS-1, SS-2 and the SS-3 material that obtains, administration form during as medical component, can be oral preparations such as tablet, capsule, soft capsule, powder, granule, granula subtilis, liquor, pill, emulsion or clouding agent, also can be non-oral formulations such as lyophilized powder, suppository, ointment, plaster, patch, sprays or eye drops.These preparations all can adopt those skilled in the art to know preparation method commonly used and obtain.
The used microbial fermentation processes of the present invention has selected to produce streptomcycete strain (Streptomyces SP.) SS with excellent antibiotic active compound S S-1, SS-2 and SS-3, adopts streptomycete fermentation condition well known in the art to get final product, and technology is simple.
Bacterial strain of the present invention is streptomycete (Sterptomyces sp.) SS, is deposited in China Committee for Culture Collection of Microorganisms common micro-organisms center (CGMCC) on July 20th, 2006, and deposit number is CGMCC No.1764.
Description of drawings
Fig. 1 is the ESI mass spectrum of compound S S-1 of the present invention;
Fig. 2 is dissolved among the d6-DMSO for compound S S-1 of the present invention
1The H-NMR spectrogram;
Fig. 3 is dissolved among the d6-DMSO for compound S S-1 of the present invention
13The C-NMR spectrogram;
Fig. 4 is dissolved in D for compound S S-1 of the present invention
2Among the O (PD=8.0)
1The H-NMR spectrogram;
Fig. 5 is dissolved in D for compound S S-1 of the present invention
2Among the O (PD=8.0)
13The C-NMR spectrogram;
Fig. 6 is that compound S S-1 of the present invention is dissolved in the hsqc spectrum figure among the d6-DMSO;
Fig. 7 is that compound S S-1 of the present invention is dissolved in the HMBC spectrogram among the d6-DMSO;
Fig. 8 is that compound S S-1 of the present invention is dissolved in the DEPT spectrogram among the d6-DMSO;
Fig. 9 is dissolved in D for compound S S-1 of the present invention
2The DEPT spectrogram of (PD=8.0) among the O;
Figure 10 is dissolved in D for compound S S-1 of the present invention
2The GCHSQC spectrogram of (PD=8.0) among the O;
Figure 11 is dissolved in D for compound S S-1 of the present invention
2The GHMBC spectrogram of (PD=8.0) among the O;
Figure 12 is dissolved in D for compound S S-1 of the present invention
2The GCOSY spectrogram of (PD=8.0) among the O;
Figure 13 is the FAB mass spectrum of compound S S-2 of the present invention;
Figure 14 is dissolved in D for compound S S-2 of the present invention
2Among the O
13The C-NMR spectrogram;
Figure 15 is dissolved in D for compound S S-2 of the present invention
2Among the O (PD=8.8)
1The H-NMR spectrogram;
Figure 16 is dissolved in D for compound S S-2 of the present invention
2The DEPT spectrogram of (PD=8.8) among the O;
Figure 17 is dissolved in D for compound S S-2 of the present invention
2The GHMBC spectrogram of (PD=8.8) among the O;
Figure 18 is dissolved in D for compound S S-2 of the present invention
2The GHSQC spectrogram of (PD=8.8) among the O;
Figure 19 is dissolved in D for compound S S-2 of the present invention
2The GCOSY spectrogram of (PD=8.8) among the O;
Figure 20 is the ESI spectrogram of compound S S-3 of the present invention;
Figure 21 is dissolved in D for compound S S-3 of the present invention
2Among the O (PD=800)
1The spectrogram of H NMR;
Figure 22 is dissolved in D for compound S S-3 of the present invention
2Among the O (PD=8.0)
13C NMR spectrogram;
Figure 23 is dissolved in the DEPT spectrogram of (PD=8.0) among the D2O for compound S S-3 of the present invention;
Figure 24 is dissolved in the COSY spectrogram of (PD=8.0) among the D2O for compound S S-3 of the present invention
Figure 25 is dissolved in the hsqc spectrum figure of (PD=8.0) among the D2O for compound S S-3 of the present invention;
Figure 26 is dissolved in the HMBC spectrogram of (PD=8.0) among the D2O for compound S S-3 of the present invention.
Embodiment
Following examples are used to illustrate the present invention, but are not used for limiting the scope of the invention.
By glucose 0.5%; Zulkovsky starch 2.4%; Extractum carnis 0.3%; Yeast extract paste 0.5%; Peptone 0.5%; Corn steep liquor 0.4%; CoCl
20.002%; CaCO
30.4%, all the other are water, and 100 milliliters of substratum of composition (pH value is 7.2) install in 500 milliliters the triangular flask, after the sterilization, inoculation streptomycete SS (Streptomyces SP.) CGMCC No.1764 is 27 ℃ of following rotational oscillations (220 times/minute, amplitude 7cm) cultivated 2 days, as seed.
Then with glucose 0.5%; Yeast extract paste 0.5%; Peptone 0.5%; Extractum carnis 0.5%; Corn steep liquor 0.4%; Soybean cake powder 1%; Starch 2%; CaCO
30.4%; CoCl
26H
2O 0.4 ‰, and all the other are water, composition fermention medium (pH value is 7.2), and packing is 100 milliliters in 500 milliliters the triangular flask, and the seed of the above-mentioned cultivation of sterilization back adding 2% got fermented liquid in 4 days in 27 ℃ of following rotational oscillations (220 times/minute, amplitude 7cm) cultivation.
Get the fermented liquid (20 liters) that above-mentioned cultivation obtains, filtering separation, filtrate is crossed 1 liter macroporous adsorbent resin (Amberlite X AD-4), respectively water (5L), water: acetone (2:1; 5L) and water: acetone (1:1,5L) wash-out are collected active part, concentrating under reduced pressure, and lyophilize obtains crude product 12g.
The 12g crude product is dissolved in 100 ml waters, transferring PH with NaOH is 10.5, cross X-5 post (2L), use earlier the 14L water elution, there is not activity, again water: acetone (4:1,40L) wash-out, be in charge of collection (70/ pipe/13 minutes), contained the crude product of SS-1 (660 milligrams), SS-2 (120 milligrams) and SS-3 (150 milligrams) respectively.
With SS-1, the SS-2 crude product is dissolved in respectively and contains 1% (NH
4)
2 CO
345% and 40% methanol in water in, be prepared with HPLC respectively that (condition of SS-1 is: moving phase is 45% methanol aqueous solution, and flow velocity is 5 ml/min; SS-2, the condition of SS-3 is: moving phase is 40% methanol aqueous solution, flow velocity is 5 ml/min).Obtain purity respectively greater than 95% white sample, SS-1 is 80 milligrams, and SS-2 is 20 milligrams, and SS-3 is 40 milligrams.
Through check analysis, SS-1 has following physico-chemical property and biological property:
1. molecular weight is 863, and molecular formula is C
40H
49N
9O
11S;
2. color state: white or off-white color pressed powder;
3. solvability: soluble in water, methyl alcohol is insoluble to chloroform, acetone;
4. UV spectrum: λ max is 259 (ε=4642) in the methyl alcohol, 221 (ε=9656), 204 (10571);
5. mass spectrum: its ESI mass spectrum as shown in Figure 1, its [M+H]
+The peak is 864, high resolution ESI mass spectroscopy [M+H]
+Be 864.33505, [M+H]
+Empirical formula be C
40H
50N
9O
11S.
6. nuclear magnetic resonance spectrum: Fig. 2,3 are respectively, it is dissolved among the d6-DMSO
1H-NMR and
13The C-NMR spectrogram, Fig. 4,5 is respectively that it is dissolved in D
2Among the O
1H-NMR and
13The C-NMR spectrogram because the rotation of peptide chain makes become in its nuclear magnetic resonance map comparatively complicated, occurs bimodally, is respectively two peaks of 0.672 and 1.039 as displacement among Fig. 2, and it is one-CH
3On three hydrogen, but be split into two peaks, according to Fig. 6,7 (for it is dissolved in HSQC and HMBC spectrogram among the d6-DMSO), its corresponding 14.067 and 14.721 two fignal centers as can be known, one-CH on the corresponding SS-1 of these two fignal centers
3Compare by the NMR with Pacidamycins, Mureidomycins, and analyze according to two-dimentional NMR, finally carbon signal and the hydrogen signal to SS-1 belongs to, and wherein the structure of methionine(Met) is determined by the NMR spectrogram that SS-1 is dissolved among the d6-DMSO.
Table 1 SS-1 is dissolved in D
2NMR data among the O
In conjunction with Fig. 1-12 and table 2, can determine that the structural formula of SS-1 is as follows:
Through check analysis, SS-2 has following physico-chemical property and biological property:
1. molecular weight is 845, and molecular formula is C
41H
51N
9O
11
2. color state: white or off-white color pressed powder;
3. solvability: soluble in water, methyl alcohol is insoluble to chloroform, acetone;
4. UV spectrum: λ max is 257 (ε=3667) in the methyl alcohol, 220 (ε=8010), 202 (9600);
5. mass spectrum: its FAB mass spectrum as shown in figure 13, its [M+H]+peak is 846;
6. nuclear magnetic resonance spectrum: its NMR such as Figure 14-19.Compare with the NMR collection of illustrative plates of SS-1, SS-2 lacked a 16.997ppm-CH
3A carbon signal and a 33.762ppm-CH
2Carbon signal, 23.786 and 24.809ppm many two-CH
3Carbon signal, 24.809ppm many carbon signal of one-CH, this shows in the SS-2 structure it is not to contain methionine(Met), but contains leucine.
Table 2 SS-2 is dissolved in D
2NMR data among the O
In conjunction with Figure 13-19 and table 2, can determine that the structural formula of SS-2 is as follows:
Through check analysis, SS-3 has following physico-chemical property and biological property:
1. molecular weight is 879, and molecular formula is C
40H
49N
9O
12S;
2. color state: white or off-white color pressed powder;
3. solvability: soluble in water, methyl alcohol is insoluble to chloroform, acetone;
4. UV spectrum: λ max is 258 (ε=4786) in the methyl alcohol, 221 (ε=9813), 204 (10388);
5. mass spectrum: its FAB mass spectrum as shown in figure 20, its [M+H]+peak is 880;
6. nuclear magnetic resonance spectrum: its NMR such as Figure 21-26.Compare with the NMR collection of illustrative plates of SS-1, originally the CH on the methionine(Met)
3Carbon signal has moved 22.5 ppm to low, and many 16 total mass numbers of the molecular weight ratio SS-1 of SS-3, so can tentatively judge and contain first sulphur sulfoxide (methioninesulfoxide) among the SS-3; Carefully check the 13C NMR of SS-3 and SS-1, find that its difference only is present in the 3rd of methionine(Met), 4, on 5 carbon atoms, the chemical shift of these three carbon atoms is respectively by original 33.8,32.1,17ppm becomes 27.5 (25.7), 51.7,39.5ppm, this has further determined to contain first sulphur sulfoxide in the structure of SS-3.
Table 3 SS-3 is dissolved in D
2NMR data among the O
In conjunction with Figure 20-26 and table 3, can determine that the structural formula of SS-3 is as follows:
Substantially the same manner as Example 1, different is that fermention medium is: glucose 0.4%; Yeast extract paste 0.4%; Peptone 0.6%; Extractum carnis 0.6%; Corn steep liquor 0.3%; Soybean cake powder 0.5%; Starch 3%; CaCO
30.5%; CoCl
26H
2O0.3 ‰, and all the other are water, and pH value is 7.2.
The crude product that contains SS-1, SS-2 and SS-3 that fermentation is obtained separates, extracts, makes with extra care, and must contain the microbiotic of SS-1, SS-2 and SS-3.Adopt neutralization reaction to make ammonia salt then.With its ammonia salt 50 grams, with semi-synthetic glyceryl ester 100 grams of matrix, the heating mixing places mould, makes suppository after the cooling again.
Substantially the same manner as Example 1, different is that fermention medium is: glucose 0.6%; Yeast extract paste 0.6%; Peptone 0.4%; Extractum carnis 0.4%; Corn steep liquor 0.5%; Soybean cake powder 1.5%; Starch 1%; CaCO
30.3%; CoCl
26H
2O0.5 ‰, and all the other are water, and pH value is 7.2.
With the SS-210 gram that embodiment 1 obtains, make 1 liter the aqueous solution, can is in ampoule, and is freezing, and drying is sealed, and promptly gets to inject dry powder.
30 of embodiment 1 acquisition is restrained the microbiotic that contains SS-1 and SS-2, and with lactose 100 grams, starch 20 grams, water mixes, and granulates, and drying adds 0.1 again and restrains Magnesium Stearate, and compressing tablet promptly gets tablet.
SS-210 gram with embodiment 1 obtains with sucrose 150 grams, mixes, and granulates, and incapsulates, and promptly gets capsule.
The microbiotic that 10 grams of embodiment 1 acquisition is contained SS-2, SS-1 and SS-3, with go into vegetables oil 300 gram, beeswax 20 grams, mixed 30 minutes with colloidal mill, mixture is granulated with automatic rotation rolling capsule machine, and drying is 24 hours under the condition of 20 ℃ of temperature, relative humidity 52%, take out, use washing with alcohol, dry 48 hours under these conditions, promptly get soft capsule.
Experimental example 1
This experimental example is to study the mycology property of described streptomycete (Sterptomyces sp.) SS CGMCC No.1764.
1. form
The branching of sporulation mycelia: single branch; The form of sporulation: straight shape or gentle curved, be and just revolve class once in a while, the form of spore is circle shape, ovum circle shape or cylindric; The number of spore: 6 to 60 spores or more than; The surface structure of spore: smooth, 1.6～2.1 * 1.8～1.8 microns; Having or not of trichospore: do not have; Sporangial having or not: do not have; The adnation position of spore handle: aerial hyphae.
2. upgrowth situation on various substratum such as following table 4:
The cultural characteristic of table 4 SS on different substratum
| Substratum | Upgrowth situation | The gas silk | The base silk | Soluble pigment |
| Yeast extract paste malt extract agar (ISP2) | Good | Ash | Yellowish → yellow ash | Do not have |
| Oat agar (ISP3) | Good | Light gray | Sallow → Huang | Do not have |
| Inorganic salt Starch Agar (ISP4) | Good | Nothing → light gray | Yellow ash | Do not have |
| Glycerine asparagine agar (ISP5) | Good | Light gray | Sallow | Do not have |
| Substratum | Upgrowth situation | The gas silk | The base silk | Soluble pigment |
| Tyrosine agar (ISP7) | Good | Light gray | Greyish brown | Do not have |
| Glucose asparagine agar | Good | Light gray | Sallow → Huang | Do not have |
| Sucrose nitrate agar | Good | Light gray | Cream-coloured | Do not have |
| Nutrient agar medium | Good | Do not have | Sallow | Do not have |
| Gauss synthesizes No. 1 agar | Good | Light gray | Pale yellow | Do not have |
| No. 1 agar of Ke Shi | Difference | Do not have | Light gray | Do not have |
3. physiological property such as table 5:
The physiological property of table 5 SS
4. thalline is formed
Full cell acid hydrolysis thing analysis shows L, and the L-diaminopimelic acid exists.
More than the feature of this bacterium, particularly the many spores that formed by substrate mycelium are formed the catenate aerial hyphae, the amino acid that cell walls is formed is L, the L-diaminopimelic acid, do not form characteristics such as trichospore and sporocyst, illustrate that this bacterium should belong to streptomycete, because its product is a new compound, so this bacterium is called streptomycete (Streptomyces sp.) SS.
Experimental example 2
Adopt tube dilution method to measure the anti-microbial activity of SS-1, SS-2 and SS-3.Broth culture with PH 7.6 carries out the two-fold dilution to compound, and every pipe contains 1.0 milliliters of dilute liquid medicines, adds 37 ℃ then, cultivates 0.1 milliliter of the bacterium liquid of 18 hours 1/200 dilution.Hatch 15 hours observationss for 37 ℃.
SS-1, SS-2 and SS-3 anti-mycobacterium tuberculosis H
37The activity of Ra records result such as table 6 with microwell plate alarm blue staining in BACTEC 12B substratum.
The anti-microbial activity of table 6 SS-1, SS-2 and SS-3
| SS-1 | SS-2 | SS-3 | |
| Test organism | MIC μg/ml | MIC μg/ml | MIC μg/ml |
| Tubercule bacillus H 37Ra | 12.5 | 12.5 | 100 |
| Pseudomonas aeruginosa ATCC10145 | 12.5 | 25 | 100 |
| Pneumobacillus | 6.25 | 12.5 | 100 |
| Klebsiella pneumoniae IF010696 | 12.5 | 6.25 | 100 |
| Streptococcus aureus ATCC6538P | >200 | >200 | >200 |
| Intestinal bacteria ATCC11775 | >200 | >200 | >200 |
Conclusion: SS-1 of the present invention, SS-2 and SS-3 have the activity of anti Bacillus pyocyaneu Flugge and tubercule bacillus.
Experimental example 3
Acute toxicity: SS-1, SS-2, the medium lethal dose of SS-3 (LD50, mouse) is 2400 mg/kg.
Conclusion: the toxicity of SS-1 of the present invention, SS-2 and SS-3 is little, can use safely.
Though above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements all belong to the scope of protection of present invention without departing from theon the basis of the spirit of the present invention.
Claims (8)
1. have the uridine peptide antibiotics of structural formula (I) and formed at pharmacy acceptable salt:
Wherein, R is
2. microbiotic according to claim 1 and formed at pharmacy acceptable salt is characterized in that, described pharmacy acceptable salt is ammonia salt, sodium salt, hydrochloride, vitriol, organic alkali salt or organic acid salt.
3. one kind prepares the described antibiotic method of claim 1, comprises fermentation culture, separation, extraction and refining, it is characterized in that bacterial strain used in the described fermentation culture is streptomycete (Sterptomyces sp.) SS CGMCC No.1764.
4. according to the described antibiotic preparation method of claim 3, it is characterized in that described fermentation culture adopts static cultivation, shaking table cultivation, stir culture or submerged culture.
5. according to the described antibiotic preparation method of claim 3, it is characterized in that any one or the combination more than two kinds are adopted in adsorption chromatography, ion-exchange or the molecular sieve in described extraction.
6. one kind is used for fermentative production claim 1 or 2 described antibiotic streptomycete (Sterptomyces sp.) SS CGMCC No.1764.
Claim 1 or 2 described microbiotic and formed at pharmacy acceptable salt in the purposes of preparation in the anti-infectives.
8. the described microbiotic of claim 7 and formed in the purposes of pharmacy acceptable salt in preparation anti Bacillus pyocyaneu Flugge or mycobacterium tuberculosis infection medicine.
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| CN102827247B (en) * | 2011-06-14 | 2015-01-28 | 中国医学科学院医药生物技术研究所 | New sansanmycins, and their uses as anti-tuberculous medicines |
| CN103183723B (en) * | 2011-12-29 | 2014-09-10 | 中国医学科学院医药生物技术研究所 | Novel uridine peptide antibiotics and application thereof |
| CN103966250B (en) * | 2013-01-31 | 2017-02-08 | 中国医学科学院医药生物技术研究所 | Adjustment effect produced by regulation and control gene on nucleoside antibiotic biosynthesis |
| CN106518964B (en) * | 2016-04-11 | 2019-11-19 | 中国医学科学院医药生物技术研究所 | The uridine peptide antibiotics and application thereof of precursor orientation biosynthesis |
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2006
- 2006-09-29 CN CN 200610141075 patent/CN101153052B/en not_active Expired - Fee Related
Non-Patent Citations (2)
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| Constantine G.Boojamra et al.Stereochemical Elucidation and Total Synthesis of Dihydropacidamycin D, a Semisynthetic Pacidamycin.J.Am.Chem.Soc123 5.2001,123(5),870-874. * |
| Constantine G.Boojamra et al.Synthetic dihydropacidamycin antibiotics: A modifiedspectrumof activity for the pacidamycin class..Bioorganic & Medicinal Chemistry Letters13 19.2003,13(19),3305-3309. * |
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| CN101153052A (en) | 2008-04-02 |
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