CN1943580B - New use of fumigacin type steroids in producing medicine for anti-drug fast bacteria - Google Patents
New use of fumigacin type steroids in producing medicine for anti-drug fast bacteria Download PDFInfo
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Abstract
The invention discloses a new uses of helvolicacid sterides in making drugs of antibiotic-resistant microbes, including helvolicacid, fusidic acid and its salt and salt hydrates acceptable in pharmacology, compound of ester or prodrug with single or multi-antibiotic, applying to preparation of drugs of antibiotic-resistant microbes.
Description
Technical field
The invention belongs to medical technical field, relate to helvolic acid and antibiotic and be combined in the new purposes of making in the drug-resistance bacteria medicine.
Background technology
Because making, the extensive use of antibiotics and the rapid evolution of microorganism multiple resistance mechanism wide-scale distribution in the source of disease bacterium cause multiple antibiotic clinical efficacy to descend.(Christopher Walsh.Molecular mechanisms that conferantibacterial drug resistance.Nature, 406:775-7812000) the drug resistance problem of some drug resistance source of disease bacterium, particularly gram positive bacteria (as staphylococcus aureus) is more and more serious at present.They not only have very strong tolerance to single antibiosis, and often simultaneously multiple antibiotic are had drug resistance, and clinical treatment is very difficult.(Alexander?Tomasz.Multiple-Antibiotic-Resistant?Pathogenic?Bacteria.The?New?England?Journal?of?Medicine.330：1247-1251?1994)
The chemical sproof main biochemistry mechanism of microorganism is that the source of disease bacterium produces multiple antibiotic enzyme (as beta-lactamase), these enzymes can make antibiotic be changed structure before arriving source of disease bacterium target spot and (be hydrolyzed as antibiotic, by hydroxylating), thus cause antibiotic to lose antibacterial activity.At this resistance mechanism, scholars have developed some in succession can suppress the active beta-lactamase inhibitor of antibiotic enzyme, as clavulanic acid, Su Batan and Tazobactam Sodium.Present many companies also Development and Production the compound preparations of these beta-lactamase inhibitors with beta-lactam antibiotic, in order to tackle the beta-lactam antibiotic fastbacteria.
So far the inhibitor that does not also have to upgrade is used for clinical, and the drug resistance problem that the multiple antibiotic enzyme beyond the beta-lactamase is caused has to be solved especially.
And have and report that the source of disease bacterium has begun to produce the beta-lactamase (Bret of counter inhibitor type, L., C.Chanel, D.Sirot, R.Labia, and J.Sirot.Characterization of an inhibitor-resistant enzyme IRT-2 derived from TEM-2 β-lactamase produced by Proteus mirabilis strains.J.Antimicrob.Chemother.38:183-191 1996).On the other hand, the drug resistance problem that the polytype antibiotic enzyme beyond the beta-lactamase is caused is still unresolved.
The present invention adopts the described method of patent (publication number: CN 1412319), obtains to have the active chemical compound of antimicrobial agent from the screening of microbial fermentation sample, and structure is accredited as the steroidal compounds of a class Aspergillus fumigatus acid type.Aspergillus fumigatus acid type steroidal is known steroidal class antibiotic, and itself has antibacterial activity, and representative has helvolic acid and fusidinic acid.Wherein helvolic acid is lower owing to antibacterial activity, thereby is not used now, and nobody studies helvolic acid and multiple antibiotic drug regimen.Leopharmaceutical Products Ltd. A/S has applied for fusidic acid derivatives 17, the patent of preparation method, drug regimen and the purposes of 20-dihydro fusidinic acid (publication number CN 1378554), but do not relate to fusidinic acid and multiple antibiotic drug regimen and purposes.
Summary of the invention
Based on above-mentioned,, the objective of the invention is to disclose the new purposes of a kind of Aspergillus fumigatus acid type steroidal in making drug-resistance bacteria medicine in order to overcome the weak point of prior art.
The Aspergillus fumigatus acid type steroidal structural formula that the present invention relates to is seen right figure, wherein, and R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12Can be the one of the following kind: hydrogen atom (H), hydroxyl (hydroxyl), carbonylic oxygen atom (O), alkyl (alkyl), olefinic double bonds (alkene), aryl (aryl), acyl group (acyl), acyloxy (acyloxy), alkoxyl (alkoxy), aldehyde radical (aldehyde), halogen (halogen), amino (amino), hydrocarbon amino (alkylamino), virtue amino (arylamino), acylamino-(acylamino) and carboxyl (carboxyl), and R
1, R
2, R
3, R
4, R
5, R
6, R
7, R
8, R
9, R
10, R
11, R
12Be not hydrogen atom (H) entirely.
Especially, work as R
1, R
3=two keys; R
5, R
6=R
9, R
10=O; R
7=acetoxy; R
2=R
4=R
8=R
11=R
12During=H, be helvolic acid, this chemical compound is as shown below.
Especially, work as R
1=R
2=R
3=R
4=R
5=R
7=R
8=R
9=R
10=R
11=H; R
6=R
12During=hydroxyl, be fusidinic acid, this chemical compound is as shown below.
Among the present invention, Aspergillus fumigatus acid type steroidal (with corresponding antibiotic combination) is applied to make antibacterials, has significant antimicrobial agent synergism.
Among the present invention, Aspergillus fumigatus acid type steroidal can be planted the antibiotic combination with single, also can with multiple antibiotic applied in any combination in the manufacturing of drug-resistance bacteria medicine.The antibiotic (beta-lactam, non-beta-lactam) of the antibiotic that can participate in making up for medically using comprises penicillin, erythromycin, streptomycin, chloromycetin, kanamycin, gentamycin, tetracycline etc.
The pharmaceutical composition that the present invention relates to is Aspergillus fumigatus acid type steroidal and antibiotic pharmaceutical composition, comprise helvolic acid, fusidinic acid and pharmaceutically hydrate, ester or the prodrug of receivable salt, salt [as with sodium, potassium and calcium, ammonia and amine (as procaine, dibenzyl amine, N-benzyl-β-phenethyl amine, N, N-dibenzyl-1 etc.) formed salt] and multiple antibiotic pharmaceutical composition.Specifically, the present invention relates to medicinal bactericidal composition, comprise helvolic acid respectively with antibiotic compositionss such as penicillin, erythromycin, streptomycin, chloromycetin, kanamycin, gentamycin, tetracycline, and fusidinic acid respectively with antibiotic compositionss such as penicillin, erythromycin, streptomycin, chloromycetin, kanamycin, gentamycin, tetracycline, these compositionss have significant antimicrobial agent synergism.
The pharmaceutical composition that the present invention relates to is characterized in that the weight proportion scope of Aspergillus fumigatus acid type steroidal and antibiotic combination is 1: 10000～64: 1.The weight proportion scope that is specially helvolic acid and chloromycetin is 1: 8～64: 1, preferably 1: 4～16: 1, and more preferably 1: 2～8: 1; The weight proportion scope of helvolic acid and erythromycin is 1: 500～64: 1, preferably 1: 64～8: 1, and more preferably 1: 8～2: 1; The weight proportion scope of helvolic acid and streptomycin is 1: 64～64: 1, preferably 1: 4～16: 1, and more preferably 1: 2～8: 1; The weight proportion scope of helvolic acid and gentamycin is 1: 8～64: 1, preferably 1: 8～16: 1, and more preferably 1: 4～8: 1; The weight proportion scope of helvolic acid and kanamycin is 1: 128～64: 1, preferably 1: 16～4: 1, and more preferably 1: 16～1: 1; The weight proportion scope of helvolic acid and tetracycline is 1: 64～64: 1, preferably 1: 8～8: 1, and more preferably 1: 4～4: 1; The weight proportion scope of helvolic acid and penicillin is 1: 64～64: 1, preferably 1: 64～4: 1, and more preferably 1: 4～4: 1.
The weight proportion scope of fusidinic acid and chloromycetin is 1: 80～8: 5, preferably 1: 80～2: 5, and more preferably 1: 40～1: 5; The weight proportion scope of fusidinic acid and erythromycin is 1: 10000～8: 5, preferably 1: 5000～1: 5, and more preferably 1: 1280～1: 10; The weight proportion scope of fusidinic acid and streptomycin is 1: 640～8: 5, preferably 1: 80～2: 5, and more preferably 1: 40～1: 5; The weight proportion scope of fusidinic acid and gentamycin is 1: 320～8: 5, preferably 1: 40～4: 5, and more preferably 1: 40～1: 5; The weight proportion scope of fusidinic acid and kanamycin is 1: 1280～8: 5, preferably 1: 640～4: 5, and more preferably 1: 640～1: 10; The weight proportion scope of fusidinic acid and tetracycline is 1: 1280～8: 5, preferably 1: 160～1: 5, and more preferably 1: 160～1: 10; The weight proportion scope of fusidinic acid and penicillin is 1: 1280～8: 5, preferably 1: 80～2: 5, and more preferably 1: 80～1: 10.
According to the present invention, can also be included in hydrate, ester or the prodrug of pharmaceutically receivable salt, salt with the Aspergillus fumigatus acid type steroidal of antibiotic combination, as sodium, potassium and calcium, ammonia and amine (as procaine, dibenzyl amine, N-benzyl-β-phenethyl amine, N, N-dibenzyl-1 etc.) formed salt.Especially helvolic acid, fusidinic acid also are included in hydrate, ester or the prodrug of pharmaceutically receivable salt, salt, as sodium, potassium and calcium, ammonia and amine (as procaine, dibenzyl amine, N-benzyl-β-phenethyl amine, N, N-dibenzyl-1 etc.) formed salt.
The route of administration of each compositions of the present invention can be drug administration by injection, oral administration, smears administration.Injection comprises intravenous injection, intramuscular injection, subcutaneous injection, intradermal injection and acupoint injection therapy etc.
Form of administration can be liquid dosage form, solid dosage forms.As liquid dosage form can be true solution class, colloidal type, particulate formulations, emulsion dosage form, mixed suspension form.
Compositions of the present invention can be made ordinary preparation, slow releasing preparation, controlled release preparation, targeting preparation.For example, compositions of the present invention is made ejection preparation, as solution, suspensoid solution, Emulsion, lyophilized injectable powder.This preparation can be moisture or non-water, can contain a kind of and/or multiple pharmaceutically acceptable carrier, diluent, binding agent, lubricant, antiseptic, surfactant or dispersant, as water, ethanol, Polyethylene Glycol, 1, the isooctadecanol of ammediol, ethoxylation, the isooctadecanol of polyoxyization, polyoxyethylene sorbitol fatty ester etc.In addition, ooze injection, can in ejection preparation, add proper amount of sodium chloride, glucose or glycerol, in addition, can also add cosolvent, buffer agent, pH regulator agent of this area routine etc. in order to prepare etc.
The dosage of pharmaceutical composition of the present invention depends on multiple factor, for example to prevent or treat the character and the order of severity of disease, the sex of patient or animal, age, body weight, individual reaction, route of administration, administration number of times etc., therefore therapeutic dose of the present invention can have large-scale variation.In general, the using dosage of Chinese materia medica composition of the present invention is well known to a person skilled in the art.The actual drug quantity that is contained in the last preparation in can thing combined according to the invention is suitably adjusted, and treats effective requirement to reach it, finishes the purpose of prevention of the present invention and treatment drug-fast bacteria infection.
When before begin treatment, lacking specific diagnosis, according to estimates, make an appointment with the dosage range of 0.1-200mg/Kg every day can effectively prevent and treat the microbial infection of drug resistance.
What the present invention related on the other hand is to contain Aspergillus fumigatus acid type steroidal and application, especially the application in drug-resistance bacteria medicine of multiple antibiotic pharmaceutical composition in the preparation antibacterials, and the purposes of prevention and the microbial disease of treatment drug resistance.
The invention still further relates to a kind of drug regimen, it comprises separately, perhaps claims respectively independently helvolic acid, fusidinic acid and multiple antibiotic preparation.In use, can be successively or simultaneously will this independent helvolic acid, the fusidinic acid preparation mixes with multiple antibiotic preparation or medication respectively, finally to reach the purpose of using compositions of the present invention.
The present invention has the following advantages:
1, pharmaceutical composition of the present invention can effectively solve antibacterial to multiple antibiotic drug resistance problem.
2, have remarkable role in synergy between the composition of pharmaceutical composition of the present invention, the fastbacteria of producing multiple antibiotic enzyme is had the obvious synergistic antibacterial action.
3, drug regimen of the present invention can reduce antibiotic consumption, thus side effect and untoward reaction that corresponding reduction antibiotic produces.
The present invention lays a good foundation for the development of novel drug-resistance bacteria medicine.
The specific embodiment
Following embodiment and pharmaceutically active experiment are used to further specify the present invention, but the mode described in the embodiment of not representing is to implement unique channel of the present invention, does not also mean that any limitation of the invention.
Embodiment 1 helvolic acid/chloromycetin group compound is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
1 materials and methods
1.1 clinical drug-resistant bacterial strain:
The clinical drug-resistant bacterial strain is Sichuan University West China first clinical laboratory of Affiliated Hospital isolating anti-multiple medicines staphylococcus aureus (Staphylococcus.aureus) from clinical patients, and bacterium number is 13929,12334,11931,12352,12798,12760.These isolated strains are carried out the cultivation of going down to posterity, be used for present embodiment then.
1.2 medicine and reagent:
Erythromycin, streptomycin, chloromycetin, kanamycin, gentamycin, tetracycline are Amresco company product, and biochemical analysis is pure; Penicillin sodium is the benzylpenicillin sodium for injection of HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory, and lot number is C 040710910.Helvolic acid separates preparation by the inventor from microbial fermenters with fusidinic acid, and purity is higher than 98%.Hydrolyzed protein peptone, Carnis Bovis seu Bubali cream are Beijing extensive and profound in meaning star biotechnology responsibility company limited product, and yeast powder is Japan's big five flourish KCC's products of supporting, and glucose is a Chengdu chemical reagent factory product.
1.3 medium component:
Hydrolyzed protein peptone 6g Carnis Bovis seu Bubali cream 1.5g
Anhydrous glucose 1g yeast powder 6g
Distilled water 1000ml (boiling cooling back filter paper filtering 10 minutes)
PH 7.0～7.5 121 ℃ 30min sterilization
1.4 experimental technique
Adopt in the present embodiment and well known to a person skilled in the art experimental technique (Ma Xurong, Su Demo. " the medicine microbiological Test handbook .P198 of Science Press～199.), chloromycetin among the present invention and helvolic acid/chloromycetin group compound have been carried out antibacterial activity in vitro mensuration (MIC) to the drug resistance staphylococcus aureus, and experimental result sees Table 1.
Table 1 helvolic acid/chloromycetin group compound is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Above experimental result shows, helvolic acid/chloromycetin group compound has clinical anti-multiple medicines staphylococcus aureus and uses helvolic acid or the stronger antibacterial activity of chloromycetin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 2 helvolic acids/erythromycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method erythromycin of embodiment 1 and the helvolic acid/erythromycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 2.
Table 2 helvolic acid/erythromycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Above experimental result shows that helvolic acid/erythromycin compositions has clinical anti-multiple medicines staphylococcus aureus uses helvolic acid or the stronger antibacterial activity of erythromycin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 3 helvolic acids/streptomycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method streptomycin of embodiment 1 and the helvolic acid/streptomycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 3.
Table 3 helvolic acid/streptomycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
With helvolic acid or the stronger antibacterial activity of streptomycin, show remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 4 helvolic acids/gentamycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method gentamycin of embodiment 1 and the helvolic acid/gentamycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 4.
Table 4 helvolic acid/gentamycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
With helvolic acid or the stronger antibacterial activity of gentamycin, show remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 5 helvolic acids/kanamycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method kanamycin of embodiment 1 and the helvolic acid/kanamycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 5.
Table 5 helvolic acid/kanamycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
With helvolic acid or the stronger antibacterial activity of kanamycin, show remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 6 helvolic acids/tetracycline compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method tetracycline of embodiment 1 and the helvolic acid/tetracycline compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 6.
Table 6 helvolic acid/tetracycline compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Use helvolic acid or the stronger antibacterial activity of tetracycline, show remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 7 helvolic acids/penicillin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method penicillin of embodiment 1 and the helvolic acid/penicillin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 7.
Table 7 helvolic acid/penicillin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Experimental result shows that helvolic acid/penicillin compositions has clinical anti-multiple medicines staphylococcus aureus uses helvolic acid or the stronger antibacterial activity of penicillin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 8 helvolic acids sodium/erythromycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method erythromycin of embodiment 1 and the helvolic acid sodium/erythromycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 8.
Table 8 helvolic acid sodium/erythromycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Above experimental result shows that helvolic acid sodium/erythromycin compositions has clinical anti-multiple medicines staphylococcus aureus uses helvolic acid sodium or the stronger antibacterial activity of erythromycin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 9 helvolic acid N, N-dibenzyl-1 salt/tetracycline compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press determination of experimental method tetracycline and the helvolic acid N of embodiment 1, N-dibenzyl-1 salt/tetracycline compositions is to the antibacterial activity of clinical drug-resistant staphylococcus aureus, and it the results are shown in Table 9.
Table 9 helvolic acid N, N-dibenzyl-1 salt/tetracycline compositions is external to the clinical drug-resistant staphylococcus aureus
Antibacterial activity is measured
Reveal remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 10 fusidinic acids/chloromycetin group compound is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method chloromycetin of embodiment 1 and the fusidinic acid/chloromycetin group compound antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 10.
Table 10 fusidinic acid/chloromycetin group compound is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Above experimental result shows, fusidinic acid/chloromycetin group compound has clinical anti-multiple medicines staphylococcus aureus and uses fusidinic acid or the stronger antibacterial activity of chloromycetin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 11 fusidinic acids/erythromycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method erythromycin of embodiment 1 and the fusidinic acid/erythromycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 11.
Table 11 fusidinic acid/erythromycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Above experimental result shows that fusidinic acid/erythromycin compositions has clinical anti-multiple medicines staphylococcus aureus uses fusidinic acid or the stronger antibacterial activity of erythromycin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 12 fusidinic acids/streptomycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method streptomycin of embodiment 1 and the fusidinic acid/streptomycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 12.
Table 12 fusidinic acid/streptomycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
The antibacterial activity that fusidinic acid or streptomycin are stronger shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 13 fusidinic acids/gentamycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method gentamycin of embodiment 1 and the fusidinic acid/gentamycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 13.
Table 13 fusidinic acid/gentamycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Use fusidinic acid or the stronger antibacterial activity of gentamycin, show remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 14 fusidinic acids/kanamycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method kanamycin of embodiment 1 and the fusidinic acid/kanamycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 14.
Table 14 fusidinic acid/kanamycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Use fusidinic acid or the stronger antibacterial activity of kanamycin, show remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 15 fusidinic acids/tetracycline compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method tetracycline of embodiment 1 and the fusidinic acid/tetracycline compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 15.
Table 15 fusidinic acid/tetracycline compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Above experimental result shows that fusidinic acid/tetracycline compositions has clinical anti-multiple medicines staphylococcus aureus uses fusidinic acid or the stronger antibacterial activity of tetracycline more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 16 fusidinic acids/penicillin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method penicillin of embodiment 1 and the fusidinic acid/penicillin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus, it the results are shown in Table 16.
Table 16 fusidinic acid/penicillin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Experimental result shows that fusidinic acid/penicillin compositions has clinical anti-multiple medicines staphylococcus aureus uses fusidinic acid or the stronger antibacterial activity of penicillin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 17 fusidinic acid N-benzyl-β-phenethyl amine salt/erythromycin compositions is measured by the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus and antibacterial activity compares
Press the determination of experimental method erythromycin of embodiment 1 and fusidinic acid N-benzyl-β-phenethyl amine salt/erythromycin compositions antibacterial activity to the clinical drug-resistant staphylococcus aureus.It the results are shown in Table 17.
Table 17 fusidinic acid N-benzyl-β-phenethyl amine salt/erythromycin compositions is measured the antibacterial activity in vitro of clinical drug-resistant staphylococcus aureus
Above experimental result shows, fusidinic acid N-benzyl-β-phenethyl amine salt/erythromycin compositions has clinical anti-multiple medicines staphylococcus aureus uses fusidinic acid N-benzyl-β-phenethyl amine salt or the stronger antibacterial activity of erythromycin more separately, shows remarkable role in synergy.The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 18 helvolic acids are united use to producing the Synergistic antimicrobial activity of beta-lactamase fastbacteria with penicillin
1 materials and methods
1.1 penicillin Resistant strain:
The penicillin Resistant strain produces bacterium for the induction type beta-lactamase: Bacillus cercus (Bacillus cereus NCPF 63509)
1.2 medicine and reagent:
Penicillin sodium is the benzylpenicillin sodium for injection of HARBIN PHARMACEUTICAL GROUP CO., LTD. General Pharm. Factory, and lot number is C 040710910.Helvolic acid separates preparation by the inventor from microbial fermenters with fusidinic acid, and purity is greater than 98%.Hydrolyzed protein peptone, Carnis Bovis seu Bubali cream are Beijing extensive and profound in meaning star biotechnology responsibility company limited product, and NaCl is dragon chemical reagent factory of a Chengdu section product, and biochemical analysis is pure.Agar powder is an Amresco company product.
1.3 medium component:
Hydrolyzed protein peptone 0.5g distilled water 1600ml
NaCl 0.5g Carnis Bovis seu Bubali cream 0.3g
Agar powder 1.0%
PH 7.0-7.2121 ℃ of 30min sterilization
1.4 experimental technique
Present embodiment the patent (publication number: CN 1412319) of people's application and the method for European patent (GB 1489235) such as sends out with reference to government authorities, helvolic acid, penicillin and helvolic acid/penicillin compositions among the present invention has been carried out antibacterial activity in vitro mensuration to the fastbacteria of producing beta-lactamase, and implementation procedure as follows.
1.4.1 the making of assay plate:
After the thawing of agar culture medium boiling water, 50 ℃ of water-baths, when treating that the culture medium temperature drops to 50 ℃, add indicator bacteria 3ml (Bacillus cercus NCPF 63509 to culture medium (100ml), 600nm light path 1cm light transmittance T=12), penicillin 2.1ml (20mg/ml) measures culture dish to each behind the mixing and adds the 15ml culture medium.After agar culture medium solidified fully, each assay plate was put into 6 scraps of paper (diameter is 6mm), and wherein alternate 3 add working sample, and 3 addings are as positive control and the corrigent reference material of vigor (clavulanic acid) in addition.Blank is dissolving reagent, and blank is dull and stereotyped for not adding the assay plate of penicillin.
1.4.2 the antimicrobial agent active level bioassay standard curve of positive control (clavulanic acid):
Respectively with the clavulanic acid of 118,168,240,343,490,700,1000 μ g/ml as measuring concentration, each scraps of paper application of sample 20 μ l (i.e. 2.36,3.36,4.8,6.86,9.8,14,20 μ g/ sheets), and correct concentration as the center with 343 μ g/ml clavulanic acids.Cultivate after about 16 hours for 30 ℃, occur inhibition zone clearly on the plating medium, with vernier caliper measurement antibacterial circle diameter (cm).
Record in 118～1000 μ g/ml scopes, the logarithm of clavulanic acid concentration (X) and antibacterial circle diameter (Y) are linear dependence.Its relation can be expressed as:
Y＝0.606Ln(X)-1.5163 r＝0.999
1.4.3 the active quantitative assay of helvolic acid:
With DMSO helvolic acid is mixed with the solution of 1mg/ml, adds the scraps of paper (i.e. 20 μ g/ sheets) by 20 μ l/ sheets.The application of sample scraps of paper are put into alternate 3 positions of assay plate (and blank flat board), and other 3 positions add the reference material (6.86 μ g/ sheet clavulanic acid) as positive control and vigor corrective.Blank is dissolving reagent, and blank is dull and stereotyped for not adding the assay plate of penicillin.
The result is as follows, penicillin in the assay plate (420 μ g/ml) separately effect can not suppress the growth of fastbacteria, and the scraps of paper (20 μ g/ sheet) that contain helvolic acid separately effect can not suppress the growth of fastbacteria in blank flat board (assay plate that does not add penicillin).But after the scraps of paper (20 μ g/ sheet) of helvolic acid are put into assay plate and cultivate, just can produce tangible inhibition zone.And be equivalent to the clavulanic acid activity of 1035.71 μ g/ml according to the activity that standard curve records 1000 μ g/ml helvolic acids, or 1mol helvolic acid activity is equivalent to 2.96mol clavulanic acid activity.
Above experimental result shows, the use of uniting of helvolic acid and penicillin has the fastbacteria of producing beta-lactamase and uses helvolic acid or the stronger antibacterial activity of penicillin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Embodiment 19 fusidinic acids are united use to producing the Synergistic antimicrobial activity of beta-lactamase fastbacteria with penicillin
Operation sequence by embodiment 18 is carried out antibacterial activity test.
The result is as follows, penicillin in the assay plate (420 μ g/ml) separately effect can not suppress the growth of fastbacteria, and the scraps of paper (0.75 μ g/ sheet) that contain fusidinic acid separately effect can not suppress the growth of fastbacteria in blank flat board (assay plate that does not add penicillin).But with the scraps of paper (0.75 μ g/ sheet) of fusidinic acid put into contain that penicillin (420 μ g/ml) is dull and stereotyped and cultivate after, can produce tangible inhibition zone.And be equivalent to the clavulanic acid activity of 13067 μ g/ml according to the activity that standard curve records 1000 μ g/ml fusidinic acids, or 1mol fusidinic acid activity is equivalent to 33.7mol clavulanic acid activity.
Above experimental result shows, the use of uniting of fusidinic acid and penicillin has the fastbacteria of producing beta-lactamase and uses fusidinic acid or the stronger antibacterial activity of penicillin more separately, shows remarkable role in synergy.
The invention is not restricted to the special ratios of embodiment Chinese medicine compositions.
Claims (5)
1. the new purposes of helvolic acid in making drug-resistance bacteria medicine, it is characterized in that: helvolic acid with following structural formula feature, with penicillin, erythromycin, streptomycin, chloromycetin, kanamycin, gentamycin, tetracycline list kind or the combination of multiple antibiotic, be applied to the manufacturing of drug-resistance bacteria medicine;
2. the new purposes of helvolic acid according to claim 1 in making drug-resistance bacteria medicine is characterized in that: the weight proportion scope of helvolic acid and antibiotic combination is 1: 10000～64: 1.
3. the new purposes of helvolic acid according to claim 1 in making drug-resistance bacteria medicine, it is characterized in that: the weight proportion scope of helvolic acid and chloromycetin is 1: 8～64: 1, the weight proportion scope of helvolic acid and erythromycin is 1: 500～64: 1, the weight proportion scope of helvolic acid and streptomycin is 1: 64～64: 1, the weight proportion scope of helvolic acid and gentamycin is 1: 8～64: 1, the weight proportion scope of helvolic acid and kanamycin is 1: 128～64: 1, the weight proportion scope of helvolic acid and tetracycline is 1: 64～64: 1, and the weight proportion scope of helvolic acid and penicillin is 1: 64～64: 1.
4. the new purposes of helvolic acid according to claim 1 in making drug-resistance bacteria medicine is characterized in that: the weight proportion scope of helvolic acid and chloromycetin is for being 1: 4～16: 1; The weight proportion scope of helvolic acid and erythromycin is 1: 64～8: 1; The weight proportion scope of helvolic acid and streptomycin is 1: 4～16: 1; The weight proportion scope of helvolic acid and gentamycin is 1: 8～16: 1; The weight proportion scope of helvolic acid and kanamycin is 1: 16～4: 1; The weight proportion scope of helvolic acid and tetracycline is 1: 8～8: 1; The weight proportion scope of helvolic acid and penicillin 1: 64～4: 1.
5. the new purposes of helvolic acid according to claim 1 in making drug-resistance bacteria medicine, it is characterized in that: the weight proportion scope of helvolic acid and chloromycetin is 1: 2～8: 1; The weight proportion scope of helvolic acid and erythromycin is 1: 8～2: 1; The weight proportion scope of helvolic acid and streptomycin is 1: 2～8: 1; The weight proportion scope of helvolic acid and gentamycin is 1: 4～8: 1; The weight proportion scope of helvolic acid and kanamycin is 1: 16～1: 1; The weight proportion scope of helvolic acid and tetracycline is 1: 4～4: 1; The weight proportion scope of helvolic acid and penicillin is 1: 4～4: 1.
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Non-Patent Citations (4)
| Title |
|---|
| FARBER B. F. |
| FARBER B. F.;YEE Y. C.;KARCHMER A. W..Interaction between Rifampin and Fusidic Acidagainst Methicillin Resistant Coagulase-Positive and-Negative Staphylococci..ANTIMICROBIAL AGENTS AND CHEMOTHERAPY30 1.1986,30(1),174-175. * |
| KARCHMER A. W..Interaction between Rifampin and Fusidic Acidagainst Methicillin Resistant Coagulase-Positive and-Negative Staphylococci..ANTIMICROBIAL AGENTS AND CHEMOTHERAPY30 1.1986,30(1),174-175. |
| YEE Y. C. |
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