CN108042531A - Application of the combination of Meropenem and donipenem in anti-mycobacterial infections - Google Patents
Application of the combination of Meropenem and donipenem in anti-mycobacterial infections Download PDFInfo
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- CN108042531A CN108042531A CN201711408654.8A CN201711408654A CN108042531A CN 108042531 A CN108042531 A CN 108042531A CN 201711408654 A CN201711408654 A CN 201711408654A CN 108042531 A CN108042531 A CN 108042531A
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- Prior art keywords
- meropenem
- donipenem
- combination
- mycobacterial infections
- mycobacteria
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- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 title claims abstract description 41
- 229960002260 meropenem Drugs 0.000 title claims abstract description 40
- 206010062207 Mycobacterial infection Diseases 0.000 title claims abstract description 11
- 208000027531 mycobacterial infectious disease Diseases 0.000 title claims abstract description 11
- 230000001355 anti-mycobacterial effect Effects 0.000 title abstract description 5
- 239000003926 antimycobacterial agent Substances 0.000 title abstract description 5
- 239000003814 drug Substances 0.000 claims abstract description 22
- 229940079593 drug Drugs 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 14
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- -1 sorbefacient Substances 0.000 claims description 3
- 239000003826 tablet Substances 0.000 claims description 3
- 238000010521 absorption reaction Methods 0.000 claims description 2
- 239000000853 adhesive Substances 0.000 claims description 2
- 230000001070 adhesive effect Effects 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000007884 disintegrant Substances 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
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- 239000004094 surface-active agent Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
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- 241000187480 Mycobacterium smegmatis Species 0.000 abstract description 13
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 108090000204 Dipeptidase 1 Proteins 0.000 description 21
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- 201000008827 tuberculosis Diseases 0.000 description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 8
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- 238000002474 experimental method Methods 0.000 description 6
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- ABVRVIZBZKUTMK-JSYANWSFSA-M potassium clavulanate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 ABVRVIZBZKUTMK-JSYANWSFSA-M 0.000 description 6
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- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 3
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- PLXBWHJQWKZRKG-UHFFFAOYSA-N Resazurin Chemical compound C1=CC(=O)C=C2OC3=CC(O)=CC=C3[N+]([O-])=C21 PLXBWHJQWKZRKG-UHFFFAOYSA-N 0.000 description 3
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- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 3
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- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
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- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
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- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 2
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- BPHPUYQFMNQIOC-NXRLNHOXSA-N isopropyl beta-D-thiogalactopyranoside Chemical compound CC(C)S[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O BPHPUYQFMNQIOC-NXRLNHOXSA-N 0.000 description 2
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- UPSFMJHZUCSEHU-JYGUBCOQSA-N n-[(2s,3r,4r,5s,6r)-2-[(2r,3s,4r,5r,6s)-5-acetamido-4-hydroxy-2-(hydroxymethyl)-6-(4-methyl-2-oxochromen-7-yl)oxyoxan-3-yl]oxy-4,5-dihydroxy-6-(hydroxymethyl)oxan-3-yl]acetamide Chemical compound CC(=O)N[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@H]1[C@H](O)[C@@H](NC(C)=O)[C@H](OC=2C=C3OC(=O)C=C(C)C3=CC=2)O[C@@H]1CO UPSFMJHZUCSEHU-JYGUBCOQSA-N 0.000 description 2
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- KMEGBUCIGMEPME-LQYKFRDPSA-N (2s,5r,6r)-6-[[(2r)-2-amino-2-phenylacetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(1r,4s)-3,3-dimethyl-2,2,6-trioxo-2$l^{6}-thiabicyclo[3.2.0]heptane-4-carboxylic acid Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)C2C(=O)C[C@H]21.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 KMEGBUCIGMEPME-LQYKFRDPSA-N 0.000 description 1
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
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- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 206010060976 Bacillus infection Diseases 0.000 description 1
- UGFAIRIUMAVXCW-UHFFFAOYSA-N Carbon monoxide Chemical compound [O+]#[C-] UGFAIRIUMAVXCW-UHFFFAOYSA-N 0.000 description 1
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- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010061977 Genital infection female Diseases 0.000 description 1
- 206010018691 Granuloma Diseases 0.000 description 1
- 241000221775 Hypocreales Species 0.000 description 1
- 101100346764 Mus musculus Mtln gene Proteins 0.000 description 1
- 241000186362 Mycobacterium leprae Species 0.000 description 1
- 101900164864 Mycobacterium tuberculosis Beta-lactamase Proteins 0.000 description 1
- 240000007594 Oryza sativa Species 0.000 description 1
- 235000007164 Oryza sativa Nutrition 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 208000035199 Tetraploidy Diseases 0.000 description 1
- 239000007983 Tris buffer Substances 0.000 description 1
- YVNQAIFQFWTPLQ-UHFFFAOYSA-O [4-[[4-(4-ethoxyanilino)phenyl]-[4-[ethyl-[(3-sulfophenyl)methyl]amino]-2-methylphenyl]methylidene]-3-methylcyclohexa-2,5-dien-1-ylidene]-ethyl-[(3-sulfophenyl)methyl]azanium Chemical compound C1=CC(OCC)=CC=C1NC1=CC=C(C(=C2C(=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S(O)(=O)=O)C)C=2C(=CC(=CC=2)N(CC)CC=2C=C(C=CC=2)S(O)(=O)=O)C)C=C1 YVNQAIFQFWTPLQ-UHFFFAOYSA-O 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000004599 antimicrobial Substances 0.000 description 1
- JPIYZTWMUGTEHX-UHFFFAOYSA-N auramine O free base Chemical compound C1=CC(N(C)C)=CC=C1C(=N)C1=CC=C(N(C)C)C=C1 JPIYZTWMUGTEHX-UHFFFAOYSA-N 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 244000144987 brood Species 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 229910002091 carbon monoxide Inorganic materials 0.000 description 1
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 description 1
- 229960004682 cefoperazone Drugs 0.000 description 1
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- 238000002648 combination therapy Methods 0.000 description 1
- 238000011284 combination treatment Methods 0.000 description 1
- 230000006196 deacetylation Effects 0.000 description 1
- 238000003381 deacetylation reaction Methods 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 229960000895 doripenem Drugs 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000002795 fluorescence method Methods 0.000 description 1
- 150000008195 galaktosides Chemical class 0.000 description 1
- 238000005227 gel permeation chromatography Methods 0.000 description 1
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- 230000036039 immunity Effects 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical class O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 239000010985 leather Substances 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 238000007747 plating Methods 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 230000008092 positive effect Effects 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
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- 241000894007 species Species 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 229960000373 tazobactam sodium Drugs 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical class OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention provides a kind of double medicines for mycobacterium smegmatis (Mycobacterium Smegmatis) to be combined combination, this pair of medicine combination is combined as Meropenem and donipenem, there is significant inhibitory activity to mycobacterium smegmatis, therefore double medicine combination combinations provided by the invention can be used for preparing the combination medicine for mycobacteria, be expected to the potential drug as anti-mycobacterial infections.
Description
Technical field
The present invention relates to the technical field of pharmacy, particular content for Meropenem and donipenem combination in anti-branch bar
Application in bacterium infection.
Background technology
Mycobacteria belongs to the actinomyces of the acids containing mycomycete, is mainly characterized by cell membrane and contains a large amount of lipids, mainly
Mycolic acid.This and its dyeability, growth characteristics, pathogenic, resistance etc. are closely related.General not easy coloring, if heated
Or extend dyeing time and the decoloration of strong decolorising agent acidic alcohol can be resisted after colouring, therefore also known as acid-fast bacilli (acid-fast
bacilli).The Pseudomonas atrichia, without brood cell, do not generate inside and outside toxin, it is pathogenic related with drive member.Caused disease
Disease is all in chronic, and with granuloma.Its species is more, can be divided into mycobacterium tuberculosis complex, non-tuberculous mycobacteria and
Mycobacterium leprae three classes.
Mycobacterium tuberculosis (Mycobacterium tuberculosis, Mtb) is cause tuberculosis (TB) pathogenic thin
Bacterium belongs to one kind of mycobacteria, mainly by respiratory infectious, can cause the diseases such as cough, pectoralgia, spitting of blood, expiratory dyspnea
Shape.Healthy People infection tulase might not fall ill, and just fall ill only when immunity of organisms declines.The World Health Organization
(WHO) statistics shows that tuberculosis 800~10,000,000 occur every year for the whole world, and there are about 3,000,000 people every year to die of tuberculosis, is to make
The single infectious disease most into death toll.WHO announces " the global tuberculosis state of emergency " within 1993, it is believed that tuberculosis has become
The important public health problem in the whole world.
Mycobacterium tuberculosis was found in 1882 by German microbiologist Robert Koch.Under the microscope, tulase
For elongated slightly bent or straight bacillus.Mycobacterium tuberculosis is obligate aerobes, and growth is very slow, on solid medium, knot
The pyrenomycetes generation time is 18-20h, and incubation time needs 8 days so that up to 8 weeks, bacterium colony was in rough type on most of culture medium.Mtb
With wax cell membrane, all there is extremely strong resistance to dry environment and strong acid and strong base, it will not be by a variety of chemical disinfections
Agent is permeated.Tulase actually includes human-like, ox type, mouse type and African type, is mycobacterium tuberculosis complex, wherein human-like,
Ox type and African type are pathogenic bacteria.
Mycobacterium smegmatis is the acidproof strain in mycobacteria, long 3.0~5.0um, in rod-shaped, can use auramine O-Luo Dan
Bright fluorescence method dyeing.Lustgarten is reported for the first time in November, 1884.Because it is " rapid growers " and non-pathogenic,
So a kind of simple model is used as by researcher to study the mycobacteria of other classes.The bacterium shares more than 2000 and knot
The homologous gene of core mycobacteria, and with the distinctive cell membrane identical with mycobacterium tuberculosis and other mycobacteria strains
Structure.It also can as mycobacterium tuberculosis aerobic oxidation carbon monoxide.Therefore, researcher is often with it come to treating tuberculosis
The drug of disease carries out phenotypic screen.
Beta-lactam class antibiotic is it is verified that have bacterium significant killing effect, but for the suppression of mycobacteria
Making unobvious.This is because the beta lactamase of mycobacteria coding can make mycobacteria produce beta-lactam class antibiotic
It is raw to resist, make beta-lactam class antibiotic ineffective by hydrolyzing the lactam bond of beta-lactam class antibiotic.Therefore, it is clinical
On by beta-lactam class antibiotic and beta lactamase restrainer combination treatment bacterium infection, classical combination combination is such as A Moxi
Woods clavulanic acid, ampicillin and sulbactam, cefoperazone sulbactam etc..Have been reported the connection for claiming Meropenem and potassium clavulanate
With entering the clinical II phases.Wherein, Meropenem is as a kind of beta-lactam class antibiotic and beta lactamase restrainer carat
Dimension acid combination inhibits mycobacterium tuberculosis.Also it is slower that Meropenem hydrolysis rate when in face of beta lactamase is mentioned in report, it can
With at some extent as beta lactamase restrainer.Beta lactamase restrainer only has traditional clavulanic acid, Shu Ba at present
Smooth, Tazobactam Sodium and the AVM hereinafter Batan reported in recent years, and it is less for the beta lactamase restrainer of mycobacteria, it would be highly desirable to more
Discovery of the spininess to the beta lactamase restrainer of mycobacteria, so as to be combined to resist branch with beta-lactam class inhibitor
Bacillus infection.Novelty of the invention is that it is carried out Meropenem as beta lactamase restrainer and beta-lactam class antibiotic
Combination, exploitation is for new double medicines combination therapy of mycobacterial infections.
Meropenem, English name are Meropenem, are a kind of carbapenem antibiotics, it is suitable for adult and children
The following infection as caused by one or more single bacteriums to Meropenem sensitivity:Endometritis site of pathological change, pneumonia are (including institute
Interior acquired pneumonia)；Urinary tract infections；Gynecological infection:Such as endometritis and pelvic infecton.
Donipenem, English name are Doripenem, are a kind of carbapenem antibiotics, it is to anaerobism or aerobic leather
Lan Shi is positive and gramnegative bacterium has powerful antibacterial activity, is broad-spectrum antibiotic.
But so far, application of the combination of Meropenem and donipenem in anti-mycobacterial infections has not been reported.
The content of the invention
The problem of in correlation technique, the present invention provide the combination of Meropenem and donipenem in anti-mycobacteria sense
Application in dye.
Meropenem CAS involved in the present invention is 96036-03-2, is bought in Selleck.cn companies, donipenem
No. CAS is 148016-81-3, is bought in Selleck.cn companies.It has been reported that Meropenem is as a kind of Carbapenems
Antibiotic, by the beta-lactam enzyme hydrolysis time-division solution rate it is slow, be in particular in that deacetylation procedure is slower, this causes Metro
Training south to a certain extent can be as the inhibitor of beta lactamase.We on a molecular scale, by setting up negative control,
It was found that Meropenem has the beta lactamase in mycobacterium tuberculosis good inhibitory activity (such as Fig. 1), and donipenem is one
The broad-spectrum antibiotic of kind beta-lactam class.We measure the combination pair of donipenem and Meropenem by resazurin Microdilution plate method
The minimal inhibitory concentration of Mycobacterium Smegmatis, find the combination of donipenem and Meropenem for tuberculosis
The higher mycobacterium smegmatis of mycobacteria homology (MycobacteriumSmegmatis) has very strong inhibitory action (such as
Fig. 3), therefore combination combination is expected to as the potential combination medicine for inhibiting mycobacterial infections.
The present invention provides a kind of double medicines combination medicine for being used to preventing or treating mycobacterial infections, and active ingredient is Metro
Training south and donipenem, the drug include above-mentioned containing Meropenem and donipenem and one or more pharmaceutically acceptable
Carrier.Diluent of the carrier including pharmaceutical field routine, excipient, filler, adhesive, wetting agent, disintegrant, suction
Receive accelerating agent, surfactant, absorption carrier, lubricant, synergist.The drug can be made into compound preparation, injection, tablet,
Pill, capsule, the form of suspending agent or emulsion use.Its administration route can be oral, percutaneous, vein or intramuscular injection.
The invention has the advantages and positive effects that：
The present invention be directed to the combination medicine of mycobacteria, this combination medicine is combined as Meropenem and donipenem.More Buddhist nuns
The combination of training south and Meropenem with the high mycobacterium smegmatis of mycobacterium tuberculosis tetraploid rice for having very strong suppression
It makes and uses.
Description of the drawings
Fig. 1 is inhibitory action schematic diagram of the Meropenem to the beta lactamase in mycobacterium tuberculosis
To the MIC schematic diagrames of mycobacterium smegmatis when Fig. 2 is single use Meropenem, donipenem and rifampin
When Fig. 3 is drug combination, to the MIC schematic diagrames of mycobacterium smegmatis
Specific embodiment：
In order to which the present invention is better described, the specific embodiment of the present invention will be described below.
1. the expression and purification of beta lactamase (BlaC) in mycobacterium tuberculosis
According to document (Wang F, Cassidy C, Sacchettini J C.Crystal Structure and
Activity Studies of the Mycobacterium tuberculosisβ-Lactamase Reveal Its
Critical Role in Resistance toβ-Lactam Antibiotics[J].Antimicrobial Agents&
Chemotherapy,2006,50(8):2762-71.)
(1) by the bacterium of the pET28a carrier Transformed E scherichia coli BL21 (DE3) containing coding BlaC genes
Strain, and with LB plating mediums (kanamycins containing 50mg/L) screening positive clone.
(2) the picking positive colony on tablet is transferred to the LB culture mediums (card containing 50mg/L of 0.8L after 37 DEG C of overnight incubations
That mycin), as its light absorption value (that is, OD at 600nm wavelength600) when reaching 0.8, add in 0.1mM IPTG (isopropylthios
Galactoside, Isopropyl β-D-Thiogalactoside) when 16 DEG C of cultures 20 are small.
(3) height crushes bacterium after collecting cell with 5000rpm centrifugations 10min；After broken bacterium solution centrifuges 30min with 10000rpm
It collects supernatant.
(4) supernatant is added in into broken bacterium buffer (25mM Tris, 0.5M NaCl, 2mM beta -mercaptoethanols, pH 8.0) in advance
In the Ni-NTA affinity columns of balance, destination protein is made fully to be combined with Ni, destination protein is made fully to be enriched with.
(5) unbonded foreign protein, Coomassie brilliant blue G250 detection stream are washed off with the broken bacterium buffer containing 20mM imidazoles
Go out liquid it is constant blue when, illustrate that most of foreign protein is rinsed totally.BlaC is eluted with the broken bacterium buffer of the imidazoles containing 200mM, so
Liquid is changed with the concentration tube concentration of 10kD afterwards, is purified to obtain the purpose with charge homogeneity with gel permeation chromatography chromatography
Albumen.
The determination of activity of 2.BlaC
Substrate is used as using CDC-1 (by laboratory synthesized) of the purity more than 95%；The instrument of fluorescent strength determining isThe multi-functional micropore board detector of M1000Pro all-wave lengths, exciting light and transmitting light wavelength be respectively 400nm and
455nm。
Albumen buffer composition is PBS buffer solution, and with buffer solution configuration BlaC (final concentration 30nM), addition is dissolved in DMSO
The compound (final concentration of 10 μM) of (dimethyl sulfoxide (DMSO)), is placed at room temperature for 5 min, is rapidly added fluorogenic substrate CDC-1, substrate is dense
It spends for 10 μM.First order fluorescence reading is recorded per 5s, measures 3000s altogether.654rpm shakes 5s, detects fluorescent value.Negative control is not
Add alternative sample, other experiment condition all sames.
Using the time as X-axis, fluorescent value can obtain enzyme activity kinetic curve for Y-axis.Pass through the phase for the enzyme reaction that microplate reader records
Related parameter, according to fluorescence intensity and reaction time, the enzymatic reaction of 300s before being analyzed using GraphPad Prism5 softwares
Rate.Initial velocity of the V0 as the enzymatic reaction of without inhibitor is set, Vi is the initial velocity of the enzymatic reaction of inhibiting.Root
According to enzyme's reaction speeding, calculate each compound residual activity Ra (Residual Activity, Ra) (Vi/V0) and
Inhibiting rate Ir (Inhibition Rate, Ir) (1-Vi/V0).
For residual activity<30% compound carries out secondary screening, excludes the possibility that operation error causes false positive.For surplus
Remaining activity<30% compound, design fluorescent quenching experiment.Consider residual activity percentage and the fluorescent quenching of compound
Rate it may determine that compound to the inhibition of BlaC.Because the system is mainly screened by fluorescence intensity, when itself
The compound for having the compound of fluorescence either similar with AMC all can generate interference to system.In addition, itself, which contains, is quenched base
Group compound may the fluorescence of system also can be quenched and cause false positive, in order to exclude false positive results, using first by BlaC with
Fluorogenic substrate reaction a period of time, the system fluorescence of allowing reach maximum Q1, again addition and the chemical combination of experimental group equivalent in system
Object, and the fluorescent value size of detection architecture is Q2.Fluorescent quenching rate Qr ((Qr are calculated according to formula in the fluorescent value of the two
=Q1-Q2)/Q2*100%).When fluorescent quenching rate is higher than 20%, it is false positive, as a result needs to exclude；When fluorescent quenching rate is low
It is positive findings when 20%.
3. resazurin Microdilution plate method measures minimal inhibitory concentration of the compound to MycobacteriumSmegmatis
(1) bacterium solution culture
According to 1 in super-clean bench:The glycerol stock of the MC2155 of 200 ratio inoculation 50ul is pressed in the centrifuge tube of 50ml
7H9 culture mediums, 37 DEG C of 220rpm shaken cultivations, until OD are added according to ratio600=1.2, (may be reused in three weeks).It adds in
With 1 in super-clean bench:100 ratios transfer seed liquor into 5mL 7H9 fluid nutrient mediums, 37 DEG C of 220rpm shaken cultivations, until
OD600=0.5 (logarithmic phase).Bacterium solution is taken to be adjusted to OD600=0.15, and dilute 100 times of uses.
(2) dilution of positive compound rifampin, combination combination Meropenem and potassium clavulanate
Using rifampin as positive control in experiment, gradient dilution is followed successively by, 32ug/ml, 16ug/ml, 8ug/ml,
4ug/ml, 2ug/ml, 1ug/ml, 0.5ug/ml, 0.25ug/ml, 0.125ug/ml, 0.0625ug/ml, 0.03125ug/ml,
The 6th dilution gradient of general warranty is the medicine to the minimal inhibitory concentration of wild-type strain.The MIC of rifampin is 1ug/ml.
Also using the combination of Meropenem and potassium clavulanate as positive control in experiment.In terms of tuberculosis is treated, Metro training
The combination in south and potassium clavulanate has progressed to the clinical II phases, and the concentration of Meropenem is set to 1ug/ml by us；Carat dimension
The gradient dilution of sour potassium is, 36ug/ml, 18ug/ml, 9ug/ml, 4.5ug/ml, 2.25ug/ml, 1.125ug/ml,
0.5625ug/ml、0.28125ug/ml、 0.140625ug/ml、0.0703125ug/ml、0.0351563ug/ml、
0.017578ug/ml.The MIC of positive control is is combined together with Meropenem 1ug/ml and clavulanic acid 9ug/ml.
(3) dilution when negative compound Meropenem and donipenem are used alone
Using Meropenem as negative control in experiment, the gradient dilution of Meropenem is 441.6ug/ml, 220.8ug/
Ml, 110.4ug/ml, 55.2ug/ml, 27.6ug/ml, 13.8ug/ml, 6.9ug/ml, 3.45ug/ml, 1.725ug/ml,
0.8625ug/ml, 0.43125ug/ml, 0.2156ug/ml.Single Meropenem is to the MIC of mycobacterium smegmatis
3.45ug/ml。
Using donipenem as negative control in experiment, the gradient dilution of donipenem is 40ug/ml, 20ug/ml,
10ug/ml, 5ug/ml, 2.5ug/ml, 1.25ug/ml, 0.625ug/ml, 0.3125ug/ml, 0.15625ug/ml,
0.078125ug/ml, 0.03906ug/ml, 0.01953ug/ml.Single donipenem is to the MIC of shame structure mycobacteria
10ug/ml。
(4) diluted associated with drug Meropenem and donipenem
Drug dilution is carried out by 2 times of dilution gradients, the concentration of Meropenem is 1ug/ml；The concentration of donipenem is successively
Be, 40ug/ml, 20ug/ml, 10ug/ml, 5ug/ml, 2.5ug/ml, 1.25ug/ml, 0.625ug/ml, 0.3125ug/ml,
0.15625ug/ml、0.078125ug/ml、0.0390625ug/ml、 0.01953125ug/ml。
(5) 40 μ l 7H9 (containing Tween-80 and ADS) fluid nutrient mediums are added into 96 orifice plates, each detected bacterial strain is set
3 drugs are parallel, and 2 μ l Meropenems and 2ul donipenems are added per a line, then add the 40 μ l of bacterium solution diluted, gently shake mixed
It is even.It is placed on 37 DEG C of incubators and is incubated 48h.
(6) 0.02% (w/v) resazurin of 8 μ l filtration sterilizations is added in super-clean bench, continues to be incubated 4 h, be put in inversion
Bacterial growth situation is observed on big mirror, pinkiness is the positive；It is then feminine gender in blueness.
The present invention relates to the technical fields of pharmacy, and specifically the combination of Meropenem and donipenem is in anti-mycobacteria
Application in infection.In the present invention, when potassium clavulanate is 9ug/ml, Meropenem is to the MIC of mycobacterium smegmatis
1ug/ml.Novelty of patent of the present invention is us using Meropenem as acyl in a kind of beta lactamase restrainer and wide spectrum β
Amine antibiotic donipenem is combined, so that the MIC of donipenem is reduced to by 10ug/ml on inhibiting to mycobacteria
0.625ug/ml, drug effect enhance 16 times, are also than the Meropenem potassium clavulanate combination combination MIC into the clinic II phases
The effect of 1ug/ml is good (such as Fig. 3).This has very big application potential in the combination prescription face for preparing anti-mycobacteria, is expected to become
The potential drug of anti-mycobacterial infections.
Method used above is method commonly used in the art unless otherwise specified.
It these are only the specific embodiment of the present invention, be not intended to limit the invention, it is all in the spiritual and former of the present invention
Within then, any modifications, equivalent replacements and improvements are made should all be included in the protection scope of the present invention.
Claims (4)
1. the application of Meropenem and donipenem in mycobacterial infections is treated.
2. application according to claim 1, wherein, the structural formula of Meropenem and donipenem is：
3. a kind of combination medicine for treating mycobacterial infections, it is characterised in that it includes the Meropenem described in claims 1
With donipenem and one or more pharmaceutically acceptable carriers；Diluent of the carrier including pharmaceutical field routine,
Excipient, filler, adhesive, wetting agent, disintegrant, sorbefacient, surfactant, absorption carrier, lubricant, synergy
Agent.
4. the drug of the treatment mycobacterial infections according to claims 3, it is characterized in that it contains the drug
Compound preparation, injection, tablet, pill, capsule, suspending agent or emulsion.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100022504A1 (en) * | 2008-07-28 | 2010-01-28 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods for treating latent tuberculosis |
| CN102559844A (en) * | 2012-01-09 | 2012-07-11 | 上海交通大学 | Preparation method of detecting system for minimal inhibitory concentration of mycobacteria |
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2017
- 2017-12-22 CN CN201711408654.8A patent/CN108042531A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100022504A1 (en) * | 2008-07-28 | 2010-01-28 | Inserm (Institut National De La Sante Et De La Recherche Medicale) | Methods for treating latent tuberculosis |
| CN102559844A (en) * | 2012-01-09 | 2012-07-11 | 上海交通大学 | Preparation method of detecting system for minimal inhibitory concentration of mycobacteria |
Non-Patent Citations (2)
| Title |
|---|
| JEAN-EMMANUEL HUGONNET等: "Meropenem-Clavulanate is effective against extensively drug-resistant mycobacterium tuberculosis", 《SCIENCE》 * |
| SAUGATA HAZRA等: "Tebipenem, a new carbapenem antibiotic, is a slow substrate that inhibits the β-lactamase from mycobacterium tuberculosis", 《BIOCHEMISTRY》 * |
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