CN113842380B - 维多氟拉迪莫作为ndm-1抑制剂或抗生素保护剂的新用途 - Google Patents
维多氟拉迪莫作为ndm-1抑制剂或抗生素保护剂的新用途 Download PDFInfo
- Publication number
- CN113842380B CN113842380B CN202111065294.2A CN202111065294A CN113842380B CN 113842380 B CN113842380 B CN 113842380B CN 202111065294 A CN202111065294 A CN 202111065294A CN 113842380 B CN113842380 B CN 113842380B
- Authority
- CN
- China
- Prior art keywords
- ndm
- antibiotic
- vitamin
- inhibitor
- beta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 239000003112 inhibitor Substances 0.000 title claims abstract description 14
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 13
- 101000740455 Klebsiella pneumoniae Metallo-beta-lactamase type 2 Proteins 0.000 title abstract 7
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims abstract description 17
- 239000002132 β-lactam antibiotic Substances 0.000 claims abstract description 17
- 229940124586 β-lactam antibiotics Drugs 0.000 claims abstract description 17
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 10
- 229930003316 Vitamin D Natural products 0.000 claims description 26
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 26
- 235000019166 vitamin D Nutrition 0.000 claims description 26
- 239000011710 vitamin D Substances 0.000 claims description 26
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 26
- 229940046008 vitamin d Drugs 0.000 claims description 26
- 238000002360 preparation method Methods 0.000 claims description 6
- 229940041011 carbapenems Drugs 0.000 claims description 4
- 229930186147 Cephalosporin Natural products 0.000 claims description 2
- 229930182555 Penicillin Natural products 0.000 claims description 2
- 229940124587 cephalosporin Drugs 0.000 claims description 2
- 150000001780 cephalosporins Chemical class 0.000 claims description 2
- 150000002960 penicillins Chemical class 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229920006063 Lamide® Polymers 0.000 claims 2
- 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 abstract description 22
- 102000004190 Enzymes Human genes 0.000 abstract description 21
- 108090000790 Enzymes Proteins 0.000 abstract description 21
- 229960002260 meropenem Drugs 0.000 abstract description 21
- 238000012360 testing method Methods 0.000 abstract description 19
- 230000005764 inhibitory process Effects 0.000 abstract description 14
- 241000894006 Bacteria Species 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 10
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 9
- 241000588724 Escherichia coli Species 0.000 abstract description 8
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 7
- 238000002474 experimental method Methods 0.000 abstract description 3
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 239000003223 protective agent Substances 0.000 abstract description 3
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 238000003113 dilution method Methods 0.000 abstract 1
- 239000011782 vitamin Substances 0.000 abstract 1
- 229940088594 vitamin Drugs 0.000 abstract 1
- 229930003231 vitamin Natural products 0.000 abstract 1
- 235000013343 vitamin Nutrition 0.000 abstract 1
- 150000003722 vitamin derivatives Chemical class 0.000 abstract 1
- 230000002401 inhibitory effect Effects 0.000 description 12
- 230000001580 bacterial effect Effects 0.000 description 10
- 108090000623 proteins and genes Proteins 0.000 description 10
- 102000004169 proteins and genes Human genes 0.000 description 9
- 238000000034 method Methods 0.000 description 8
- 239000003814 drug Substances 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- IZEKFCXSFNUWAM-UHFFFAOYSA-N dipyridamole Chemical compound C=12N=C(N(CCO)CCO)N=C(N3CCCCC3)C2=NC(N(CCO)CCO)=NC=1N1CCCCC1 IZEKFCXSFNUWAM-UHFFFAOYSA-N 0.000 description 6
- 229960002768 dipyridamole Drugs 0.000 description 6
- 229940079593 drug Drugs 0.000 description 6
- 238000003032 molecular docking Methods 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 229940088710 antibiotic agent Drugs 0.000 description 4
- 244000052616 bacterial pathogen Species 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- PTFCDOFLOPIGGS-UHFFFAOYSA-N Zinc dication Chemical compound [Zn+2] PTFCDOFLOPIGGS-UHFFFAOYSA-N 0.000 description 3
- 102000006635 beta-lactamase Human genes 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 230000012010 growth Effects 0.000 description 3
- 239000001963 growth medium Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000004615 ingredient Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 238000005259 measurement Methods 0.000 description 3
- 239000002609 medium Substances 0.000 description 3
- 102000020235 metallo-beta-lactamase Human genes 0.000 description 3
- 108060004734 metallo-beta-lactamase Proteins 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000010413 mother solution Substances 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 239000013641 positive control Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 238000009631 Broth culture Methods 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- 108090000204 Dipeptidase 1 Proteins 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 239000002671 adjuvant Substances 0.000 description 2
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound 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 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 2
- 229960000723 ampicillin Drugs 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 125000003460 beta-lactamyl group Chemical group 0.000 description 2
- 101150059180 blaNDM-1 gene Proteins 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 238000003776 cleavage reaction Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000000502 dialysis Methods 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N diphenyl Chemical group C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000010799 enzyme reaction rate Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 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
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 239000006166 lysate Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- -1 oral administration Substances 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000011148 porous material Substances 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 230000007017 scission Effects 0.000 description 2
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 238000001712 DNA sequencing Methods 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241001198387 Escherichia coli BL21(DE3) Species 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101100111649 Klebsiella pneumoniae blaNDM-1 gene Proteins 0.000 description 1
- 102000004856 Lectins Human genes 0.000 description 1
- 108090001090 Lectins Proteins 0.000 description 1
- 208000005777 Lupus Nephritis Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins Proteins 0.000 description 1
- 102000004495 STAT3 Transcription Factor Human genes 0.000 description 1
- 108010017324 STAT3 Transcription Factor Proteins 0.000 description 1
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 210000001744 T-lymphocyte Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 238000001042 affinity chromatography Methods 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000003275 alpha amino acid group Chemical group 0.000 description 1
- 230000003698 anagen phase Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 230000001363 autoimmune Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000010290 biphenyl Nutrition 0.000 description 1
- 159000000007 calcium salts Chemical class 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 238000006555 catalytic reaction Methods 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 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 1
- 229960003324 clavulanic acid Drugs 0.000 description 1
- 230000000112 colonic effect Effects 0.000 description 1
- 230000001010 compromised effect Effects 0.000 description 1
- 239000012050 conventional carrier Substances 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- DBLXOVFQHHSKRC-UHFFFAOYSA-N ethanesulfonic acid;2-piperazin-1-ylethanol Chemical compound CCS(O)(=O)=O.OCCN1CCNCC1 DBLXOVFQHHSKRC-UHFFFAOYSA-N 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003889 eye drop Substances 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000013355 food flavoring agent Nutrition 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000010353 genetic engineering Methods 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000002519 immonomodulatory effect Effects 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000002523 lectin Substances 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000001404 mediated effect Effects 0.000 description 1
- 238000005142 microbroth dilution method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 210000003819 peripheral blood mononuclear cell Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000034190 positive regulation of NF-kappaB transcription factor activity Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 238000007920 subcutaneous administration Methods 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
- 239000006228 supernatant Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- FPZLLRFZJZRHSY-HJYUBDRYSA-N tigecycline Chemical compound C([C@H]1C2)C3=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C3C(=O)C1=C(O)[C@@]1(O)[C@@H]2[C@H](N(C)C)C(O)=C(C(N)=O)C1=O FPZLLRFZJZRHSY-HJYUBDRYSA-N 0.000 description 1
- 229960004089 tigecycline Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000000108 ultra-filtration Methods 0.000 description 1
- 239000011701 zinc Substances 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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
- A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Communicable Diseases (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明公开了维多氟拉迪莫作为NDM‑1抑制剂或抗生素保护剂的新用途,属于维多氟拉迪莫新医药用途领域。本发明通过NDM‑1酶抑制试验、微量棋盘稀释法、时间‑杀菌曲线等试验发现维多氟拉迪莫能够显著抑制NDM‑1的活性并恢复美罗培南对产NDM‑1大肠杆菌的抗菌活性。因此,本发明确定维多氟拉迪莫可作为NDM‑1抑制剂,其与β‑内酰胺类抗生素联合应用,能够减少甚至消除NDM‑1对β‑内酰胺类抗生素的水解、恢复耐药菌对β‑内酰胺类抗生素的敏感性。
Description
技术领域
本发明涉及维多氟拉迪莫的新药理用途,尤其涉及维多氟拉迪莫作为NDM-1抑制剂或抗生素保护剂的新药理用途,属于维多氟拉迪莫药理活性新用途领域。
背景技术
β-内酰胺类抗生素杀菌活性强、毒性低、适应症广,是目前治疗细菌所致感染性疾病的重要药物。β-内酰胺类抗生素包括碳青霉烯类、头孢菌素类、青霉素类等,它们结构上都有一个发挥抗菌活性的β-内酰胺环。随着β-内酰胺类抗生素的广泛使用,使得越来越多的细菌产生由β-内酰胺酶介导的耐药性。
产生β-内酰胺酶是诱发细菌耐药的重要机制之一,该酶可催化β-内酰胺类抗生素中的β-内酰胺环上的C-N键断裂而开环,导致抗生素失活。基于氨基酸序列同源性,β-内酰胺酶可以分为丝氨酸-β-内酰胺酶和金属-β-内酰胺酶,丝氨酸-β-内酰胺酶依赖于活性中心的丝氨酸发挥催化作用,可以被克拉维酸、舒巴坦和他唑巴坦等临床上使用的抗生素所抑制。金属β-内酰胺酶依靠活性中心的锌离子发挥催化作用,可水解包括碳青霉烯类在内的所有β-内酰胺类抗生素,广泛存在多种革兰氏阴性和阳性致病菌中,临床上尚无有效的抑制剂。
2010年8月,《柳叶刀》杂志报道了一种水解碳青霉烯类药物的新德里金属-β-内酰胺酶-1(NDM-1),由于产NDM-1细菌其广泛的耐药性导致感染治疗十分困难,称之为“超级细菌”。blaNDM-1基因是位于质粒上,可以独立于染色体之外自主复制,并可在不同菌种之间水平转移,使原本对抗生素敏感的菌株获得耐药性。NDM-1是近年来发现的影响范围最广、危害程度最严重的金属-β-内酰胺酶,它对几乎所有抗生素均表现出高度的耐药性,仅有替加环素和多黏菌素对其有一定的抑制作用,不断进化的突变株使得临床治疗更加艰难。NDM-1能水解临床常用的β-内酰胺类抗生素,而其抑制剂能够抑制NDM-1酶的活性,从而保护β-内酰胺类抗生素,恢复其抗菌效果,因此,寻找NDM-1的抑制剂是遏制“超级细菌”引起的感染最迫切的要求。
维多氟拉迪莫是一种口服给药的新型的二氢山梨酸脱氢酶(DHODH)的小分子抑制剂,具有潜在的抗炎、免疫调节和抗病毒活性。在体外研究中,维多氟拉迪莫通过抑制嘧啶从头合成,浓度依赖性抑制植物凝集素刺激的PBMC增殖,通过抑制STAT3和NF-κB活化,减弱IL-17从结肠带的分泌。在体外研究中,维多氟拉迪莫能够降低系统自身免疫性,改善狼疮性肾炎,有效减少宏观组织病理和CD3+T细胞的数量。截至目前,国内外未见维多氟拉迪莫在可用于NDM-1抑制剂的任何报道。
发明内容
本发明的主要目的是提供维多氟拉迪莫作为NDM-1抑制剂或抗生素保护剂的新用途。
为了实现上述目的,本发明所采用的技术方案包括:
本发明一方面提供了维多氟拉迪莫作为NDM-1抑制剂的新药理用途,即抑制NDM-1对β-内酰胺类抗生素的水解作用,恢复β-内酰胺类抗生素对携带NDM-1阳性菌的抗菌活性。因此,维多氟拉迪莫能够作为抗生素保护剂,尤其是作为β-内酰胺类抗生素的保护剂。
本发明另一方面提供了一种抑制致病菌的药物组合物,包括有效量的抗生素、抗生素保护剂和药学上可接受的载体或辅料,其中,所述的抗生素优选为β-内酰胺类抗生素;所述的抗生素保护剂是维多氟拉迪莫。
按照本领域的常规制剂方法将所述的药物组合物制备成临床常用的制剂,譬如是粉剂、颗粒剂、片剂、胶囊剂、注射剂等,通过注射、口服、滴鼻、滴眼、物理或化学介导的方法将其导入肌肉、内皮、皮下、静脉、粘膜组织,或是被其他物质混合或包裹后导入肌体。
所述的载体或辅料是指药学领域常规的载体或辅料,例如:稀释剂、崩解剂、润滑剂、赋形剂、粘合剂、助流剂、填充剂、表面活性剂等;另外,还可以在组合物中加入其它辅助剂如香味剂和甜味剂。
所述稀释剂可以是一种或几种增加片剂重量和体积的成分;常用的稀释剂包括乳糖、淀粉、预胶化淀粉、微晶纤维素、山梨醇、甘露醇以及无机钙盐等。其中最常用为乳糖、淀粉、微晶纤维素。
所述崩解剂可以为交联聚乙烯吡咯烷酮(与总重量比为2-6%),交联羧甲基纤维素钠(与总重量比为2-6%)、海藻酸(与总重量比为2-5%)、微晶纤维素(与总重量比为5-15%)中之一种或几种混合物。其中以交联聚乙烯吡咯烷酮(与总重量比为2-7%),交联羧甲基纤维素钠(与总重量比为2-6%)为佳。最佳为交联聚乙烯吡咯烷酮(与总重量比为2-6%)。
所述的润滑剂包括硬脂酸,硬脂酸钠,硬脂酸镁,硬脂酸钙,聚乙二醇,滑石粉,氢化植物油中之一种或几种混合物。其中以硬脂酸镁最为适宜。润滑剂的用量范围(与总重量比)为0.10-1%,一般用量为0.25-0.75%,最佳用量为0.5-0.7%。
所述的粘合剂可以是一种或几种有利于制粒的成分。可以是淀粉浆(10-30%,与粘合剂总重量比),羟丙基甲基纤维素(2-5%,与粘合剂总重量比),聚乙烯吡咯烷酮(2-20%,与粘合剂总重量比),以聚乙烯吡咯烷酮的乙醇水溶液为佳,最佳为聚乙烯吡咯烷酮的50%乙醇水溶液。
所述助流剂可以为微粉硅胶、滑石粉、三硅酸镁中之一种或几种混合物。
所述表面活性剂可以为一种或几种能够提高润湿性和增加药物溶出的成分。常用为十二烷基硫酸钠(常用范围为0.2-6%,与总重量比)。
本发明中所述的维多氟拉迪莫包括其原型、药学上可接受的盐或者含维多氟拉迪莫的制剂。
本发明中的所述β-内酰胺类抗生素的代表药物是美罗培南,其分子式为:C17H25N3O5S,分子量为:383.5。
本发明中所述的NDM-1酶是从自然界中提取或用基因工程菌制备得到重组NDM-1酶。
本发明中所述的“致病菌”优选为革兰氏阴性和阳性致病菌,更优先为NDM-1阳性菌。
维多氟拉迪莫,别名:SC12267、4SC-101、2-[[(3-氟代-3'-甲氧基[1,1'-联二苯]-4-基)氨基]羰基]-1-环戊烯-1-羧酸;其分子式为:C20H18FNO4,分子量为:355.4,其结构式如下:
本发明通过NDM-1酶抑制试验、酶抑制率与半抑制浓度测定、棋盘法测定最小抑菌浓度以及时间-杀菌曲线法等试验验证维多氟拉迪莫能够抑制NDM-1的活性并恢复美罗培南对携带NDM-1耐药菌的抗菌活性,用于治疗细菌感染性疾病,具有广泛的医用用途。
本发明整体技术方案详述
本试验以蛋白质数据库中NDM-1(PDB:4EY2)晶体结构为靶标蛋白,应用计算机辅助药物设计软件GLIDE和MAESTRO,采用分子对接的方法计算维多氟拉迪莫与NDM-1配体结合部位的结合自由能。对接产物结合自由能小于-10.0Kcal/mol,且维多氟拉迪莫紧密结合在NDM-1以锌离子为中心的活性区域,因此维多氟拉迪莫被视为具有潜在NDM-1抑制作用的候选化合物。
在此基础上,本发明进行了维多氟拉迪莫对NDM-1酶抑制活性的检测试验,检测结果表明维多氟拉迪莫能够剂量依赖地抑制NDM-1酶的活性,最大抑制率为79.2%,IC50为18.9±1.0μM。
最小抑菌浓度试验结果表明维多氟拉迪莫单独使用不具备抑菌效果,与美罗培南联合使用能够使美罗培南对NDM-1阳性大肠杆菌MIC值降低32倍。FIC指数表明维多氟拉迪莫与美罗培南联合使用,对抑制产NDM-1的菌株有显著的协同作用。
根据时间-杀菌曲线可见,维多氟拉迪莫联用美罗培南能够显著抑制NDM-1阳性大肠杆菌的生长。
附图说明
图1为维多氟拉迪莫-NDM-1复合物体系活性区域结合模式图。
图2为维多氟拉迪莫联用美罗培南对NDM-1阳性大肠杆菌的时间杀菌曲线。
具体实施方式
以下结合具体实施例来进一步描述本发明,本发明的优点和特点将会随着描述而更为清楚。但这些实施例仅是范例性的,并不对本发明的范围构成任何限制。本领域技术人员应该理解的是,在不偏离本发明的精神和范围下可以对本发明的细节和形式进行修改或替换,但这些修改和替换均落入本发明的保护范围内。
试验例1维多氟拉迪莫与靶蛋白NDM-1的分子对接试验
本试验以蛋白质数据库中NDM-1(PDB:4EY2)晶体结构为靶标蛋白,应用计算机辅助药物设计软件GLIDE和MAESTRO,采用分子对接的方法计算维多氟拉迪莫与NDM-1配体结合部位的结合自由能。分子对接结果发现,对接产物结合自由能小于-10.0Kcal/mol,且维多氟拉迪莫紧密结合在NDM-1以锌离子为中心的活性区域(图1),因此,维多氟拉迪莫被视为具有潜在NDM-1抑制作用的候选化合物。
试验例2 NDM-1蛋白的表达及分离纯化
通过EcoRⅠ和XhoⅠ酶切位点,将blaNDM-1的基因序列插入到pET32(α)质粒中,构建pET32(α)-NDM-1重组质粒,经DNA测序验证,在连接过程中blaNDM-1基因无突变。
把重组质粒转入大肠杆菌BL21(DE3)感受态细胞中,通过氨苄青霉素平板进行筛选,挑选单克隆菌落,接种到5mL LB液体培养基,37℃180rpm振荡过夜,将50%甘油与菌液为1:1的比例混合,于-80℃保存工程菌E.coli BL21(DE3)-pET32(α)-NDM-1。
将工程菌在含有氨苄青霉素的LB培养基中,37℃、180rpm培养至OD值为0.6-0.8的对数生长期,应用终浓度为1mM的异丙基-β-D-硫代半乳糖苷(IPTG),37℃诱导诱导4.5h,4℃离心收集细菌。
将收集的细菌用磷酸盐缓冲液(PBS,pH=8.0)重悬,超声细胞破碎仪冰浴破碎菌液,将细菌裂解液离心,收集上清过Ni-NTA His标签亲和层析柱,使用0、10、20、40、250mM浓度咪唑梯度洗脱,分离纯化NDM-1蛋白。最后将NDM-1蛋白使用分子截留量为10KD透析袋,透析36h除盐,使用分子截留量10KD超滤管浓缩,SDS-PAGE印记检测NDM-1蛋白表达纯化结果,获得纯度大于90%的NDM-1重组蛋白。
试验例3维多氟拉迪莫对NDM-1酶抑制试验
酶抑制活性反应体系中包含120μM美罗培南为底物、10mM 4-羟乙基哌嗪乙磺酸(HEPES,pH=8.0)为缓冲液、NDM-1酶量为3.0U及不同浓度梯度的维多氟拉迪莫溶液,30℃条件下孵育15min,利用酶标仪295nm波长检测酶活性。同时用EDTA做阳性对照,DMSO做阴性对照,空白对照组既不含抑制剂也不含有酶,作为体系的底值。反应在96孔板中进行,每个反应均设置3个复孔。
具体过程如下:
首先将NDM-1酶用缓冲液配置成浓度3.0U的溶液,置于30℃孵育10min,使得Zn2+充分占据活性中心;将维多氟拉迪莫溶于缓冲液中,配制成100mM浓度的母液,再将母液梯度稀释,加入到NDM-1酶中,30℃孵育10min,使维多氟拉迪莫与酶充分结合;在96孔板反应体系中加入50μL美罗培南,置于酶标仪中振荡混匀,30℃孵育15min检测295nm紫外吸收变化。计算不同浓度的维多氟拉迪莫对NDM-1酶水解底物的抑制率,抑制率的计算公式如下:
抑制率(%)=(1-维多氟拉迪莫样品酶反应速率/阴性对照孔的平均酶反应速率)×100%
计算维多氟拉迪莫对NDM-1的半抑制浓度IC50值,结果表明维多氟拉迪莫能够剂量依赖地抑制NDM-1酶的活性,最大抑制率为79.2%,IC50为18.9±1.0μM。
试验例4最小抑菌浓度试验
取2μL NDM-1阳性大肠杆菌接种至5ml LB培养基中,37℃、180rpm振荡培养活化约12h至细菌处于对数生长期后期。取菌液至MH肉汤培养基中,调整菌液浓度至5×106CFU/mL,采用微量肉汤稀释法分别进行维多氟拉迪莫、美罗培南(浓度梯度为1-2048μg/mL)的药敏试验,同时设置不含美罗培南的菌悬液作阳性对照,MH肉汤作阴性对照。将96孔板在37℃培养24h后,读取MIC结果,均平行操作3次,药物MIC值为96孔板中浑浊孔的前一个澄清孔的药物浓度。
取上述活化培养的菌液,采用棋盘法配96孔板,同时检测77种可能的浓度组合,加入不同浓度组合的维多氟拉迪莫、美罗培南,并将96孔板置于37℃恒温生化培养箱中孵育24h,进行维多氟拉迪莫、美罗培南二者联用抗NDM-1阳性菌的抑菌活性实验,确定二者联合应用最小抑菌浓度MIC值。同时设置阴性对照组和阳性对照组,均平行操作3次,根据MIC值计算部分抑菌浓度指数FIC值,计算方法如下:
FIC=MIC(美罗培南联用)/MIC(美罗培南单用)+MIC(维多氟拉迪莫联用)/MIC(维多氟拉迪莫单用)
当FICI≤0.5,二者为协同作用;0.5<FICI≤4,二者为无关作用;FICI>4,两者为拮抗作用。
表1美罗培南联用维多氟拉迪莫对表达NDM-1阳性大肠杆菌的MIC值及FIC值
最小抑菌浓度试验结果表明维多氟拉迪莫单独使用不具备抑菌效果,与美罗培南联合使用能够使美罗培南对NDM-1阳性大肠杆菌MIC值降低32倍。FIC指数表明维多氟拉迪莫与美罗培南联合使用,对抑制产NDM-1的菌株有显著的协同作用。
试验例5时间-杀菌曲线试验
从NDM-1阳性大肠杆菌的纯培养平皿上挑取单菌落于MH肉汤培养基中37℃培养6~8h,取细菌培养物,用麦氏比浊仪以无菌生理盐水调节菌液浓度至5×107CFU/mL,再以无菌MH肉汤10倍稀释,使其终浓度为106CFU/mL。
设置无抗生素空白对照组、4μg/mL美罗培南组、4μg/mL美罗培南与128μg/mL维多氟拉迪莫联用组。试验组与对照组在同样菌液浓度的条件下于37℃培养,分别于0、1、3、5、7、9、11h从各组取出定量培养液转种于相应琼脂培养基中,37℃培养18~24h后作菌落计数,以菌落数的对数为纵坐标,以培养时间为横坐标,绘制时间-杀菌曲线(图2)。
根据图2的时间-杀菌曲线可见,维多氟拉迪莫联用美罗培南能够显著抑制NDM-1阳性大肠杆菌的生长。
Claims (4)
1.维多氟拉迪莫在制备新德里金属-β-内酰胺酶-1抑制剂中的用途。
2.维多氟拉迪莫在制备抗生素保护剂中的用途;所述抗生素是β-内酰胺类抗生素。
3.按照权利要求2所述的用途,其特征在于:所述β-内酰胺类抗生素包括碳青霉烯类、头孢菌素类和青霉素类。
4.按照权利要求1或2所述的用途,其特征在于:所述维多氟拉迪莫包括其原型、药学上可接受的盐或者含维多氟拉迪莫的制剂。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111065294.2A CN113842380B (zh) | 2021-09-12 | 2021-09-12 | 维多氟拉迪莫作为ndm-1抑制剂或抗生素保护剂的新用途 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111065294.2A CN113842380B (zh) | 2021-09-12 | 2021-09-12 | 维多氟拉迪莫作为ndm-1抑制剂或抗生素保护剂的新用途 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113842380A CN113842380A (zh) | 2021-12-28 |
CN113842380B true CN113842380B (zh) | 2024-03-19 |
Family
ID=78973633
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111065294.2A Active CN113842380B (zh) | 2021-09-12 | 2021-09-12 | 维多氟拉迪莫作为ndm-1抑制剂或抗生素保护剂的新用途 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113842380B (zh) |
Family Cites Families (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2019074870A1 (en) * | 2017-10-09 | 2019-04-18 | The Broad Institute, Inc. | COMPOSITIONS AND METHODS FOR DISCOVERING COMBINATORY DRUG IN DROPLETS OF THE NANOLITRE ORDER |
-
2021
- 2021-09-12 CN CN202111065294.2A patent/CN113842380B/zh active Active
Also Published As
Publication number | Publication date |
---|---|
CN113842380A (zh) | 2021-12-28 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
AU2008258152A1 (en) | Broad spectrum inhibitors | |
EP3447058A1 (en) | Novel broad-spectrum -lactamase inhibitor | |
US11299514B2 (en) | Antimicrobial peptide AS-hepc3(48-56) of Acanthopagrus schlegelii and method thereof | |
CN113842380B (zh) | 维多氟拉迪莫作为ndm-1抑制剂或抗生素保护剂的新用途 | |
CN113712975B (zh) | 氨磷汀作为ndm-1抑制剂或抗生素保护剂的新用途 | |
CN113842379B (zh) | 倍他洛尔作为ndm-1抑制剂或抗生素保护剂的新用途 | |
Mitsuhashi | Drug resistance in bacteria: history, genetics and biochemistry | |
JPS599155B2 (ja) | 抗生物質 | |
CN115192593A (zh) | 柔红霉素在治疗多重耐药菌感染疾病中的应用 | |
CN113750084A (zh) | 酞磺醋胺作为ndm-1抑制剂或抗生素保护剂的新用途 | |
CN105147652B (zh) | 蒽贝素或蒽贝素类化合物在抑制细菌中的新用途 | |
CN109200038B (zh) | 异甘草素在制备抑菌、干预生物被膜及治疗奶牛乳房炎的药物中的用途 | |
CN116236475A (zh) | 桑黄素在制备ndm-1酶抑制剂中的医用用途 | |
KR102457866B1 (ko) | 다제내성 박테리아에서 생성되는 메탈로-베타-락타마제에 대한 신규 저해제 및 이의 제조방법 | |
Powell et al. | In-vitro susceptibility of Haemophilus influenzae to meropenem compared with imipenem, five other β-lactams, chloramphenicol and ciprofloxacin | |
Karaman et al. | Antibacterial activity of novel prodrugs of amoxicillin and cephalexin | |
WO2010142027A1 (en) | Guanine riboswitch binding compounds and their use as antibiotics | |
CN110787164A (zh) | 奥替尼啶在抑制乙酰基转移酶和抗分枝杆菌感染中的应用 | |
Tong et al. | Antibiotics synthesis: history and modern applications | |
CN116688090A (zh) | 一种增敏耐药菌的药物组合物及其应用 | |
CN113382734A (zh) | 一种治疗耐碳青霉烯类抗生素鲍曼不动杆菌感染的组合物 | |
CN118126132A (zh) | 多肽及其与头孢噻肟舒巴坦的组合 | |
CN117964741A (zh) | 具有抑菌消炎活性的重组人vi型胶原蛋白及眼科外用药 | |
CN118001290A (zh) | 化合物0407-0013作为ndm-1抑制剂在抗菌中的应用 | |
CN118141808A (zh) | 临床药物在抑制具核梭状杆菌生长中的应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
GR01 | Patent grant | ||
GR01 | Patent grant |