CN113842379A - New application of betaxolol as NDM-1 inhibitor or antibiotic protective agent - Google Patents
New application of betaxolol as NDM-1 inhibitor or antibiotic protective agent Download PDFInfo
- Publication number
- CN113842379A CN113842379A CN202111065289.1A CN202111065289A CN113842379A CN 113842379 A CN113842379 A CN 113842379A CN 202111065289 A CN202111065289 A CN 202111065289A CN 113842379 A CN113842379 A CN 113842379A
- Authority
- CN
- China
- Prior art keywords
- betaxolol
- ndm
- beta
- antibiotic
- inhibitor
- 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.)
- Granted
Links
- 101000740455 Klebsiella pneumoniae Metallo-beta-lactamase type 2 Proteins 0.000 title claims abstract description 58
- 229960004324 betaxolol Drugs 0.000 title claims abstract description 57
- 230000003115 biocidal effect Effects 0.000 title claims abstract description 14
- 239000003112 inhibitor Substances 0.000 title claims abstract description 13
- 239000003223 protective agent Substances 0.000 title claims abstract description 8
- NWIUTZDMDHAVTP-UHFFFAOYSA-N betaxolol Chemical compound C1=CC(OCC(O)CNC(C)C)=CC=C1CCOCC1CC1 NWIUTZDMDHAVTP-UHFFFAOYSA-N 0.000 title abstract 6
- 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 claims abstract description 22
- 229960002260 meropenem Drugs 0.000 claims abstract description 22
- 239000003782 beta lactam antibiotic agent Substances 0.000 claims abstract description 20
- 239000002132 β-lactam antibiotic Substances 0.000 claims abstract description 20
- 229940124586 β-lactam antibiotics Drugs 0.000 claims abstract description 20
- 241000894006 Bacteria Species 0.000 claims abstract description 18
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 14
- CHDPSNLJFOQTRK-UHFFFAOYSA-N betaxolol hydrochloride Chemical compound [Cl-].C1=CC(OCC(O)C[NH2+]C(C)C)=CC=C1CCOCC1CC1 CHDPSNLJFOQTRK-UHFFFAOYSA-N 0.000 claims description 50
- 230000002401 inhibitory effect Effects 0.000 claims description 15
- 244000052616 bacterial pathogen Species 0.000 claims description 8
- 239000000203 mixture Substances 0.000 claims description 8
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- 229940041011 carbapenems Drugs 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 229930186147 Cephalosporin Natural products 0.000 claims description 3
- 229930182555 Penicillin Natural products 0.000 claims description 3
- 229940124587 cephalosporin Drugs 0.000 claims description 3
- 150000001780 cephalosporins Chemical class 0.000 claims description 3
- 150000002960 penicillins Chemical class 0.000 claims description 3
- 150000003839 salts Chemical class 0.000 claims description 3
- 239000002671 adjuvant Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 229920004943 Delrin® Polymers 0.000 claims 1
- 101000978430 Gibberella moniliformis (strain M3125 / FGSC 7600) Gamma-lactamase MBL1 Proteins 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 abstract description 20
- 108090000790 Enzymes Proteins 0.000 abstract description 20
- 238000012360 testing method Methods 0.000 abstract description 17
- 230000005764 inhibitory process Effects 0.000 abstract description 15
- 241000588724 Escherichia coli Species 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 9
- 230000000694 effects Effects 0.000 abstract description 9
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 8
- 229940079593 drug Drugs 0.000 abstract description 6
- 238000004659 sterilization and disinfection Methods 0.000 abstract description 6
- 230000007062 hydrolysis Effects 0.000 abstract description 3
- 238000006460 hydrolysis reaction Methods 0.000 abstract description 3
- 230000035945 sensitivity Effects 0.000 abstract description 2
- 238000003113 dilution method Methods 0.000 abstract 1
- 230000001580 bacterial effect Effects 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 229940088710 antibiotic agent Drugs 0.000 description 6
- 238000003032 molecular docking Methods 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 6
- 239000011230 binding agent Substances 0.000 description 5
- 239000007788 liquid Substances 0.000 description 5
- 108090000623 proteins and genes Proteins 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 108090000204 Dipeptidase 1 Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 102000006635 beta-lactamase Human genes 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000001963 growth medium Substances 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
- 230000000144 pharmacologic effect Effects 0.000 description 4
- 239000013612 plasmid Substances 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 206010059866 Drug resistance Diseases 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
- 238000012258 culturing Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 239000010413 mother solution Substances 0.000 description 3
- 239000011148 porous material Substances 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
- 238000009631 Broth culture Methods 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 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
- 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
- 239000007853 buffer solution Substances 0.000 description 2
- 238000004364 calculation method Methods 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 210000004027 cell Anatomy 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
- 238000001514 detection method Methods 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
- 239000007884 disintegrant Substances 0.000 description 2
- 231100000673 dose–response relationship Toxicity 0.000 description 2
- 238000010799 enzyme reaction rate Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 230000001939 inductive effect Effects 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- 239000004615 ingredient Substances 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
- 238000002372 labelling Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 108060004734 metallo-beta-lactamase Proteins 0.000 description 2
- 102000020235 metallo-beta-lactamase Human genes 0.000 description 2
- 239000000843 powder 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
- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 230000002195 synergetic effect Effects 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
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 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
- 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
- 208000007530 Essential hypertension Diseases 0.000 description 1
- 239000007995 HEPES buffer Substances 0.000 description 1
- 101100111649 Klebsiella pneumoniae blaNDM-1 gene Proteins 0.000 description 1
- 239000012880 LB liquid culture medium Substances 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 206010030348 Open-Angle Glaucoma Diseases 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
- 102000007056 Recombinant Fusion Proteins Human genes 0.000 description 1
- 108010008281 Recombinant Fusion Proteins 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
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 239000000332 adrenergic beta-1 receptor antagonist Substances 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
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 238000002815 broth microdilution Methods 0.000 description 1
- 229910001424 calcium ion Inorganic materials 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
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 230000008859 change Effects 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
- 238000003776 cleavage reaction Methods 0.000 description 1
- 238000005520 cutting process Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007865 diluting Methods 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
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 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
- 210000003038 endothelium Anatomy 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
- 239000003889 eye drop Substances 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
- -1 glidants Substances 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
- 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
- 230000002779 inactivation Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009249 intrinsic sympathomimetic activity Effects 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000006166 lysate Substances 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
- 239000002609 medium Substances 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000002156 mixing 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
- 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
- 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
- 201000006366 primary open angle glaucoma Diseases 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000012216 screening Methods 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
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 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
- 239000003765 sweetening agent Substances 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
- 238000000108 ultra-filtration Methods 0.000 description 1
- 238000009736 wetting Methods 0.000 description 1
- 239000011701 zinc Substances 0.000 description 1
Images
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
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
-
- 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)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (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)
Abstract
The invention discloses a new application of betaxolol as an NDM-1 inhibitor or an antibiotic protective agent, belonging to the field of new medical application of betaxolol. According to the invention, through NDM-1 enzyme inhibition tests, a trace chessboard dilution method, time-sterilization curves and other tests, betaxolol can obviously inhibit the activity of NDM-1 and recover the antibacterial activity of meropenem on NDM-1-producing escherichia coli. The invention determines that the betaxolol can be used as an NDM-1 inhibitor, and the combined application of the betaxolol and the beta-lactam antibiotics can reduce or even eliminate the hydrolysis of NDM-1 to the beta-lactam antibiotics and restore the sensitivity of drug-resistant bacteria to the beta-lactam antibiotics.
Description
Technical Field
The invention relates to a new pharmacological application of betaxolol, in particular to a new pharmacological application of betaxolol as an NDM-1 inhibitor or an antibiotic protective agent, belonging to the field of new pharmacological activity of betaxolol.
Background
The beta-lactam antibiotics have strong bactericidal activity, low toxicity and wide adaptation diseases, and are important medicaments for treating infectious diseases caused by bacteria at present. Beta-lactam antibiotics include carbapenems, cephalosporins, penicillins, and the like, all of which structurally have a beta-lactam ring that exerts antibacterial activity. With the widespread use of beta-lactam antibiotics, more and more bacteria are developing beta-lactamase mediated resistance.
The production of beta-lactamase, which catalyzes the cleavage of the C-N bond at the beta-lactam ring in beta-lactam antibiotics to open the ring, resulting in inactivation of the antibiotic, is one of the important mechanisms for inducing bacterial resistance. Based on amino acid sequence homology, beta-lactamase can be divided into serine-beta-lactamase and metallo-beta-lactamase, and the serine-beta-lactamase plays a catalytic role depending on serine of an active center and can be inhibited by clinically used antibiotics such as clavulanic acid, sulbactam, tazobactam and the like. The metal beta-lactamase plays a catalytic role by depending on zinc ions of an active center, can hydrolyze all beta-lactam antibiotics including carbapenems, widely exists in various gram-negative and positive pathogenic bacteria, and has no clinically effective inhibitor.
In 8 months 2010, a new Delhi metallo-beta-lactamase-1 (NDM-1) which hydrolyzes carbapenem drugs is reported in a J.Lancet.Scent, and is called as 'super bacteria' because NDM-1-producing bacteria have wide drug resistance to cause difficult infection treatment. The blaNDM-1 gene is positioned on a plasmid, can be independently replicated outside chromosomes and can be horizontally transferred among different strains, so that strains which are originally sensitive to antibiotics can obtain drug resistance. NDM-1 is metallo-beta-lactamase which is discovered in recent years and has the widest influence range and the most serious harm degree, shows high drug resistance to almost all antibiotics, only tigecycline and polymyxin have certain inhibition effect on the antibiotics, and the continuously evolved mutant strains make clinical treatment harder. NDM-1 can hydrolyze beta-lactam antibiotics commonly used in clinic, and the inhibitor can inhibit the activity of NDM-1 enzyme, so that the beta-lactam antibiotics are protected, and the antibacterial effect of the beta-lactam antibiotics is recovered, therefore, the search for the inhibitor of NDM-1 is the most urgent requirement for inhibiting infection caused by 'super bacteria'.
Betaxolol is a beta 1 adrenergic receptor blocker, has calcium ion antagonism, no intrinsic sympathomimetic activity and weak membrane stabilization, and is mainly used for treating primary hypertension and open-angle glaucoma clinically. Until now, no report that betaxolol can be used as an NDM-1 inhibitor is found at home and abroad.
Disclosure of Invention
The invention mainly aims to provide a new application of betaxolol as an NDM-1 inhibitor or an antibiotic protective agent.
In order to achieve the above object, the technical solution adopted by the present invention comprises:
on the one hand, the invention discloses a new pharmacological application of betaxolol as an NDM-1 inhibitor, namely, the hydrolysis of NDM-1 on beta-lactam antibiotics is inhibited, and the antibacterial activity of the beta-lactam antibiotics on NDM-1-carrying positive bacteria is recovered. Thus, betaxolol can be used as an antibiotic protectant, especially as a protectant of beta-lactam antibiotics.
The invention provides a pharmaceutical composition for inhibiting pathogenic bacteria, which comprises an effective amount of antibiotics, an antibiotic protective agent and a pharmaceutically acceptable carrier or auxiliary material, wherein the antibiotics are preferably beta-lactam antibiotics; the antibiotic protective agent is betaxolol.
The pharmaceutical composition for inhibiting pathogenic bacteria is prepared into clinically common preparations according to the conventional preparation method in the field, such as powder, granules, tablets, capsules, injections and the like, and is introduced into muscle, endothelium, subcutaneous, intravenous and mucosal tissues by injection, oral administration, nasal drip, eye drop, physical or chemical mediated methods, or is mixed or coated by other substances and then is introduced into the body.
The carrier or the auxiliary material refers to a carrier or an auxiliary material which is conventional in the pharmaceutical field, such as: diluents, disintegrants, lubricants, excipients, binders, glidants, fillers, surfactants, and the like; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
The diluent may be one or more ingredients that increase the weight and volume of the tablet; common diluents include lactose, starch, pregelatinized starch, microcrystalline cellulose, sorbitol, mannitol, and inorganic calcium salts. The most common of them are lactose, starch, microcrystalline cellulose.
The disintegrant can be one or more of crosslinked polyvinylpyrrolidone (with a total weight ratio of 2-6%), crosslinked sodium carboxymethylcellulose (with a total weight ratio of 2-6%), alginic acid (with a total weight ratio of 2-5%), and microcrystalline cellulose (with a total weight ratio of 5-15%). Wherein the preferred ratio is crosslinked polyvinylpyrrolidone (2-7% by weight) and crosslinked sodium carboxymethylcellulose (2-6% by weight). Most preferably crosslinked polyvinylpyrrolidone (in a ratio of 2-6% by weight relative to the total weight).
The lubricant comprises one or a mixture of stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, talcum powder and hydrogenated vegetable oil. Magnesium stearate is most preferred. The amount of the lubricant is in the range of 0.10 to 1% (by total weight), and is generally 0.25 to 0.75%, and preferably 0.5 to 0.7%.
The binder may be one or more ingredients that facilitate granulation. It may be starch slurry (10-30% by weight of the total binder), hydroxypropyl methylcellulose (2-5% by weight of the total binder), polyvinylpyrrolidone (2-20% by weight of the total binder), preferably ethanol aqueous solution of polyvinylpyrrolidone, and most preferably 50% ethanol aqueous solution of polyvinylpyrrolidone.
The glidant can be one or a mixture of more of superfine silica gel powder, talcum powder and magnesium trisilicate.
The surfactant may be one or more components that improve wetting and increase drug dissolution. Sodium lauryl sulfate is often used (the usual range is 0.2-6% by weight, based on the total weight).
The betaxolol of the present invention includes prototypes, pharmaceutically acceptable salts thereof, or betaxolol-containing formulations.
A representative drug of the beta-lactam antibiotics in the present invention is meropenemThe molecular formula is as follows: c17H25N3O5S, molecular weight is: 383.5.
the NDM-1 enzyme is a recombinant NDM-1 enzyme extracted from nature or prepared by using genetic engineering bacteria.
The pathogenic bacteria in the invention are preferably gram-negative or positive pathogenic bacteria, and more preferably NDM-1 positive bacteria.
Betaxolol, alternative name: 1- [4- [2- (cyclopropylmethoxy) ethyl]Phenoxy radical]-3- (isopropylamino) propan-2-ol, bepotolol, duomedoxomil. The molecular formula is as follows: c18H29NO3Molecular weight: 307.43. white crystalline solid, melting point 61-63 deg.C, strong fat solubility, almost completely absorbed after oral administration, high bioavailability, and long half-life, and has the following structural formula:
according to the invention, through NDM-1 enzyme inhibition test, enzyme inhibition rate and half inhibition concentration determination, chessboard method determination minimum inhibitory concentration, time-sterilization curve method and the like, betaxolol is verified to be capable of inhibiting the activity of NDM-1, and the antibacterial activity of meropenem on drug-resistant bacteria carrying NDM-1 is recovered, so that the betaxolol can be used for treating bacterial infectious diseases and has wide medical application.
Detailed description of the invention
The invention uses NDM-1 (PDB: 4EY2) crystal structure in protein database as target protein, applies computer aided drug design software GLIDE and MAESTRO, and calculates the binding free energy of betaxolol and NDM-1 ligand binding site by molecular docking method. The docking product binding free energy is less than-10.0 Kcal/mol, and betaxolol is tightly bound in the active region of NDM-1 centered on zinc ion, so that betaxolol is considered as a candidate compound with potential NDM-1 inhibition effect.
On the basis, the invention carries out the detection test of betaxolol on the NDM-1 enzyme inhibition activity, and the detection result shows that the betaxolol can inhibit the NDM-1 enzyme activity in a dose-dependent manner, the maximum inhibition rate is 93.2 percent, and the IC50 is 19.3 +/-0.9 mu M.
The test result of the minimum inhibitory concentration shows that betaxolol has no inhibitory effect when used alone, and the combination of betaxopenem and meropenem can reduce the MIC value of the meropenem to NDM-1 positive escherichia coli by 32 times. The FIC index shows that the betaxolol and the meropenem are combined to have a remarkable synergistic effect on inhibiting the strain producing NDM-1.
According to the test result of the time-sterilization curve, the betaxolol combined with the meropenem can completely kill NDM-1 positive escherichia coli within 5 hours.
Drawings
FIG. 1 is a schematic diagram of the combination of active regions of a betaxolol-NDM-1 complex system.
FIG. 2 is a time sterilization curve of betaxolol in combination with meropenem on NDM-1 positive E.coli.
Detailed Description
The invention is further described below in conjunction with specific embodiments, the advantages and features of which will become apparent from the description. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be within the scope of the invention.
Test example 1 molecular docking test of betaxolol with target protein NDM-1
The experiment uses the crystal structure of NDM-1 (PDB: 4EY2) in a protein database as a target protein, applies computer-aided drug design software GLIDE and MAESTRO, and calculates the binding free energy of the betaxolol and NDM-1 ligand binding site by adopting a molecular docking method. Molecular docking results found that the docking product binding free energy was less than-10.0 Kcal/mol, and that betaxolol was tightly bound in the active region of NDM-1 centered on zinc ion (fig. 1), therefore betaxolol was considered as a candidate compound with potential NDM-1 inhibitory effect.
Experimental example 2 expression of NDM-1 protein and isolation and purification
The gene sequence of blaNDM-1 is inserted into pET32 (alpha) plasmid through EcoRI and Xho I enzyme cutting sites to construct pET32 (alpha) -NDM-1 recombinant plasmid, and DNA sequencing verifies that the blaNDM-1 gene has no mutation in the connection process.
The recombinant plasmid is transferred into escherichia coli BL21(DE3) competent cells, screening is carried out through an ampicillin plate, a monoclonal colony is selected and inoculated into 5mL LB liquid culture medium, shaking is carried out at 37 ℃ and 180rpm overnight, 50% glycerol and bacterial liquid are mixed according to the proportion of 1:1, and the engineering bacteria E.coli BL21(DE3) -pET32 (alpha) -NDM-1 is preserved at-80 ℃.
Culturing the engineering bacteria in LB culture medium containing ampicillin at 37 deg.C and 180rpm to logarithmic growth phase with OD value of 0.6-0.8, inducing with isopropyl-beta-D-thiogalactoside (IPTG) with final concentration of 1mM at 37 deg.C for 4.5h, and centrifuging at 4 deg.C to collect bacteria.
The collected bacteria were resuspended in phosphate buffer (PBS, pH 8.0), the bacterial suspension was disrupted by an ultrasonic cell disruptor in ice bath, the bacterial lysate was centrifuged, the supernatant was collected and passed through a Ni-NTA His tag affinity column, and NDM-1 protein was isolated and purified by gradient elution using 0, 10, 20, 40, and 250mM imidazole. And finally, carrying out dialysis on the NDM-1 protein for 36h by using a dialysis bag with the molecular cut-off of 10KD to remove salt, concentrating by using an ultrafiltration tube with the molecular cut-off of 10KD, and detecting an NDM-1 protein expression and purification result by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) imprinting to obtain the NDM-1 recombinant protein with the purity of more than 90%.
Test example 3 betaxolol inhibition test for NDM-1 enzyme
The enzyme inhibition reaction system comprises 120 mu M of meropenem as a substrate, 10mM of 4-hydroxyethyl piperazine ethanesulfonic acid (HEPES, pH 8.0) as a buffer solution, 3.0U of NDM-1 enzyme and betaxolol solutions with different concentration gradients. Incubating for 15min at 30 ℃, and detecting the enzyme activity by utilizing the 295nm wavelength of an enzyme-labeling instrument. Meanwhile, EDTA is used as a positive control, DMSO is used as a negative control, and a blank control group does not contain an inhibitor or an enzyme and is used as a bottom value of the system. Reactions were performed in 96-well plates, each reaction provided 3 replicate wells.
The specific process is as follows:
NDM-1 enzyme was first prepared to concentration with a buffer3.0U of solution, incubated at 30 ℃ for 10min to allow Zn to form2+Fully occupy the active center; dissolving betaxolol in buffer solution to prepare mother solution with the concentration of 100mM, then diluting the mother solution in a gradient manner, adding the diluted mother solution into NDM-1 enzyme, and incubating for 10min at 30 ℃ to ensure that the betaxolol and the enzyme are fully combined; adding 50 mu L of meropenem into a 96-pore plate reaction system, placing the mixture into an enzyme labeling instrument, oscillating and uniformly mixing the mixture, and incubating the mixture for 15min at the temperature of 30 ℃ to detect the 295nm ultraviolet absorption change. Calculating the inhibition rate of betaxolol with different concentrations on NDM-1 enzyme hydrolysis substrate, wherein the calculation formula of the inhibition rate is as follows:
inhibition (%). ratio (1-betaxolol sample enzyme reaction rate/average enzyme reaction rate of negative control well) × 100%
The half inhibition concentration IC50 value of betaxolol on NDM-1 is calculated, and the result shows that betaxolol can inhibit the activity of NDM-1 enzyme in a dose-dependent manner, the maximum inhibition rate is 93.2%, and the IC50 is 19.3 +/-0.9 mu M.
Test example 4 test for minimum inhibitory concentration
2 mu.L of NDM-1 positive Escherichia coli is inoculated into 5mL of LB culture medium, and the culture is carried out at 37 ℃ and 180rpm shaking for activation for about 12h until the bacteria are in the late logarithmic phase. Taking the bacterial liquid into MH broth culture medium, adjusting the concentration of the bacterial liquid to 5 × 106CFU/mL, adopting trace broth dilution method to respectively carry out drug sensitivity tests of betaxolol and meropenem (concentration gradient is 1-2048 mu g/mL), and meanwhile, setting bacterial suspension without meropenem as a positive control and MH broth as a negative control. After the 96-well plate is cultured for 24h at 37 ℃, MIC results are read and are all operated in parallel for 3 times, and the MIC value of the medicine is the medicine concentration of a clear well in front of a turbid well in the 96-well plate.
Taking the activated and cultured bacterial liquid, matching a 96-pore plate by adopting a chessboard method, simultaneously detecting 77 possible concentration combinations, adding betaxolol and meropenem with different concentration combinations, placing the 96-pore plate in a constant-temperature biochemical incubator at 37 ℃ for incubation for 24h, carrying out an antibacterial activity experiment of the betaxolol and meropenem combined anti-NDM-1 positive bacteria, and determining the minimum inhibitory concentration MIC value of the two combined applications. And simultaneously setting a negative control group and a positive control group, performing parallel operation for 3 times, and calculating a part of antibacterial concentration index FIC value according to the MIC value by the following calculation method:
FIC ═ MIC (combined meropenem)/MIC (single meropenem) + MIC (combined betaxolol)/MIC (single betaxolol)
When FICI is less than or equal to 0.5, the FICI and the FICI act synergistically; 0.5< FICI is less than or equal to 4, and the two are unrelated; FICI >4, both antagonistic.
TABLE 1 MIC and FIC values of meropenem in combination with betaxolol for NDM-1 expressing positive E.coli
The test result of the minimum inhibitory concentration shows that betaxolol has no inhibitory effect when used alone, and the combination of betaxopenem and meropenem can reduce the MIC value of the meropenem to NDM-1 positive escherichia coli by 32 times. FIC index shows that betaxolol and meropenem are combined for use, and have obvious synergistic effect on inhibiting NDM-1 producing strains.
Test example 5 time-Sterilization Curve test
Selecting single colony from pure culture plate of NDM-1 positive Escherichia coli, inoculating in MH broth culture medium at 37 deg.C, culturing for 6-8 hr, collecting bacterial culture, and adjusting bacterial liquid concentration to 5 × 10 with sterile physiological saline by McLee turbidimeter7CFU/mL, and 10-fold dilution in sterile MH broth to a final concentration of 106CFU/mL。
A drug-free blank control group, a 2 mu g/mL meropenem and 64 mu g/mL betaxolol combination group are arranged. The test group and the control group were cultured at 37 ℃ under the same concentration of bacterial solution, a quantitative culture solution was taken out from each group at 0, 1, 3, 5, 7, 9, and 11 hours, and transferred to the corresponding agar medium, and after culturing at 37 ℃ for 18 to 24 hours, the number of colonies was counted, and a time-sterilization curve was plotted with the logarithm of the number of colonies as the ordinate and the culture time as the abscissa (FIG. 2).
As can be seen from the time-kill curve of FIG. 2, betaxolol in combination with meropenem was able to completely kill NDM-1 positive E.coli in 5 h.
Claims (10)
1. Use of betaxolol in the preparation of a new delrin metallo-beta-lactamase-1 inhibitor.
2. The use of betaxolol in the preparation of an antibiotic protectant.
3. Use according to claim 2, characterized in that: the antibiotic is a beta-lactam antibiotic.
4. Use according to claim 3, characterized in that: the beta-lactam antibiotics comprise carbapenems, cephalosporins or penicillins.
5. Use according to claim 1 or 2, characterized in that: the betaxolol includes a prototype, a pharmaceutically acceptable salt thereof, or a formulation containing betaxolol.
6. A pharmaceutical composition for inhibiting pathogenic bacteria, comprising: a prophylactically or therapeutically effective amount of an antibiotic, an antibiotic protectant, and a pharmaceutically acceptable adjuvant or carrier; wherein the antibiotic protective agent is betaxolol.
7. The pharmaceutical composition according to claim 6, wherein: the pathogenic bacteria are bacteria.
8. The pharmaceutical composition according to claim 7, wherein: the bacteria are gram-negative or gram-positive pathogenic bacteria, preferably NDM-1 positive bacteria.
9. The pharmaceutical composition according to claim 6, wherein: the beta-lactam antibiotics comprise carbapenems, cephalosporins or penicillins.
10. The pharmaceutical composition according to claim 6 or 9, characterized in that: the beta-lactam antibiotic is meropenem.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111065289.1A CN113842379B (en) | 2021-09-12 | 2021-09-12 | New application of betaxolol as NDM-1 inhibitor or antibiotic protectant |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202111065289.1A CN113842379B (en) | 2021-09-12 | 2021-09-12 | New application of betaxolol as NDM-1 inhibitor or antibiotic protectant |
Publications (2)
Publication Number | Publication Date |
---|---|
CN113842379A true CN113842379A (en) | 2021-12-28 |
CN113842379B CN113842379B (en) | 2024-04-23 |
Family
ID=78973621
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202111065289.1A Active CN113842379B (en) | 2021-09-12 | 2021-09-12 | New application of betaxolol as NDM-1 inhibitor or antibiotic protectant |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN113842379B (en) |
Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040022844A1 (en) * | 2001-10-30 | 2004-02-05 | Steffen Hasenzahl | Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions |
CN101137369A (en) * | 2005-02-09 | 2008-03-05 | 马库赛特公司 | Formulations for ocular treatment |
CN101522174A (en) * | 2006-05-10 | 2009-09-02 | 赢创德固赛有限责任公司 | Use of roll compacted pyrogenically produced silicon dioxide in pharmaceutical compositions |
US20100261646A1 (en) * | 2007-06-21 | 2010-10-14 | Yale University | Sustained intraocular delivery of drugs from biodegradable polymeric microparticles |
US20110053848A1 (en) * | 2008-02-01 | 2011-03-03 | Ascendis Pharma As | Prodrug comprising a drug linker conjugate |
CN103006662A (en) * | 2011-09-20 | 2013-04-03 | 北京秦武田制药有限公司 | Brimonidine and betaxolol composition for local ophthalmology application |
CN105687499A (en) * | 2016-03-27 | 2016-06-22 | 济南邦文医药科技有限公司 | Betaxolol containing pharmaceutical composition for treating hypertension and preparation method thereof |
US20180185410A1 (en) * | 2016-12-05 | 2018-07-05 | Arne Holmgren | Antibiotic Compositions |
US20200121652A1 (en) * | 2017-06-16 | 2020-04-23 | The Doshisha | Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent |
-
2021
- 2021-09-12 CN CN202111065289.1A patent/CN113842379B/en active Active
Patent Citations (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040022844A1 (en) * | 2001-10-30 | 2004-02-05 | Steffen Hasenzahl | Use of granular materials based on pyrogenically produced silicon dioxide in pharmaceutical compositions |
CN101137369A (en) * | 2005-02-09 | 2008-03-05 | 马库赛特公司 | Formulations for ocular treatment |
CN101522174A (en) * | 2006-05-10 | 2009-09-02 | 赢创德固赛有限责任公司 | Use of roll compacted pyrogenically produced silicon dioxide in pharmaceutical compositions |
US20100261646A1 (en) * | 2007-06-21 | 2010-10-14 | Yale University | Sustained intraocular delivery of drugs from biodegradable polymeric microparticles |
US20110053848A1 (en) * | 2008-02-01 | 2011-03-03 | Ascendis Pharma As | Prodrug comprising a drug linker conjugate |
CN103006662A (en) * | 2011-09-20 | 2013-04-03 | 北京秦武田制药有限公司 | Brimonidine and betaxolol composition for local ophthalmology application |
CN105687499A (en) * | 2016-03-27 | 2016-06-22 | 济南邦文医药科技有限公司 | Betaxolol containing pharmaceutical composition for treating hypertension and preparation method thereof |
US20180185410A1 (en) * | 2016-12-05 | 2018-07-05 | Arne Holmgren | Antibiotic Compositions |
US20200121652A1 (en) * | 2017-06-16 | 2020-04-23 | The Doshisha | Compounds having caspase inhibitory activity, pharmaceutical agent containing said compounds and for treating or preventing corneal endothelial symptoms, disorders, or diseases, and application of said pharmaceutical agent |
Also Published As
Publication number | Publication date |
---|---|
CN113842379B (en) | 2024-04-23 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
WAISBREN et al. | A clinical appraisal of neomycin | |
AU2011373911B2 (en) | Pharmaceutical compositions comprising sulbactam and beta-lactamase inhibitor | |
AU2008258152A1 (en) | Broad spectrum inhibitors | |
EP2714034B1 (en) | Compositions comprising cefepime and tazobactam | |
Robertson et al. | Endogenous Candida oculomycosis: report of two patients treated with flucytosine | |
CN113842379B (en) | New application of betaxolol as NDM-1 inhibitor or antibiotic protectant | |
JPH05301826A (en) | Prolylendopeptidase inhibitor | |
CN113712975B (en) | New use of amifostine as NDM-1 inhibitor or antibiotic protectant | |
CN113750084B (en) | New application of phthalosulfamide as NDM-1 inhibitor or antibiotic protectant | |
CN113842380A (en) | New application of vedofluridimod as NDM-1 inhibitor or antibiotic protective agent | |
CN113750084A (en) | New application of phthalazinone sulfate as NDM-1 inhibitor or antibiotic protective agent | |
US20070042995A1 (en) | Use of acetyl-d-aminoglycosamine in treatment of local lesions and systematic symptoms related to infections of virus or bacteria | |
CN114478742B (en) | Helicobacter pylori resistant active polypeptide and application thereof | |
CN112999220B (en) | Application of alpha-lipoic acid as and/or preparing metallo-beta-lactamase inhibitor | |
CN115192593A (en) | Application of daunorubicin in treating multiple drug-resistant bacteria infection diseases | |
EP3919059A1 (en) | Composition for treating carbapenem-resistant antibiotic acinetobacter baumannii infection | |
Fuiano et al. | Effectiveness of single daily intraperitoneal administration of aztreonam and cefuroxime in the treatment of peritonitis in continuous ambulatory peritoneal dialysis (CAPD) | |
CN115414342B (en) | Application of fenbufen in preparation of medicines for killing gram-negative bacteria | |
US20050037478A1 (en) | Crystal structure of glutamate racemase (MurI) | |
CN116236475A (en) | Medical application of morin in preparation of NDM-1 enzyme inhibitor | |
CN115869309B (en) | Application of BPTU in preparation of antibacterial drugs | |
CN110787164A (en) | Application of octenidine in inhibiting acetyl transferase and resisting mycobacterial infection | |
Young et al. | Sulfacetimide: Toxicity and Efficacy in Gonorrhea and Urinary Tract Infections Preliminary Report | |
CN111374984A (en) | Application of cloxolone in resisting mycobacterium tuberculosis infection | |
CN118001290A (en) | Use of compound 0407-0013 as NDM-1 inhibitor in antibiosis |
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 |