CN107951870A - A kind of pharmaceutical composition of the suppression drug-resistant staphylococcus aureus containing resveratrol - Google Patents
A kind of pharmaceutical composition of the suppression drug-resistant staphylococcus aureus containing resveratrol Download PDFInfo
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- CN107951870A CN107951870A CN201610901103.4A CN201610901103A CN107951870A CN 107951870 A CN107951870 A CN 107951870A CN 201610901103 A CN201610901103 A CN 201610901103A CN 107951870 A CN107951870 A CN 107951870A
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- Prior art keywords
- resveratrol
- staphylococcus aureus
- compound
- resistant staphylococcus
- resistance
- Prior art date
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- QNVSXXGDAPORNA-UHFFFAOYSA-N Resveratrol Natural products OC1=CC=CC(C=CC=2C=C(O)C(O)=CC=2)=C1 QNVSXXGDAPORNA-UHFFFAOYSA-N 0.000 title claims abstract description 50
- 235000021283 resveratrol Nutrition 0.000 title claims abstract description 50
- 229940016667 resveratrol Drugs 0.000 title claims abstract description 50
- 239000003814 drug Substances 0.000 title claims abstract description 41
- 241000191967 Staphylococcus aureus Species 0.000 title claims abstract description 34
- 229940079593 drug Drugs 0.000 title claims description 24
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 8
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 title abstract description 48
- 230000001629 suppression Effects 0.000 title description 4
- 230000003115 biocidal effect Effects 0.000 claims abstract description 24
- OGJPXUAPXNRGGI-UHFFFAOYSA-N norfloxacin Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 OGJPXUAPXNRGGI-UHFFFAOYSA-N 0.000 claims abstract description 21
- 229960001180 norfloxacin Drugs 0.000 claims abstract description 21
- 229940124307 fluoroquinolone Drugs 0.000 claims abstract description 11
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 claims abstract description 9
- 230000000144 pharmacologic effect Effects 0.000 claims abstract description 4
- -1 resveratrol compound Chemical class 0.000 claims description 17
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 claims description 13
- 239000011737 fluorine Substances 0.000 claims description 13
- 229910052731 fluorine Inorganic materials 0.000 claims description 13
- SMWDFEZZVXVKRB-UHFFFAOYSA-N anhydrous quinoline Natural products N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 claims description 12
- 230000002421 anti-septic effect Effects 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 30
- 229960003085 meticillin Drugs 0.000 abstract description 13
- 230000000694 effects Effects 0.000 abstract description 9
- 108090000623 proteins and genes Proteins 0.000 abstract description 8
- HDWLUGYOLUHEMN-UHFFFAOYSA-N Dinobuton Chemical compound CCC(C)C1=CC([N+]([O-])=O)=CC([N+]([O-])=O)=C1OC(=O)OC(C)C HDWLUGYOLUHEMN-UHFFFAOYSA-N 0.000 abstract description 7
- 241000425573 Talanes Species 0.000 abstract description 7
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 6
- 238000002474 experimental method Methods 0.000 abstract description 6
- 230000036457 multidrug resistance Effects 0.000 abstract description 5
- 244000153955 Reynoutria sachalinensis Species 0.000 abstract description 3
- 235000003202 Reynoutria sachalinensis Nutrition 0.000 abstract description 3
- 235000009754 Vitis X bourquina Nutrition 0.000 abstract description 3
- 235000012333 Vitis X labruscana Nutrition 0.000 abstract description 3
- 240000006365 Vitis vinifera Species 0.000 abstract description 3
- 235000014787 Vitis vinifera Nutrition 0.000 abstract description 3
- 235000017060 Arachis glabrata Nutrition 0.000 abstract description 2
- 244000105624 Arachis hypogaea Species 0.000 abstract description 2
- 235000010777 Arachis hypogaea Nutrition 0.000 abstract description 2
- 235000018262 Arachis monticola Nutrition 0.000 abstract description 2
- 241000196324 Embryophyta Species 0.000 abstract description 2
- 235000020232 peanut Nutrition 0.000 abstract description 2
- LUKBXSAWLPMMSZ-UHFFFAOYSA-N resveratrol Chemical compound C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-UHFFFAOYSA-N 0.000 abstract description 2
- 231100000331 toxic Toxicity 0.000 abstract description 2
- 230000002588 toxic effect Effects 0.000 abstract description 2
- 241000894006 Bacteria Species 0.000 description 14
- 206010059866 Drug resistance Diseases 0.000 description 14
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical group OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 206010041925 Staphylococcal infections Diseases 0.000 description 8
- 230000001580 bacterial effect Effects 0.000 description 8
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 8
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000000741 silica gel Substances 0.000 description 5
- 229910002027 silica gel Inorganic materials 0.000 description 5
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 101100077702 Escherichia coli (strain K12) mog gene Proteins 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 240000003968 Sophora davidii Species 0.000 description 4
- 235000007245 Sophora davidii Nutrition 0.000 description 4
- 241000191940 Staphylococcus Species 0.000 description 4
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 4
- 230000002195 synergetic effect Effects 0.000 description 4
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 229940088710 antibiotic agent Drugs 0.000 description 3
- 239000004599 antimicrobial Substances 0.000 description 3
- 239000003120 macrolide antibiotic agent Substances 0.000 description 3
- 238000004809 thin layer chromatography Methods 0.000 description 3
- VFZRZRDOXPRTSC-UHFFFAOYSA-N 3,5-Dimethoxybenzaldehyde Chemical class COC1=CC(OC)=CC(C=O)=C1 VFZRZRDOXPRTSC-UHFFFAOYSA-N 0.000 description 2
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 2
- 241000295644 Staphylococcaceae Species 0.000 description 2
- 239000004098 Tetracycline Substances 0.000 description 2
- 108010059993 Vancomycin Proteins 0.000 description 2
- CSCPPACGZOOCGX-WFGJKAKNSA-N acetone d6 Chemical compound [2H]C([2H])([2H])C(=O)C([2H])([2H])[2H] CSCPPACGZOOCGX-WFGJKAKNSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 150000003935 benzaldehydes Chemical class 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 210000000349 chromosome Anatomy 0.000 description 2
- 229960003405 ciprofloxacin Drugs 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 230000012010 growth Effects 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
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- 230000003834 intracellular effect Effects 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 238000003808 methanol extraction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
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- 239000000243 solution Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000003595 spectral effect Effects 0.000 description 2
- 235000019364 tetracycline Nutrition 0.000 description 2
- 150000003522 tetracyclines Chemical class 0.000 description 2
- 229960003165 vancomycin Drugs 0.000 description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 2
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 2
- FFRBMBIXVSCUFS-UHFFFAOYSA-N 2,4-dinitro-1-naphthol Chemical compound C1=CC=C2C(O)=C([N+]([O-])=O)C=C([N+]([O-])=O)C2=C1 FFRBMBIXVSCUFS-UHFFFAOYSA-N 0.000 description 1
- UWSONZCNXUSTKW-UHFFFAOYSA-N 4,5-Dimethylthiazole Chemical compound CC=1N=CSC=1C UWSONZCNXUSTKW-UHFFFAOYSA-N 0.000 description 1
- SIMYWHHAEQQGEH-UHFFFAOYSA-N 5-[2-(4-hydroxyphenyl)ethenyl]benzene-1,3-diol Chemical compound C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1.C1=CC(O)=CC=C1C=CC1=CC(O)=CC(O)=C1 SIMYWHHAEQQGEH-UHFFFAOYSA-N 0.000 description 1
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- 101710125089 Bindin Proteins 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- UIOFUWFRIANQPC-JKIFEVAISA-N Floxacillin Chemical compound N([C@@H]1C(N2[C@H](C(C)(C)S[C@@H]21)C(O)=O)=O)C(=O)C1=C(C)ON=C1C1=C(F)C=CC=C1Cl UIOFUWFRIANQPC-JKIFEVAISA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 244000283207 Indigofera tinctoria Species 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 208000037942 Methicillin-resistant Staphylococcus aureus infection Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010029803 Nosocomial infection Diseases 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 241000205407 Polygonum Species 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 1
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 1
- QOPAMSBHSSXKGC-UHFFFAOYSA-N [F].C1=CC=C2NC(=O)C=CC2=C1 Chemical class [F].C1=CC=C2NC(=O)C=CC2=C1 QOPAMSBHSSXKGC-UHFFFAOYSA-N 0.000 description 1
- 102000035181 adaptor proteins Human genes 0.000 description 1
- 108091005764 adaptor proteins Proteins 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 description 1
- 230000003712 anti-aging effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 238000001460 carbon-13 nuclear magnetic resonance spectrum Methods 0.000 description 1
- GPRBEKHLDVQUJE-VINNURBNSA-N cefotaxime Chemical compound N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C(O)=O)=O)C(=O)/C(=N/OC)C1=CSC(N)=N1 GPRBEKHLDVQUJE-VINNURBNSA-N 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001335 demethylating effect Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical group OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- QGBSISYHAICWAH-UHFFFAOYSA-N dicyandiamide Chemical compound NC(N)=NC#N QGBSISYHAICWAH-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 230000001076 estrogenic effect Effects 0.000 description 1
- 229960004273 floxacillin Drugs 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 238000007654 immersion Methods 0.000 description 1
- 230000001900 immune effect Effects 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 1
- 150000003951 lactams Chemical class 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 235000013372 meat Nutrition 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 101150021123 msrA gene Proteins 0.000 description 1
- 239000002547 new drug Substances 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 230000002018 overexpression Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 150000003242 quaternary ammonium salts Chemical class 0.000 description 1
- 229960001285 quercetin Drugs 0.000 description 1
- 235000005875 quercetin Nutrition 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 238000000825 ultraviolet detection Methods 0.000 description 1
- 229940072335 vancocin Drugs 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
- C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
- C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
The invention belongs to pharmaceutical field, is related to 3,4 ', 5 trihydroxy talan (resveratrol Resveratrol) of compound and its purposes in the anti-methicillin-resistant staphylococcus aureus of resistance to fluoroquinolones hypersitization medicine is prepared.The compound 3,4 ', 5 trihydroxy talan (Resveratrol) are widely distributed, at present at least resveratrol Resveratrol is found in 21 sections, 31 categories, 72 kinds of plants, wherein content is higher in grape, giant knotweed and peanut, and without obvious toxic side effect.The compound of the present invention shows the pharmacological activity with raising multidrug resistance staphylococcus aureus to the sensitiveness of Norfloxacin through antibacterial experiment, in particular for the methicillin-resistant staphylococcus aureus SA1199B containing the gene of resistance to fluoroquinolones NorA, compound of the present invention can make the MIC value of Norfloxacin reduce by 16 times with Norfloxacin combination, can be further used for preparing antibiotic synergism medicine.
Description
Technical field
The invention belongs to pharmaceutical field, is related to the pharmaceutical composition for suppressing drug-resistant staphylococcus aureus, and in particular to compound 3,4 ',
5- trihydroxy talan (resveratrol Resveratrol) and its preparing the anti-methicillin-resistant staphylococcus of resistance to fluoroquinolones
Purposes in staphylococcus medicine.
Background technology
Prior art discloses methicillin-resistant Staphylococcus aureus (Methicillin-Resistant
Staphylococcus aureus, MRSA) it is one of most common disease carrying germ in hospital, except superficial skin infection, it is also
The deep infection of inside of human body can be caused.Clinical practice shows have to medicines such as all lactam antibioticses such as penicillin
There is the MRSA of drug resistance, drug resistance is also generated to antibiotic such as macrolide, fluorine quinolione, tetracyclines, this causes its sense
Dye becomes more difficult to treat.At present, the antibiotic available for treatment MRSA only has vancomycin, Unfortunately, completely
Anti-vancocin MRSA bacterial strains had occurred for 2002 already in the U.S..China is widely used due to antibiotic in recent years, or even excessively
With for particularly vancomycin after multiple hospitals become Conventional antibiotic class medication, this situation becomes further severe.Except
Take measures to slow down the speed that drug resistance MRSA increases by limiting abuse of antibiotics, while research and develop new anti-multidrug resistance MRSA
Medicine is particularly important, it will be to when existing antibacterials can not work, the large-scale outbreak of bacterium plays prevention
Effect.
Studies have shown that bacterium can produce drug resistance (Drug Resistance) through a variety of ways, and wherein bacterium is to medicine
Outer pump (efflux) drug resistance is important mechanism of drug resistance caused by producing outer row's effect.According to the report of the World Health Organization
Accuse, the bacterial infection with multidrug resistance efflux pump has accounted for the 60% of nosocomial infection.
Studies have reported that methicillin-resistant staphylococcus aureus has a variety of resistance mechanisms, except being with chromosome
The drug resistant gene (mecA) of 40Kb is produced by encoding methicillin adaptor protein (Penicilin Bindin Protein, PBP)
Outside life is to the drug resistance of beta-lactam antibiotic, also to macrolides (macrolide), fluoroquinolones
(fluoroqiunolones), tetracycline and quaternary ammonium salt produce resistance to by MsrA, NorA, TekA, the outer chlGs of QacA respectively
Medicine mechanism, bacterial cell pumps out the most antibiotic generally used extracellularly in these resistance mechanisms, makes intracellular
Antibiotic concentration reduce and antibacterial action can not be played.The gene of resistance to fluoroquinolones NorA (42kDa) is present in S. aureus L-forms
In the Sma I D fragments of S.aureus chromosomes, at first it is only regarded as fluoroquinolones drug resistant gene, shows later pair
The drug resistance of Multiple Classes of Antibiotics type.NorA genes over-express product NorA albumen in S.aureus and are located on cytoplasma membrane
It is sub (transporter) as main transhipment, using the multi-medicament including fluoroquinolones as matrix, or it is sub with other transhipments
Synergistic effect, pumps out cell by drug molecule, produces the drug resistance of bacterium.Therefore, the multiple medicine with NorA drug resistant genes is chosen
Drug-resistant staphylococcus aureus are an important channels for finding new drug resistance bacteria inhibitor in the industry as target.
It is reported that resveratrol has antitumor, anti-inflammatory, immunological regulation, antibacterial, antiviral, anti-aging and estrogen-like
The multiple pharmacological effects such as activity, wherein in terms of antimicrobial agent, have been reported resveratrol joint Ciprofloxacin to resistance to methoxy west
The gold-coloured staphylococci MTCC 902 of woods has good inhibitory action, and FICI values reach 0.14, and (FICI values ＜ 0.5 is to have association
Same-action)；And resveratrol joint cefotaxime equally has the gold-coloured staphylococci MTCC 902 for cooperateing with anti-methicillin-resistant
Effect, FICI values reach 0.31；Resveratrol combines fluorine quinolone compounds Ciprofloxacin to bacillus subtilis MTCC
2756 (FICI values are 0.13) and Escherichia coli MTCC 2622 (FICI values are 0.12) and pseudomonas aeruginosa MTCC 2642
(FICI values are 0.25) equally has coordinate repression；Still some researches show that resveratrol joint Quercetin can cooperate with anti-
Drug-resistant staphylococcus aureus SA1056 (FICI values are 0.375)；, resveratrol may interfere with quorum sensing (quorum sensing, QS, again
Claim threshold value sensitive, be that bacterium carries out the exchange of intracellular or cell-tocell according to population density size, coordinate group behavior and adjust
Control gene expression a kind of mode) and surface protein and capsular polysaccharide synthesis；The prior art discloses resveratrol can
Can participate in the auxiliary treatment of MRSA infection by acting on biomembrane.
So far, there is not yet on resveratrol to the antibacterial action with the MRSA bacterial strains that gene is pumped outside NorA
Report.Based on this, present inventor intends providing a kind of drug regimen of the suppression drug-resistant staphylococcus aureus containing resveratrol
Thing, wherein resveratrol are combined with Norfloxacin, will be had to fluorine-resistant promise quinoline ketone antibiotic Methicillin-resistant Staphylococcus aureus good
Coordinate repression.
The prior art related to the present invention has：
[1] Guay, G.G., et al. (1993) .The Tet (K) Gene of Plasmid PT181of
Staphylococcus aureus Encodes an Efflux Protein that Contains 14Transmenbrane
Helices.Plasmid, 30 (2)：163-166.
[2] Ng, E.Y.W., et al. (1994) .Quinolone Resistance Mediated by NorA：
Physiological Characterization and Relationship to Flqb, A Quinolone
Resistance Locus on The Staphylococcus aureus Chromosome.Antibacterial Agents
And Chemotherapy, 38 (6)：1345-1355.
[3] Marshall, N.J., et al, (1997) .Antibacterial efflux
Systems.Microbiologia, 13：285-300.
[4] Hiyas A J, et al, (2010), Synergy-Directed Fractionation of Botanical
Medicines：A Case Study with Goldenseal (Hydrastis canadensis), J.Nat.Prod., 4：
1621-1629.
[5] Carolina EM, et al, (2011), Characterization of a xylose containing
Oligosaccharide, an inhibitor of multidrug resistance in Staphylococcus
Aureus, from Ipomoea pes-caprae, J.phytochemistry, 71：1769-1801.
[6] Su YL, et al, (2014), Studies of the in Vitro Antibacterial
Activities of Several Polyphenols against Clinical Isolates of Methicillin-
Resistant Staphylococcus aureus, Molecules, 19：12630-12639.
[7] Nishanth KS, et al, (2012), Activity and synergistic interactions of
Stilbenes and antibiotic combinations against bacteria in vitro, World J
Microbiol Biotechnol, 28：3143-3150.
[8] Qin N, et al, (2014), RNA-Seq-based transcriptome analysis of
methicillin-resistant Staphylococcus aureus biofilm inhibition by ursolic
Acid and resveratrol, Scientific Reports, 4：5467.
The content of the invention
The object of the present invention is to provide a kind of pharmaceutical composition for suppressing drug-resistant staphylococcus aureus, more particularly to compound 3,4 ',
5- trihydroxy talan (resveratrol Resveratrol) and its preparing the anti-methicillin-resistant staphylococcus of resistance to fluoroquinolones
Purposes in staphylococcus hypersitization medicine.
The present invention provides a kind of compound with collaboration overriding resistance staphylococcus aureus, is related to 3,4 ', 5- trihydroxies
Talan (resveratrol Resveratrol).And its preparing the purposes in cooperateing with overriding resistance staphylococcus aureus medicine.
The present invention further provides compound 3,4 ', 5- trihydroxy talan (resveratrol Resveratrol) is being made
Purposes in the standby anti-methicillin-resistant staphylococcus aureus of resistance to fluoroquinolones hypersitization medicine；Wherein compound 3,4 ', 5- tri-
Hydroxy diphenyl ethylene (resveratrol Resveratrol) has collaboration fluorine promise quinoline ketone antibiotic overriding resistance staphylococcus aureus
Effect.
In the present invention, the drug resistance Staphylococcus aureus strain SA1199B that there is tolerance to fluorine promise quinoline ketone antibiotic is chosen
The activity experiment test of collaboration antimicrobial agent is carried out, this kind of bacterial strain is the golden yellow grape ball with chlG outside fluorine-resistant promise quinoline ketone
Bacterium.For antibody-resistant bacterium SA1199B, the MIC value of Norfloxacin is 16mg/L；The present invention is through experiment, the results showed that, resveratrol
Joint Norfloxacin has good coordinate repression to fluorine-resistant promise quinoline ketone antibiotic Methicillin-resistant Staphylococcus aureus SA1199B
(FICI values are 0.31).
The present invention provides suppress multidrug resistance staphylococcus aureus (multidrug resistant available for collaboration
MRSA natural inhibitor (compound 3,4 ', 5- trihydroxy talan (resveratrol Resveratrol))).
Compound R esveratrol provided by the invention, its molecular formula are C14H12O3, the structure with formula (I).
The compound R esveratrol of the present invention is prepared by following methods,
Dry Sophora viciifolia (Sophora davidii) root is taken, is crushed, the immersion of 95% ethanol, obtains medicinal extract, medicinal extract is used successively
Petroleum ether, chloroform, methanol extraction, with silica gel ,/gel, column chromatography obtains colourless acicular crystal repeatedly at obtained methanol position, warp
Silica gel thin-layer chromatography and HPLC are detected as a pure compound, and Resveratrol is accredited as by spectral data.
The hydrogen nuclear magnetic resonance modal data (400MHz, solvent d6-acetone) of the compound R esveratrol is：
7.42 (2H, d, J=8Hz, H-2 ', 6 '), 6.85 (2H, d, J=8Hz, H-3 ', 5 '), 7.02 (1H, d, J=16Hz, H-a),
6.88 (1H, d, J=16Hz, H-b), 6.54 (2H, d, J=2Hz, H-2,6), 6.27 (1H, t, J=2Hz, H-4), 8.51 (1H,
S, 4 '-OH), 8.24 (2H, s, 3-OH, 4-OH)；Carbon-13 nmr spectra data (125MHz, solvent d6-acetone) are：
101.2 (C-4), 104.2 (C-2,6), 125.3 (C-b), 127.2 (C-2 ', 6 '), 127.6 (C-a), 128.5 (C-1 '),
139.4 (C-1), 156.6 (C-4 '), 158.1 (C-3,5).
Compound (resveratrol Resveratrol) Resveratrol of the present invention route can be synthesized as shown in Figure 1.
In the present invention, the drug resistance Staphylococcus aureus strain SA1199B that there is tolerance to fluorine promise quinoline ketone antibiotic is chosen
The activity experiment test of collaboration antimicrobial agent is carried out, this kind of bacterial strain has the Staphylococcus aureus of the outer chlG of fluorine-resistant promise quinoline ketone,
Positive control medicine Norfloxacin (norfloxacin)；The results show that for antibody-resistant bacterium SA1199B, the MIC of Norfloxacin
It is worth and 128mg/L, but compound R esveratrol and promise is more than to the MIC of this bacterial strain for 16mg/L, compound R esveratrol
Flucloxacillin combines the used time, i.e., when compound concentration is 32mg/L, the MIC value of antibiotic is down to 1mg/L, individually makees with antibiotic
Used time, which is compared, reduces 16 times；Resveratrol of the present invention has obvious Synergistic antimicrobial activity.
In the present invention, involved methicillin-resistant Staphylococcus aureus has to fluorine promise quinoline ketone antibiotic medicine at the same time
Drug resistance；The hypersitization medicine for suppressing drug-resistant staphylococcus aureus can be prepared.
Further, the present invention provides the medicine group of the suppression drug-resistant staphylococcus aureus containing resveratrol (Resveratrol)
Compound, it is combined with fluorine promise quinoline ketone antibiotic by resveratrol (Resveratrol) and is made,.It is excellent in the embodiment of the present invention
Select fluorine promise quinoline ketone antibiotic Norfloxacin.
The pharmaceutical composition can be made into antiseptic injection, oral agents or external medicine preparation.
The present invention provides compound 3,4',5-trihydroxystilbene (Resveratrol) and its preparing antibiotic
Purposes in synergism medicine, the compound is widely distributed, is at least found in 21 sections, 31 categories, 72 kinds of plants at present
Resveratrol, wherein content is higher in grape, giant knotweed and peanut, and without obvious toxic side effect.The chemical combination of the present invention
Thing is shown with pharmacological activity of the multidrug resistance staphylococcus aureus to the sensitiveness of Norfloxacin is improved, especially through antibacterial experiment
It is to be directed to the methicillin-resistant staphylococcus aureus SA1199B containing the gene of resistance to fluoroquinolones NorA, the present invention relates to
The combination of compound and Norfloxacin the MIC value of Norfloxacin can be made to reduce by 16 times, can be further used for preparing antibiotic synergy
Medicine.
Brief description of the drawings
Fig. 1 is the synthetic route schematic diagram of resveratrol.
Embodiment
1 prepare compound Resveratrol of embodiment
Dry Sophora viciifolia (Sophora davidii) root 202.6g is taken, is crushed, soaks (3L × 3 time) with 95% ethanol,
Extracting solution merges evaporated under reduced pressure and obtains medicinal extract 18.5g.Successively with petroleum ether, chloroform, methanol extraction, wherein methanol position obtains medicinal extract
13.9g, methanol position is separated with silica gel column chromatography, and eluant, eluent is methylene chloride-methanol (100: 0-0: 100), gradient elution,
Silica gel thin-layer chromatography detects, and collects fraction and obtains 570.4mg mixtures 9, column chromatography obtains mixture 9 repeatedly through gel, silica gel
27.2mg colourless acicular crystals, are detected as a pure compound through silica gel thin-layer chromatography and HPLC, are accredited as by spectral data
Resveratrol。
2 prepare compound Resveratrol of embodiment
Giant knotweed (Polygonum is isolated and purified using high speed adverse current chromatogram (TBE-300 types high-speed counter-current chromatograph)
Cuspidatum resveratrol in), select dicyandiamide solution for：Chloroform: methanol: water=4: 3: 2, rotating speed 850r/min, flow velocity
2ml/min, ultraviolet detection wavelength 280nm；Under the conditions of this, resveratrol yield is 0.186%, and purity is more than 96%.
3 prepare compound Resveratrol of embodiment
With 3,5- dimethoxy benzaldehydes (1) for starting material, through demethylating reaction under the action of aluminum trichloride (anhydrous)
3,5- 4-dihydroxy benzaldehydes (2) are obtained, Perkin then occurs under the action of acetic anhydride and triethylamine with p-hydroxyphenylaceticacid
(E) -2- (4 '-hydroxy phenyl) -3- (3 ', 5 '-dihydroxy phenyl) acrylic acid (4) is condensed to yield, last synchronized decarboxylation-different
Structure reacts to obtain target compound resveratrol (5), total recovery 41.9%.
The Synergistic antimicrobial experiment of 4 compound R esveratrol of embodiment
Norfloxacin and MTT are purchased from Sigma (Sigma Chemical Co.), Muller-Hendon's meat soup
(mueller-hinton brooth, MHB) is purchased from Oxoid companies.μ L bacteria suspensions are added into every hole in addition to the 12nd arranges.
This 96 orifice plate is cultivated in 37 DEG C of incubator 18-24 it is small when, observe result.Record often row bacterium just it is non-growing that
The concentration of Norfloxacin corresponding to hole, wherein H rows be shown Norfloxacin it is alone when MIC, other rows be shown with
The MIC value of Norfloxacin when Resveratrol is combined；
Concentration is 3- [4,5- dimethylthiazole base -2] -2,5- diphenyltetrazoliumbromide indigo plant bromides (MTT of 5 mg/mls；
Sigma 20 microlitres of growths for being used for detection bacterium) are added per hole, MTT becomes au bleu by yellow and then indicated bacterial growth；
Experimental bacteria SA1199B is the staphylococcus aureus of the outer chlG of overexpression NorA multidrug resistances, Norfloxacin
It is 16mg/L to its MIC value, the NorA albumen is the main efflux pump (efflux pump) of S. aureus L-forms；
The results show that for antibody-resistant bacterium SA1199B, the MIC value of Norfloxacin is 16mg/L, compound
Resveratrol is more than the MIC of this bacterial strain 128mg/L, but when compound R esveratrol is shared with Norfloxacin, that is, works as
When compound concentration is 32mg/L, the MIC value of antibiotic is down to 1mg/L, when antibiotic independent role compared with reduce 16 times,
Resveratrol has obvious Synergistic antimicrobial activity.
Claims (5)
1. purposes of the resveratrol compound of formula (I) in the anti-drug-resistant staphylococcus aureus of resistance to fluoroquinolones hypersitization medicine is prepared.
2. purposes according to claim 1, it is characterized in that, the S. aureus L-forms are with resistance to methicillin class antibiotic
The staphylococcus aureus of pharmacological property.
3. it is a kind of suppress drug-resistant staphylococcus aureus pharmaceutical composition, it is characterised in that its by formula (I) resveratrol compound and fluorine
The combination of promise quinoline ketone antibiotic is made；
4. the pharmaceutical composition according to claim 3 for suppressing drug-resistant staphylococcus aureus, it is characterised in that the fluorine promise quinoline ketone
Class antibiotic is Norfloxacin.
5. the pharmaceutical composition according to claim 3 for suppressing drug-resistant staphylococcus aureus, it is characterised in that the drug regimen
Antiseptic injection, oral agents or external medicine preparation is made in thing.
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN111084836A (en) * | 2019-12-17 | 2020-05-01 | 清华德人西安幸福制药有限公司 | Application of combination of thermionic acid and antibiotics in intervention of antibacterial action against pathogenic bacteria |
| CN112194575A (en) * | 2020-09-24 | 2021-01-08 | 嘉圣生物医药(嘉兴)有限公司 | Modified compound of marine antibiotic and application thereof |
| CN112843047A (en) * | 2021-03-31 | 2021-05-28 | 重庆市公共卫生医疗救治中心 | Application of quercetin in enhancing bactericidal ability of antibacterial drugs |
| CN113797109A (en) * | 2020-06-12 | 2021-12-17 | 华东理工大学 | Anti-aging application of sarcin medicine |
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| CN111084836A (en) * | 2019-12-17 | 2020-05-01 | 清华德人西安幸福制药有限公司 | Application of combination of thermionic acid and antibiotics in intervention of antibacterial action against pathogenic bacteria |
| CN113797109A (en) * | 2020-06-12 | 2021-12-17 | 华东理工大学 | Anti-aging application of sarcin medicine |
| CN112194575A (en) * | 2020-09-24 | 2021-01-08 | 嘉圣生物医药(嘉兴)有限公司 | Modified compound of marine antibiotic and application thereof |
| CN112843047A (en) * | 2021-03-31 | 2021-05-28 | 重庆市公共卫生医疗救治中心 | Application of quercetin in enhancing bactericidal ability of antibacterial drugs |
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