CN102871996B - Antibiotic composition and application thereof - Google Patents
Antibiotic composition and application thereof Download PDFInfo
- Publication number
- CN102871996B CN102871996B CN201210333694.1A CN201210333694A CN102871996B CN 102871996 B CN102871996 B CN 102871996B CN 201210333694 A CN201210333694 A CN 201210333694A CN 102871996 B CN102871996 B CN 102871996B
- Authority
- CN
- China
- Prior art keywords
- ser
- meropenem
- aminoacid
- methionine
- antibiotic
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 230000003115 biocidal effect Effects 0.000 title abstract description 25
- 239000000203 mixture Substances 0.000 title abstract description 7
- 241000894006 Bacteria Species 0.000 claims abstract description 28
- 239000003814 drug Substances 0.000 claims abstract description 18
- 230000002924 anti-infective effect Effects 0.000 claims abstract description 8
- MTCFGRXMJLQNBG-UWTATZPHSA-N D-Serine Chemical compound OC[C@@H](N)C(O)=O MTCFGRXMJLQNBG-UWTATZPHSA-N 0.000 claims description 49
- 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 description 42
- 230000000844 anti-bacterial effect Effects 0.000 claims description 38
- 229960002260 meropenem Drugs 0.000 claims description 38
- 229940032049 enterococcus faecalis Drugs 0.000 claims description 29
- 241000194032 Enterococcus faecalis Species 0.000 claims description 25
- FFEARJCKVFRZRR-SCSAIBSYSA-N D-methionine Chemical compound CSCC[C@@H](N)C(O)=O FFEARJCKVFRZRR-SCSAIBSYSA-N 0.000 claims description 22
- 229930182818 D-methionine Natural products 0.000 claims description 22
- AYFVYJQAPQTCCC-STHAYSLISA-N D-threonine Chemical compound C[C@H](O)[C@@H](N)C(O)=O AYFVYJQAPQTCCC-STHAYSLISA-N 0.000 claims description 19
- 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 claims description 16
- 229960000723 ampicillin Drugs 0.000 claims description 16
- 230000000845 anti-microbial effect Effects 0.000 claims description 11
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 9
- 241000191967 Staphylococcus aureus Species 0.000 claims description 8
- 241000588724 Escherichia coli Species 0.000 claims description 7
- 229960005475 antiinfective agent Drugs 0.000 claims description 7
- 241000589291 Acinetobacter Species 0.000 claims description 4
- 241000588747 Klebsiella pneumoniae Species 0.000 claims description 4
- 238000005728 strengthening Methods 0.000 claims description 4
- 241000193830 Bacillus <bacterium> Species 0.000 claims description 3
- 241000191963 Staphylococcus epidermidis Species 0.000 claims description 3
- 241000588923 Citrobacter Species 0.000 claims description 2
- 241000193468 Clostridium perfringens Species 0.000 claims description 2
- 241000588697 Enterobacter cloacae Species 0.000 claims description 2
- 241000588770 Proteus mirabilis Species 0.000 claims description 2
- 241000588767 Proteus vulgaris Species 0.000 claims description 2
- 241000607142 Salmonella Species 0.000 claims description 2
- 241000607715 Serratia marcescens Species 0.000 claims description 2
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 2
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 2
- MYPYJXKWCTUITO-KIIOPKALSA-N chembl3301825 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(O)[C@H](C)O1 MYPYJXKWCTUITO-KIIOPKALSA-N 0.000 claims description 2
- 229940007042 proteus vulgaris Drugs 0.000 claims description 2
- 238000001228 spectrum Methods 0.000 claims description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 claims description 2
- 230000001580 bacterial effect Effects 0.000 abstract description 14
- 229940088710 antibiotic agent Drugs 0.000 abstract description 13
- 206010059866 Drug resistance Diseases 0.000 abstract description 9
- 238000011160 research Methods 0.000 abstract description 7
- 150000008574 D-amino acids Chemical class 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 6
- 239000003242 anti bacterial agent Substances 0.000 abstract description 3
- 238000013459 approach Methods 0.000 abstract description 3
- 230000008901 benefit Effects 0.000 abstract description 2
- 238000000338 in vitro Methods 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 230000004060 metabolic process Effects 0.000 abstract description 2
- 238000000034 method Methods 0.000 abstract description 2
- 239000002547 new drug Substances 0.000 abstract description 2
- 238000012827 research and development Methods 0.000 abstract description 2
- 230000002349 favourable effect Effects 0.000 abstract 1
- 239000000890 drug combination Substances 0.000 description 34
- 239000007788 liquid Substances 0.000 description 34
- 239000010413 mother solution Substances 0.000 description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 20
- 238000010790 dilution Methods 0.000 description 14
- 239000012895 dilution Substances 0.000 description 14
- 230000000694 effects Effects 0.000 description 13
- 208000015181 infectious disease Diseases 0.000 description 12
- 235000001014 amino acid Nutrition 0.000 description 11
- 150000001413 amino acids Chemical class 0.000 description 11
- 239000002054 inoculum Substances 0.000 description 10
- 108010059993 Vancomycin Proteins 0.000 description 9
- 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 9
- 229960003165 vancomycin Drugs 0.000 description 9
- 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 9
- 238000011534 incubation Methods 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 208000035473 Communicable disease Diseases 0.000 description 5
- 241001597008 Nomeidae Species 0.000 description 5
- 238000004500 asepsis Methods 0.000 description 5
- 239000001963 growth medium Substances 0.000 description 5
- 238000011081 inoculation Methods 0.000 description 5
- 238000009834 vaporization Methods 0.000 description 5
- 230000008016 vaporization Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 206010041925 Staphylococcal infections Diseases 0.000 description 4
- 229940032713 merrem Drugs 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 238000009631 Broth culture Methods 0.000 description 3
- 241000194033 Enterococcus Species 0.000 description 3
- 241000943303 Enterococcus faecalis ATCC 29212 Species 0.000 description 3
- 241000553372 Enterococcus faecalis EnGen0297 Species 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- 208000037942 Methicillin-resistant Staphylococcus aureus infection Diseases 0.000 description 3
- 206010034133 Pathogen resistance Diseases 0.000 description 3
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 2
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 2
- WHUUTDBJXJRKMK-GSVOUGTGSA-N D-glutamic acid Chemical compound OC(=O)[C@H](N)CCC(O)=O WHUUTDBJXJRKMK-GSVOUGTGSA-N 0.000 description 2
- ROHFNLRQFUQHCH-RXMQYKEDSA-N D-leucine Chemical compound CC(C)C[C@@H](N)C(O)=O ROHFNLRQFUQHCH-RXMQYKEDSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 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 description 2
- 241000699666 Mus <mouse, genus> Species 0.000 description 2
- 241000699670 Mus sp. Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- KYGZCKSPAKDVKC-UHFFFAOYSA-N Oxolinic acid Chemical compound C1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC2=C1OCO2 KYGZCKSPAKDVKC-UHFFFAOYSA-N 0.000 description 2
- 239000002647 aminoglycoside antibiotic agent Substances 0.000 description 2
- 230000000941 anti-staphylcoccal effect Effects 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical class ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 230000002458 infectious effect Effects 0.000 description 2
- 238000001802 infusion Methods 0.000 description 2
- 238000007912 intraperitoneal administration Methods 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229960003085 meticillin Drugs 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000010172 mouse model Methods 0.000 description 2
- 230000036457 multidrug resistance Effects 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000003306 quinoline derived antiinfective agent Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 235000014347 soups Nutrition 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000002132 β-lactam antibiotic Substances 0.000 description 2
- 229940124586 β-lactam antibiotics Drugs 0.000 description 2
- 244000063299 Bacillus subtilis Species 0.000 description 1
- 235000014469 Bacillus subtilis Nutrition 0.000 description 1
- 102100025142 Beta-microseminoprotein Human genes 0.000 description 1
- DCXYFEDJOCDNAF-UWTATZPHSA-N D-Asparagine Chemical compound OC(=O)[C@H](N)CC(N)=O DCXYFEDJOCDNAF-UWTATZPHSA-N 0.000 description 1
- XUJNEKJLAYXESH-UWTATZPHSA-N D-Cysteine Chemical compound SC[C@@H](N)C(O)=O XUJNEKJLAYXESH-UWTATZPHSA-N 0.000 description 1
- AGPKZVBTJJNPAG-RFZPGFLSSA-N D-Isoleucine Chemical compound CC[C@@H](C)[C@@H](N)C(O)=O AGPKZVBTJJNPAG-RFZPGFLSSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UHFFFAOYSA-N D-OH-Asp Natural products OC(=O)C(N)CC(O)=O CKLJMWTZIZZHCS-UHFFFAOYSA-N 0.000 description 1
- ONIBWKKTOPOVIA-SCSAIBSYSA-N D-Proline Chemical compound OC(=O)[C@H]1CCCN1 ONIBWKKTOPOVIA-SCSAIBSYSA-N 0.000 description 1
- ODKSFYDXXFIFQN-SCSAIBSYSA-N D-arginine Chemical compound OC(=O)[C@H](N)CCCNC(N)=N ODKSFYDXXFIFQN-SCSAIBSYSA-N 0.000 description 1
- CKLJMWTZIZZHCS-UWTATZPHSA-N D-aspartic acid Chemical compound OC(=O)[C@H](N)CC(O)=O CKLJMWTZIZZHCS-UWTATZPHSA-N 0.000 description 1
- ZDXPYRJPNDTMRX-GSVOUGTGSA-N D-glutamine Chemical compound OC(=O)[C@H](N)CCC(N)=O ZDXPYRJPNDTMRX-GSVOUGTGSA-N 0.000 description 1
- HNDVDQJCIGZPNO-RXMQYKEDSA-N D-histidine Chemical compound OC(=O)[C@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-RXMQYKEDSA-N 0.000 description 1
- KDXKERNSBIXSRK-RXMQYKEDSA-N D-lysine Chemical compound NCCCC[C@@H](N)C(O)=O KDXKERNSBIXSRK-RXMQYKEDSA-N 0.000 description 1
- COLNVLDHVKWLRT-MRVPVSSYSA-N D-phenylalanine Chemical compound OC(=O)[C@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-MRVPVSSYSA-N 0.000 description 1
- 229930182832 D-phenylalanine Natural products 0.000 description 1
- QIVBCDIJIAJPQS-SECBINFHSA-N D-tryptophane Chemical compound C1=CC=C2C(C[C@@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-SECBINFHSA-N 0.000 description 1
- OUYCCCASQSFEME-MRVPVSSYSA-N D-tyrosine Chemical compound OC(=O)[C@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-MRVPVSSYSA-N 0.000 description 1
- 229930195709 D-tyrosine Natural products 0.000 description 1
- KZSNJWFQEVHDMF-SCSAIBSYSA-N D-valine Chemical compound CC(C)[C@@H](N)C(O)=O KZSNJWFQEVHDMF-SCSAIBSYSA-N 0.000 description 1
- 241001360526 Escherichia coli ATCC 25922 Species 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 101100185029 Homo sapiens MSMB gene Proteins 0.000 description 1
- 101000740455 Klebsiella pneumoniae Metallo-beta-lactamase type 2 Proteins 0.000 description 1
- 206010068052 Mosaicism Diseases 0.000 description 1
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 description 1
- 101150026476 PAO1 gene Proteins 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
- 208000037581 Persistent Infection Diseases 0.000 description 1
- 102000011195 Profilin Human genes 0.000 description 1
- 108050001408 Profilin Proteins 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 210000000683 abdominal cavity Anatomy 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000010065 bacterial adhesion Effects 0.000 description 1
- 230000037358 bacterial metabolism Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 229940041514 candida albicans extract Drugs 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 229940097572 chloromycetin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000009849 deactivation Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229960000304 folic acid Drugs 0.000 description 1
- 235000019152 folic acid Nutrition 0.000 description 1
- 239000011724 folic acid Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- -1 imipenum Chemical compound 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 230000000937 inactivator Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 210000004072 lung Anatomy 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000015688 methicillin-resistant staphylococcus aureus infectious disease Diseases 0.000 description 1
- 230000004899 motility Effects 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 238000001668 nucleic acid synthesis Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 239000000575 pesticide Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 239000003910 polypeptide antibiotic agent Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000000306 recurrent effect Effects 0.000 description 1
- 230000002000 scavenging effect Effects 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 210000003765 sex chromosome Anatomy 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 229940072335 vancocin Drugs 0.000 description 1
- 239000012138 yeast extract Substances 0.000 description 1
Classifications
-
- 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
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
Abstract
The invention provides a novel antibiotic composition and an application thereof. The antibiotic composition consists of two components: D-amino acid and an antibiotic activity drug and/or derivative of the antibiotic activity drug. The D-amino acid is composited with the available antibiotics for the first time, and used to interfere with physiologic metabolism of bacteria to improve the antibiotic activity of the antibiotics, thereby providing a brand-new approach to dealing with the problem of increasingly severe bacterial drug resistance. Compared with the traditional new drug research and development, the antibiotic composition and a method of combined administration have the advantages of high efficiency, quickness, low cost, multiple optional compositions and the like, and show the favorable antibiotic activity in in-vitro and in-vivo anti-infection researches.
Description
Technical field
The invention belongs to pharmaceutical field, specifically, relate to a kind of antibacterial combination and application thereof.
Background technology
Infectious disease is the common frdquently encountered disease threatening human life's health, is also one of the important complication and the cause of the death of Multiple organs disorders.The application of anti-infectives greatly reduces the death of infectious disease.Conventional anti-infectives comprises beta-lactam antibiotic, quinolone antibiotic, aminoglycoside antibiotics etc.Its mechanism of action comprises anti-bacteria Cell wall synthesis, some function of T suppression cell film, and Profilin matter is synthesized, and suppresses nucleic acid synthesis, suppresses folic acid synthesis etc.
D-aminoacid is natural to be present in many biologies, and play specific function, if D-alanine and D-Glu are the important component of bacteria cell wall, and D-Ser is the neurotransmitter etc. of the mankind.But under usual condition, these relatively rare aminoacid are very low at bacterium bulk concentration.And recent report finds that the various D-aminoacid that antibacterial produces when steady state period can accumulate mM level that reaches, prompting D-aminoacid is relevant to the physiological status of antibacterial.
Biofilm is by bacterial adhesion in contact surface, and secretion polysaccharide matrix, fibrin, lipid protein etc., by himself embedding wherein a large amount of bacterial accumulation film sample things formed.Various bacteria can form biofilm (as Pseudomonas aeruginosa, staphylococcus aureus, staphylococcus epidermidis, escherichia coli etc.).It is cause some chronic infection recurrent exerbation to be difficult to the major reason of curing and bacterial drug resistance produces that bacterial biofilm is formed, and its mechanism mainly comprises: reduce antibiotic permeability; Absorption antibiotic inactivator, deactivation antibiotic; Bacterial metabolism slows down, and in " sub-hibernation-like state ", reduces (antibacterial of antibacterial to the sensitivity specific ionization state of medicine forming biofilm is low more than 1000 times) antibiotic sensitivity; Escape the scavenging action etc. of body immune system.And study discovery recently, the D-ispol of nanomolar range can make the bacterial strains such as the bacillus subtilis of formation biofilm return free state, thus recover the sensitivity of strains, and the amino acid whose fact of D-can be produced based on many bacterial strains, infer that D-aminoacid may be the universal signal that biofilm dissociates.
There is drawback due on the pesticide application strategy that traditional anti-infectives is treated, add that substance abuse problems is serious, thus microecological balance is created have a strong impact on.Under antibiotic selective pressure, occur as MRSA(methicillin-resistant staphylococcus aureus), VRE(vancomycin-resistant enterococcus), PRSP(penicillin resistance pneumococcus) etc. Gram-positive fastbacteria and multidrug resistance gram negative bacteria as Acinetobacter bauamnnii, klebsiella pneumoniae, escherichia coli, bacillus pyocyaneus etc., and fastbacteria treatment is very thorny, infectious age is made sharply to increase, serious threat (Clin Microbiol Rev is constituted to the health of the whole mankind, 22 (4): 582-610,2009).
The situation is tense for China's bacterial resistance, and multidrug resistance G-bacterium infection problems is serious, and be widely current clinically to the Pseudomonas aeruginosa of carbapenem antibiotic drug resistance, Acinetobacter bauamnnii, treatment difficulty, even pasts medical help.Become the primary cause of death of infectious disease at U.S. MRSA, superbacteria NDM-1 breaks out with popular in the whole world, more causes showing great attention to of the whole world.And bacterial resistance gene is also often positioned on displaceable element, thus accelerate the propagation of drug resistant gene between different strains.Therefore in the urgent need to strengthening the research and development to drug-resistance bacteria medicine.
Many drug resistant genes derive from the non-pathogenic bacteria in environment, and the powerful drug resistance system that non-pathogenic bacteria carries comprises natural, semi-synthetic and complete synthesis antibiotic drug resistance element, and the generation of drug resistance is seemingly inevitable.Seldom have the antibiotic of newtype to come out in recent decades, and the exploitation being novel drug-resistance bacteria medicine by the antibacterial adjuvant of antibiotic and other biological bioactive molecule and existing Antibiotic combination medication provide new approaches.
Summary of the invention
The object of this invention is to provide the application of D-aminoacid in the antibacterial activity strengthening antibacterials.
Another object of the present invention is to provide a kind of novel antibacterial pharmaceutical composition and application thereof.
Another object of the present invention is to provide D-aminoacid and the application of antibacterials drug combination in infectious disease treatment.
In order to realize the object of the invention, a kind of antibacterial combination of the present invention, is made up of two kinds of components, and one is D-aminoacid, and another kind is antimicrobial active medicament and/or its derivant; Wherein, described D-aminoacid be D-alanine, D-Ser, D-methionine, D-Thr, D-phenylalanine, D-Glu, D-Gln, D-PROLINE, D-Arg, D-Lys, D-Cys, D-Val, D-Leu, D-Ile, D-trp, D-Tyrosine, D-Asp, D-His, D-Asn and do not possess in the glycine of D L typing one or more; Described antimicrobial active medicament and/or its derivant are one or more in beta-lactam antibiotic, aminoglycoside antibiotics, quinolone antibiotic, macrolide antibiotics, chloromycetin series antibiotics, glycopeptide antibiotics or fosfomycin etc.
In aforesaid antibacterial combination, the amino acid whose concentration range of D-is 0.001mM ~ 10M.The selection of the amino acid whose kind of D-and concentration in compositions, according to the bacterial strain of work done in the manner of a certain author, antibiotic kind and different, preferably resists specific bacterial strain to affect one or more D-aminoacid drug combinations of obvious (MIC value is lower) on this antibiotic.Final purpose obtains a series of D-aminoacid antibacterial combination that effectively can resist specific strain infection respectively.
The preparation method of aforementioned antibacterial combination comprises two kinds, the first is: first two kinds of component D-aminoacid, antimicrobial active medicament and/or its derivant are mixed with mother solution with water or suitable solvent (selecting according to D-aminoacid, antimicrobial active medicament) respectively, then and required D-amino acid concentration active according to antibacterials is mixed with both drug combination liquid.The second is: be mixed in proportion D-aminoacid, antimicrobial active medicament and/or its derivant, then adds water or suitable solvent (selecting according to D-aminoacid, antimicrobial active medicament) and is directly mixed with both drug combination liquid.Such as, for dissolve D-Leu, imipenum, erythromycin, chloromycetin solvent be respectively 1M hydrochloric acid solution, 0.01M phosphate buffer (pH7.2), 95% ethanol or glacial acetic acid, 95% ethanol.
The present invention also provides described antibacterial combination preparing the application in anti-infectives.
The antimicrobial spectrum of this anti-infectives is Gram-positive and/or gram negative bacteria and their fastbacteria.Preferably, described gram-positive bacterium is: one or more in staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis, enterococcus faecalis, streptococcus pneumoniae, streptococcus pyogenes etc.
Described gram negative bacteria is: one or more in Acinetobacter bauamnnii, klebsiella pneumoniae, escherichia coli, bacillus pyocyaneus, serratia marcescens, proteus mirabilis, proteus vulgaris, Mo Genmo Salmonella, special-shaped citrobacter, enterobacter cloacae, clostridium perfringen, thunder Ji Shi Pu Lufeideng bacillus etc.The present invention further provides D-aminoacid and the application of antibacterials drug combination in infectious disease treatment, comprising: 1) D-aminoacid and antibacterials make compound formulation drug combination; Or 2) D-aminoacid and antibacterials medication successively, namely first give D-aminoacid, after give antibacterials; Or first give antibacterials, after give D-aminoacid.
D-aminoacid and existing antibacterials are carried out science, reasonably combine by the present invention first, be used for strengthening the antibacterial activity of antibacterials by D-aminoacid interference Bacterial Physiological metabolism, for the day by day serious bacterial resistance sex chromosome mosaicism of reply provides a brand-new approach.The advantages such as the method for antibacterial combination provided by the invention and drug combination has efficiently for traditional new drug development, quick, low cost, alternate combinations are many, and demonstrate good antibacterial activity in infection research in vivo and in vitro.
Detailed description of the invention
Following examples for illustration of the present invention, but are not used for limiting the scope of the invention.If do not specialize, the conventional means that technological means used in embodiment is well known to those skilled in the art, is raw materials usedly commercial goods.
The preparation of embodiment 1 D-Ser and meropenem drug combination liquid
1. take D-Ser powder (molecular weight 105.09, purity 98%) 0.429g, be settled to 10ml with sterilized water, aseptic filtration, obtain 0.4M mother solution.
2. get 0.4M D-Ser mother solution 0.25ml, be settled to 10ml with sterilized water, obtain 10mMD-serine mother solution.
3. get 10mM D-Ser mother solution 0.1ml, be settled to 10ml with sterilized water, obtain 0.1mM D-Ser mother solution.
4. take meropenem powder (purity 99.1%; Moisture 12.4%) 57.6mg, be settled to 10ml with sterilized water, aseptic filtration, obtain 5mg/mL mother solution.
5. 0.4M D-Ser mother solution 0.25ml and 5mg/ml meropenem mother solution 0.512ml is mixed, be settled to 10ml with sterilized water, obtain the drug combination liquid of 10mM D-Ser and 256 μ g/ml meropenems.
6. 10mM D-Ser mother solution 0.1ml and 5mg/ml meropenem mother solution 0.512ml is mixed, be settled to 10ml with sterilized water, obtain the drug combination liquid of 0.1mM D-Ser and 256 μ g/ml meropenems.
7. 0.1mM D-Ser mother solution 0.1ml and 5mg/ml meropenem mother solution 0.512ml is mixed, be settled to 10ml with sterilized water, obtain the drug combination liquid of 0.001mM D-Ser and 256 μ g/ml meropenems.
The preparation of embodiment 2 D-Ser and meropenem drug combination liquid
1. take D-Ser powder (molecular weight 105.09, purity 98%) 3.43g.
2. take meropenem powder (purity 99.1%; Moisture 12.4%) 115.2g.
3. both are mixed, be settled to 10ml with sterilized water, obtain the drug combination liquid of 3.2M D-Ser and 10mg/ml meropenem.
The preparation of the antibacterial combination be made up of with antimicrobial active medicament and/or its derivant other D-aminoacid is carried out according to the description in embodiment 1 or embodiment 2.
Methicillin-resistant resistant Staphylococcus aureus (MRSA) activity research of embodiment 3 D-Ser and meropenem drug combination
1. get D-Ser (available from Sigma), be mixed with 0.4M mother solution with sterilized water, filter for subsequent use.Merrem (purchased from Hebei Zhongrun Pharmaceutical Co.ltd., Shiyao Group), is formulated as 5mg/mL mother solution with sterilized water.
2. meropenem is carried out two times of Concentraton gradient dilutions with the MH broth bouillon containing 0mM, 0.2mM, 2mM and 20mM D-Ser respectively, concentration range is 64 μ g/mL-0.03 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes is added in aseptic 96 orifice plates.Establish simultaneously and do not contrast containing the strain growth of meropenem.
3. by MRSA reference culture ATCC 33591, ATCC 43300, N315, and Beijing area clinical separation strain 06-3,06-16,06-23,06-37,08-6,08-26,08-32,08-36,08-44,08-45,08-48,08-50 are inoculated in 1mL MH broth bouillon respectively, 37 ° of C overnight incubation.
4. the bacterium liquid of incubated overnight is adjusted to 0.5 Maxwell turbidity and (is about 1.0 × 10
8cFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 × 10
5cFU/mL.
5. 96 well culture plates are suitably wrapped up, prevent liquid excessive vaporization, be placed in 37 ° of C and cultivate 16-18h.
6. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (Minimal Inhibitory Concentration, MIC).Result is as shown in table 1.
Table 1D-serine affects result to the anti-MRSA activity of meropenem
As can be seen from Table 1,20mM D-Ser and meropenem drug combination, can improve the antibacterial activity of meropenem, and with compared with D-Ser, MIC have dropped more than 32 times.The strain growth of each concentration D-Ser contrasts compared with not containing the growth control of D-Ser without significant difference.
The activity research of the anti-klebsiella pneumoniae of embodiment 4D-methionine and meropenem drug combination, escherichia coli, bacillus pyocyaneus
1. get D-methionine (available from Sigma), be mixed with 0.25M mother solution with sterilized water, filter for subsequent use.Merrem (purchased from Hebei Zhongrun Pharmaceutical Co.ltd., Shiyao Group), is formulated as 5mg/mL mother solution with sterilized water.
2. meropenem is carried out two times of Concentraton gradient dilutions with the MH broth bouillon containing 0mM, 0.2mM, 2mM and 20mM D-methionine respectively, concentration range is 8 μ g/mL-0.004 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes is added in aseptic 96 orifice plates.Establish simultaneously and do not contrast containing the strain growth of meropenem.
3. by tested reference culture klebsiella pneumoniae ATCC 700603, escherichia coli ATCC25922, bacillus pyocyaneus ATCC 27853, bacillus pyocyaneus PAO1, and Beijing area Clinical isolation lung gram bacillus 7, escherichia coli 1515 are inoculated in 1mL MH broth bouillon respectively, 37 ° of C overnight incubation.
4. the bacterium liquid of incubated overnight is adjusted to 0.5 Maxwell turbidity and (is about 1.0 × 10
8cFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 × 10
5cFU/mL.
5. 96 well culture plates are suitably wrapped up, prevent liquid excessive vaporization, be placed in 37 ° of C and cultivate 16-18h.
6. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (MIC).Result is as shown in table 2.
Table 2D-methionine is on the impact of the anti-klebsiella pneumoniae of meropenem, escherichia coli and bacillus pyocyaneus activity
As can be seen from Table 2,20mM D-methionine and meropenem drug combination, can improve the antibacterial activity of meropenem, and with compared with D-methionine, MIC have dropped 4-8 doubly.The strain growth of each concentration D-methionine contrasts compared with not containing the growth control of D-methionine without significant difference.
The anti-Staphylococcus aureus activity research of embodiment 5D-methionine and ampicillin, D-Ser and ampicillin and D-Thr and ampicillin drug combination
1. get D-methionine, D-Ser and D-Thr (available from Sigma), be mixed with 0.25M, 0.4M and 0.4M mother solution respectively with sterilized water, filter for subsequent use.Ampicillin standard substance (purchased from Nat'l Pharmaceutical & Biological Products Control Institute), are formulated as 5mg/mL mother solution with sterilized water.
2. two times of Concentraton gradient dilutions are carried out with the MH broth bouillon containing 0mM, 0.1mM, 10mM D-methionine, D-Ser or D-Thr respectively in ampicillin, concentration range is 512 μ g/mL-0.125 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes is added in aseptic 96 orifice plates.Establish simultaneously and do not contrast containing the strain growth of ampicillin.
3. tested reference culture staphylococcus aureus ATCC 43300, staphylococcus aureus N315, staphylococcus aureus Mu50 are inoculated in 1mL MH broth bouillon respectively, 37 ° of C overnight incubation.
4. the bacterium liquid of incubated overnight is adjusted to 0.5 Maxwell turbidity and (is about 1.0 × 10
8cFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 × 10
5cFU/mL.
5. 96 well culture plates are suitably wrapped up, prevent liquid excessive vaporization, be placed in 37 ° of C and cultivate 16-18h.
6. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (MIC).Result is as shown in table 3.
Table 3D-methionine, D-Ser and D-Thr are on the impact of ampicillin anti-Staphylococcus aureus activity
As can be seen from Table 3,10mM D-methionine and ampicillin drug combination, can improve the antibacterial activity 2-4 of ampicillin doubly; 10mM D-Ser and ampicillin drug combination, can improve the antibacterial activity 2-4 of ampicillin doubly; 10mM D-Thr and ampicillin drug combination, can improve the antibacterial activity 1-2 of ampicillin doubly.The contrast of each concentration D-amino acid whose strain growth with not containing compared with the amino acid whose growth control of D-without significant difference.
Anti-enterococcus faecalis, the enterococcus faecalis activity research of embodiment 6 D-methionine, D-Ser, D-Thr three kinds of D-aminoacid and meropenem drug combination
1. get D-methionine, D-Ser, D-Thr (available from Sigma), be mixed with 0.25M, 0.4M, 0.4M mother solution respectively with sterilized water, filter for subsequent use.Merrem (purchased from Hebei Zhongrun Pharmaceutical Co.ltd., Shiyao Group), is formulated as 5mg/mL mother solution with sterilized water.
2. preparation contains the brain heart infusion broth culture medium (Brain heart infusion, BHI) of three kinds of D-aminoacid (D-methionine, D-Ser, D-Thr) of 0.2mM, 2mM and 20mM respectively.
3. meropenem is carried out two times of Concentraton gradient dilutions with three kinds of amino acid whose BHI of D-containing 0mM, 0.2mM, 2mM and 20mM respectively, concentration range is 256 μ g/mL-0.125 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes is added in aseptic 96 orifice plates.Establish simultaneously and do not contrast containing the strain growth of meropenem.
4. by tested reference culture enterococcus faecalis ATCC 51299, enterococcus faecalis ATCC29212, enterococcus faecalis ATCC 700802, enterococcus faecalis ATCC 51575 and enterococcus faecalis ATCC 700221, Clinical isolation enterococcus faecalis HH22 and enterococcus faecalis EFL4041 is inoculated in 1mL brain-heart broth culture medium respectively, 37 ° of C overnight incubation.
5. the bacterium liquid of incubated overnight is adjusted to 0.5 Maxwell turbidity and (is about 1.0 × 10
8cFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 × 10
5cFU/mL.
6. 96 well culture plates are suitably wrapped up, prevent liquid excessive vaporization, be placed in 37 ° of C and cultivate 16-18h.
7. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (MIC).Result is as shown in table 4.
Anti-enterococcus faecalis, the enterococcus faecalis of table 4D-methionine, D-Ser, D-Thr three kinds of D-aminoacid and meropenem drug combination are active
As can be seen from Table 4, the D-methionine of 20mM, D-Ser, D-Thr three kinds of D-aminoacid and meropenem drug combination, can improve the antibacterial activity of meropenem.With compared with D-aminoacid, MIC have dropped 8-32 doubly.The contrast of each concentration D-amino acid whose strain growth with not containing compared with the amino acid whose growth control of D-, except three kinds of amino acid whose culture medium of D-containing 20mM have minimal effect to enterococcus faecalis ATCC 51299, other are without significant difference.
Anti-enterococcus faecalis, the enterococcus faecalis activity research of embodiment 7 D-methionine, D-Ser, D-Thr three kinds of D-aminoacid and vancomycin drug combination
1. get D-methionine, D-Ser, D-Thr (available from Sigma), be mixed with 0.25M, 0.4M, 0.4M mother solution respectively with sterilized water, filter for subsequent use.Vancomycin standard substance (purchased from Nat'l Pharmaceutical & Biological Products Control Institute), are formulated as 10mg/mL mother solution with sterilized water.
2. preparation contains the BHI of three kinds of D-aminoacid (D-methionine, D-Ser, D-Thr) of 0.2mM, 2mM and 20mM respectively.
3. vancomycin is carried out two times of Concentraton gradient dilutions with three kinds of amino acid whose BHI of D-containing 0mM, 0.2mM, 2mM and 20mM respectively, concentration range is 256 μ g/mL-0.125 μ g/mL.The amount of each concentration liquid by 100 μ L/ holes is added in aseptic 96 orifice plates.Establish simultaneously and do not contrast containing the strain growth of vancomycin.
4. strain subject enterococcus faecalis ATCC 51299, enterococcus faecalis HH22, enterococcus faecalis ATCC 29212, enterococcus faecalis ATCC 700802, enterococcus faecalis ATCC 51575, enterococcus faecalis EFL4041 and enterococcus faecalis ATCC 700221 are inoculated in 1mL brain-heart broth culture medium respectively, 37 ° of C overnight incubation.
5. the bacterium liquid of incubated overnight is adjusted to 0.5 Maxwell turbidity and (is about 1.0 × 10
8cFU/mL), then by 20 times of Concentraton gradient dilution conduct inoculation bacterium liquid, inoculum concentration is 10 μ L/ holes, and inoculum density is about 5.0 × 10
5cFU/mL.
6. 96 well culture plates are suitably wrapped up, prevent liquid excessive vaporization, be placed in 37 ° of C and cultivate 16-18h.
7. take out 96 well culture plates, observed result, the minimum antibiotic concentration of asepsis growth is minimal inhibitory concentration (MIC).Result is as shown in table 5.
Anti-enterococcus faecalis, the enterococcus faecalis of table 5D-methionine, D-Ser, D-Thr three kinds of D-aminoacid and vancomycin drug combination are active
As can be seen from Table 5, the D-methionine of 20mM, D-Ser, D-Thr three kinds of D-aminoacid and vancomycin drug combination, the activity of the anti-vancocin drug resistance enterococcus (enterococcus faecalis ATCC 51299, enterococcus faecalis ATCC 700802, enterococcus faecalis ATCC51575, enterococcus faecalis EFL4041 and enterococcus faecalis ATCC 700221) of vancomycin can be improved, with compared with D-aminoacid, MIC have dropped 8-16 doubly.And to the activity influence of the anti-non-Vancomycin-resistant Enterococcus (enterococcus faecalis HH22 and enterococcus faecalis ATCC 29212) of vancomycin not obvious (MIC is constant or decline 2 times).The contrast of each concentration D-amino acid whose strain growth with not containing compared with the amino acid whose growth control of D-, except three kinds of amino acid whose culture medium of D-containing 20mM have minimal effect to enterococcus faecalis ATCC 51299, other are without significant difference.
Embodiment 8 D-Ser is studied the clinical protective effect being separated Mrsa In Rabbits (MRSA) 08-50 infecting mouse with meropenem drug combination
1. clinical for Beijing area separation MRSA bacterial strain 08-50 being inoculated in 10mL increases in bacterial context soup (0.5%MH+2.5% yeast extract, autoclaving), transfers in 10mL fresh increasing bacterial context soup, continue overnight incubation (16-18h) after 37 ° of C cultivate 6h.
2. after the bacterium liquid of overnight incubation being carried out 100,1000,10000 times of dilutions, with the sterilised yeast suspension (w/v of 5%, use after autoclaving, yeast is purchased from sugar refinery, Dongguan, Guangdong Province yeast subsidiary factory) be mixed with to infect by the volume ratio of 1:9 and use bacterium liquid, carry out 1000,10000,100000 times of dilutions respectively.
3. choose 100 ICR mices (purchased from Beijing Vital River Experimental Animals Technology Co., Ltd.), male and female half and half, body weight 18-21g, be divided into 20 groups at random, often organize 5 (2 female 3 male or 2 male 3 female), a 0.5mL bacterium liquid/abdominal cavity infection mice, wherein all establishes contrast by the infectious bacteria liquid after 1000,10000,100000 times of dilutions, remains 12 groups and gives different pharmaceutical with after the bacterium liquid inductance dye after 10000 times of dilutions.
4. get D-Ser (available from Sigma) and Merrem (purchased from Hebei Zhongrun Pharmaceutical Co.ltd., Shiyao Group), be mixed with the drug combination liquid containing variable concentrations D-Ser and meropenem respectively with normal saline, as shown in table 6:
The pharmaceutical formulation of table 6D-serine and meropenem drug combination
5. after Murine Model of Intraperitoneal Infection, 1h and 6h is administered once respectively, and each 0.2mL/ only, observes animals survived number in 7 days.Analyze the curative effect of D-Ser and meropenem drug combination.Result is as shown in table 7,
Table 7D-serine and meropenem drug combination are to the therapeutical effect result (survival rate) of mouse infection MRSA bacterial strain 08-50
As can be seen from Table 7, when D-Ser is used alone to zoogenetic infection MRSA bacterial strain 08-50 without therapeutical effect; When meropenem is used alone; animal dis motility rate is up to 40%; and during the two drug combination >=200mM D-Ser+10mg/mL meropenem or 400mMD-serine+>=2.5mg/mL meropenem all can make the survival rate of animal to 100%, show that D-Ser and meropenem drug combination have good protective effect to Murine Model of Intraperitoneal Infection Mrsa In Rabbits 08-50.
Although above the present invention is described in detail with a general description of the specific embodiments, on basis of the present invention, can make some modifications or improvements it, this will be apparent to those skilled in the art.Therefore, these modifications or improvements without departing from theon the basis of the spirit of the present invention, all belong to the scope of protection of present invention.
Claims (4)
1. an antibacterial combination, is characterized in that, is made up of two kinds of components, and one is antimicrobial active medicament, the another kind of D-aminoacid for strengthening described antimicrobial active medicament antibacterial activity; Specifically be made up of D-Ser and meropenem, or be made up of D-methionine and meropenem, or be made up of D-methionine and ampicillin, or be made up of D-Ser and ampicillin, or be made up of D-Thr and ampicillin, or be made up of D-methionine, D-Ser, D-Thr three kinds of D-aminoacid and meropenem, or be made up of D-methionine, D-Ser, D-Thr three kinds of D-aminoacid and vancomycin.
2. antibacterial combination according to claim 1 is preparing the application in anti-infectives, and the antimicrobial spectrum of described anti-infectives is Gram-positive and/or gram negative bacteria and their fastbacteria.
3. application according to claim 2, is characterized in that, described gram-positive bacterium is: one or more in staphylococcus aureus, staphylococcus epidermidis, enterococcus faecalis, enterococcus faecalis, streptococcus pneumoniae, streptococcus pyogenes.
4. application according to claim 2, it is characterized in that, described gram negative bacteria is: one or more in Acinetobacter bauamnnii, klebsiella pneumoniae, escherichia coli, bacillus pyocyaneus, serratia marcescens, proteus mirabilis, proteus vulgaris, Mo Genmo Salmonella, special-shaped citrobacter, enterobacter cloacae, clostridium perfringen, thunder Ji Shi Pu Lufeideng bacillus.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210333694.1A CN102871996B (en) | 2012-09-10 | 2012-09-10 | Antibiotic composition and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201210333694.1A CN102871996B (en) | 2012-09-10 | 2012-09-10 | Antibiotic composition and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102871996A CN102871996A (en) | 2013-01-16 |
| CN102871996B true CN102871996B (en) | 2014-12-24 |
Family
ID=47473670
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201210333694.1A Active CN102871996B (en) | 2012-09-10 | 2012-09-10 | Antibiotic composition and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102871996B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017111601A1 (en) * | 2015-12-24 | 2017-06-29 | Universiteit Leiden | Composition and method for treating infections caused by vancomycin-resistant infectious agents in a subject |
Families Citing this family (32)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104546856B (en) * | 2013-10-18 | 2016-11-23 | 北京北科德源生物医药科技有限公司 | A kind of antibacterial application of beta-lactam |
| CN103931614B (en) * | 2014-04-01 | 2015-08-26 | 重庆大学 | A kind of plant pathogenetic bacteria kills/bacteriostatic agent and application thereof |
| CN104586869B (en) * | 2014-12-31 | 2019-01-11 | 中山大学 | A kind of small molecule metabolites for improving antibiotic and removing pathogen |
| WO2016106712A1 (en) * | 2014-12-31 | 2016-07-07 | 中山大学 | Small molecule metabolite for improving antibiotic clearance of pathogenic bacteria |
| CN104721176B (en) * | 2015-02-02 | 2018-07-10 | 中山大学 | Application of the α-ketoglutaric acid in terms of sensibility of bacteria on antibiotic is improved |
| CN106860466A (en) * | 2017-01-22 | 2017-06-20 | 河南师范大学 | A kind of synergist for improving neomycinsulphate antibacterial drug effect |
| CN106667984A (en) * | 2017-01-22 | 2017-05-17 | 河南师范大学 | Small-molecule substance capable of enhancing antibacterial drug effects of florfenicol |
| CN106860467A (en) * | 2017-01-22 | 2017-06-20 | 河南师范大学 | Aspartic acid as neomycinsulphate synergist application |
| CN107412225A (en) * | 2017-05-26 | 2017-12-01 | 蔡挺 | Application of the D tryptophans in pseudomonas aeruginosa production pyo is suppressed |
| CN107050018A (en) * | 2017-05-26 | 2017-08-18 | 蔡挺 | D tryptophans are suppressing the application during pseudomonas aeruginosa biofilm is formed |
| CN106974909A (en) * | 2017-05-26 | 2017-07-25 | 蔡挺 | Application of the D tryptophans in pseudomonas aeruginosa production elastoser is suppressed |
| CN107308453B (en) * | 2017-06-30 | 2020-04-14 | 河南科技大学 | Application of cystine or cysteine and bacteriostatic agent |
| CN107998118B (en) * | 2017-11-30 | 2020-09-25 | 厦门显德生物科技有限公司 | Preparation combining glycine and tetracycline antibiotics |
| CN108125952A (en) * | 2017-11-30 | 2018-06-08 | 厦门显德生物科技有限公司 | A kind of glycine and preparation associated with Amoxicillin |
| CN107889939B (en) * | 2017-11-30 | 2020-12-25 | 福建九为生物技术有限公司 | Glycine glucose extracellular polysaccharide compound feed additive |
| CN107998138A (en) * | 2017-11-30 | 2018-05-08 | 福建九为生物技术有限公司 | A kind of glycine and preparation associated with kanamycins |
| CN107737338A (en) * | 2017-11-30 | 2018-02-27 | 厦门显德生物科技有限公司 | A kind of preparation for improving sensibility of bacteria on antibiotic |
| CN109464449A (en) * | 2018-11-30 | 2019-03-15 | 河南师范大学 | A kind of aquatic products antibacterial combination and its application |
| CN109464448A (en) * | 2018-11-30 | 2019-03-15 | 河南师范大学 | A kind of antibacterials compound preparation and its application containing small molecule metabolites |
| CN109464435B (en) * | 2018-11-30 | 2021-06-29 | 河南师范大学 | Pharmaceutical composition for preventing and treating fish liver inflammation |
| CN111714482A (en) * | 2019-03-18 | 2020-09-29 | 深圳罗兹曼国际转化医学研究院 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN111714481A (en) * | 2019-03-18 | 2020-09-29 | 深圳市益米诺医药科技有限公司 | Application of valine in improving staphylococcus aureus removing capability of host and application in preparing medicine for resisting staphylococcus aureus infection |
| CN111714496A (en) * | 2019-03-18 | 2020-09-29 | 深圳市益米诺医药科技有限公司 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN111714495A (en) * | 2019-03-18 | 2020-09-29 | 深圳罗兹曼国际转化医学研究院 | Application of small molecular compound in improving host pathogenic bacteria removing capability and application in preparing anti-pathogenic bacteria infection medicine |
| CN110064075B (en) * | 2019-04-23 | 2020-10-13 | 北京科技大学 | Self-assembled antibacterial coating based on nano silver/D-cysteine and preparation method thereof |
| CN111773206A (en) * | 2020-06-29 | 2020-10-16 | 广东利泰制药股份有限公司 | Application of glutamine in preparation of medicine for inhibiting gene mutation generated by escherichia coli |
| CN113876952B (en) * | 2020-07-03 | 2023-04-14 | 厦门大学 | Application of nitrogen source for inhibiting bacterial type III secretion system |
| CN111744016B (en) * | 2020-08-06 | 2021-08-13 | 中山大学 | Application of compound amino acid in preparation of medicine for improving sensitivity of bacteria to antibiotics |
| CN113999282B (en) * | 2021-01-21 | 2023-08-22 | 扬州大学 | Antibacterial peptide LI7, repeated polypeptides LI14 and LI21 thereof, derivatives and application thereof |
| CN113045498B (en) * | 2021-03-24 | 2023-01-24 | 江苏食品药品职业技术学院 | 1, 5-diaryl pyrazole derivative, synthesis method and application |
| CN116063390B (en) * | 2022-09-07 | 2023-11-24 | 东北农业大学 | Antibacterial peptide VCK-17 and application of antibacterial peptide VCK-17 and citronellal combined as antibacterial drug |
| CN117298076A (en) * | 2023-08-17 | 2023-12-29 | 遵义医科大学珠海校区 | Application of bletilla striata biphenanthrene B in preparation of antibacterial products |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1441668A (en) * | 2000-06-21 | 2003-09-10 | 卡比斯特制药公司 | Compositions and methods to improve oral absorption of antimicrobial agents |
| CN101933921A (en) * | 2009-07-01 | 2011-01-05 | 江苏正大天晴药业股份有限公司 | Composition of Doripenem and amino acid |
| CN102579430A (en) * | 2011-01-10 | 2012-07-18 | 王乐 | Composition of meropenem and L-arginine |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20100003276A1 (en) * | 2004-12-07 | 2010-01-07 | Hermes Jeffery D | Methods for treating anthrax and inhibiting lethal factor |
-
2012
- 2012-09-10 CN CN201210333694.1A patent/CN102871996B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1441668A (en) * | 2000-06-21 | 2003-09-10 | 卡比斯特制药公司 | Compositions and methods to improve oral absorption of antimicrobial agents |
| CN101933921A (en) * | 2009-07-01 | 2011-01-05 | 江苏正大天晴药业股份有限公司 | Composition of Doripenem and amino acid |
| CN102579430A (en) * | 2011-01-10 | 2012-07-18 | 王乐 | Composition of meropenem and L-arginine |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017111601A1 (en) * | 2015-12-24 | 2017-06-29 | Universiteit Leiden | Composition and method for treating infections caused by vancomycin-resistant infectious agents in a subject |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102871996A (en) | 2013-01-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102871996B (en) | Antibiotic composition and application thereof | |
| AU772332B2 (en) | Probiotic, lactic acid-producing bacteria and uses thereof | |
| Ghazi et al. | Humanized exposures of cefiderocol, a siderophore cephalosporin, display sustained in vivo activity against siderophore-resistant Pseudomonas aeruginosa | |
| WO2010021930A1 (en) | Prevention and treatment of mrsa infections with chitosan-derivatives | |
| Eliopoulos et al. | Susceptibility of enterococci and Listeria monocytogenes to N-formimidoyl thienamycin alone and in combination with an aminoglycoside | |
| Grosserode et al. | The continuing importance of staphylococci as major hospital pathogens | |
| US20210283215A1 (en) | Bacteriotherapy against proprionibacterium acnes for the treatment of acne | |
| Deveikis et al. | Antimicrobial therapy of experimental group B streptococcal infection in mice | |
| JP2961182B2 (en) | Pharmaceutical composition for prevention and treatment of Clostridium difficile diarrhea and pseudomembranous colitis | |
| Moghadam et al. | Comparison of the effects of Lactobacillus plantarum versus imipenem on infected burn wound healing | |
| CN103920137B (en) | A kind of pharmaceutical composition with the effect of anti-drug resistance gram-positive bacteria | |
| Xu et al. | Enterococci facilitate polymicrobial infections | |
| JPH05271096A (en) | Antimicrobial composition and pharmaceutical preparation containing the same as active ingredient | |
| CN110974814A (en) | Potential application of disulfiram in bacterial infection diseases | |
| Wilson | The role of fourth-generation cephalosporins in the treatment of serious infectious diseases in hospitalized patients | |
| CN102911257B (en) | Cyclic lipopeptide antibiotic and preparation and application thereof | |
| CN113318149B (en) | Jasminum extract and preparation method and application thereof | |
| CN102558307A (en) | Octapeptin as well as preparation and application thereof | |
| CN114149483A (en) | Antibacterial peptide composition and application thereof | |
| CN101849947A (en) | Composition of cefazedone sodium and tazobactam sodium and ratio of cefazedone sodium to tazobactam sodium | |
| CN101816669B (en) | Composition containing gentamicin and borneol and use thereof | |
| Zbar et al. | Synergistic effect of partially purified bacteriocin from Cronobacter sakazakii and antibiotics against staphylococcus aureus | |
| RU2792679C1 (en) | Bactericidal pharmaceutical composition for parenteral use in the form of lyophilizate with endolysin | |
| CN104971342A (en) | Pharmaceutical composition for resisting methicillin-resistant staphylococcus aureus (mrsa) | |
| CN106673989A (en) | Pharmaceutical composition as well as preparation method and application thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |