JP2012514656A - 多価オリゴヌクレオチド修飾ナノ粒子コンジュゲートによる細菌タンパク質産生の阻害 - Google Patents
多価オリゴヌクレオチド修飾ナノ粒子コンジュゲートによる細菌タンパク質産生の阻害 Download PDFInfo
- Publication number
- JP2012514656A JP2012514656A JP2011545476A JP2011545476A JP2012514656A JP 2012514656 A JP2012514656 A JP 2012514656A JP 2011545476 A JP2011545476 A JP 2011545476A JP 2011545476 A JP2011545476 A JP 2011545476A JP 2012514656 A JP2012514656 A JP 2012514656A
- Authority
- JP
- Japan
- Prior art keywords
- prokaryotic
- oligonucleotide
- antibiotic composition
- gene
- sequence
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000002105 nanoparticle Substances 0.000 title claims abstract description 125
- 108091034117 Oligonucleotide Proteins 0.000 title claims abstract description 94
- 230000014616 translation Effects 0.000 title claims abstract description 27
- 230000005764 inhibitory process Effects 0.000 title claims description 19
- 108010077805 Bacterial Proteins Proteins 0.000 title abstract description 8
- 108090000623 proteins and genes Proteins 0.000 claims abstract description 148
- 239000000203 mixture Substances 0.000 claims abstract description 100
- 230000003115 biocidal effect Effects 0.000 claims abstract description 88
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 64
- 108091026890 Coding region Proteins 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims abstract description 42
- 238000009396 hybridization Methods 0.000 claims abstract description 39
- 210000001236 prokaryotic cell Anatomy 0.000 claims abstract description 32
- 238000013518 transcription Methods 0.000 claims abstract description 27
- 230000035897 transcription Effects 0.000 claims abstract description 27
- 230000000295 complement effect Effects 0.000 claims abstract description 25
- 238000013519 translation Methods 0.000 claims abstract description 15
- 230000002401 inhibitory effect Effects 0.000 claims abstract description 7
- 102000004169 proteins and genes Human genes 0.000 claims description 54
- 230000001580 bacterial effect Effects 0.000 claims description 47
- 229940088710 antibiotic agent Drugs 0.000 claims description 32
- 210000004027 cell Anatomy 0.000 claims description 31
- 230000014509 gene expression Effects 0.000 claims description 29
- 208000015181 infectious disease Diseases 0.000 claims description 29
- 230000000694 effects Effects 0.000 claims description 25
- -1 Cefprodil Chemical compound 0.000 claims description 24
- 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 claims description 24
- 229960000723 ampicillin Drugs 0.000 claims description 15
- 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 15
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical group 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 claims description 13
- 230000010261 cell growth Effects 0.000 claims description 13
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 claims description 12
- 229960003276 erythromycin Drugs 0.000 claims description 12
- 238000004519 manufacturing process Methods 0.000 claims description 11
- 230000032823 cell division Effects 0.000 claims description 10
- 229960003022 amoxicillin Drugs 0.000 claims description 8
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin 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=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 claims description 8
- 238000000338 in vitro Methods 0.000 claims description 8
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 claims description 8
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 230000004663 cell proliferation Effects 0.000 claims description 7
- 238000001727 in vivo Methods 0.000 claims description 7
- 229960002292 piperacillin Drugs 0.000 claims description 7
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 claims description 7
- 239000004098 Tetracycline Substances 0.000 claims description 6
- 108010059993 Vancomycin Proteins 0.000 claims description 6
- 229960003405 ciprofloxacin Drugs 0.000 claims description 6
- 229960000282 metronidazole Drugs 0.000 claims description 6
- VAOCPAMSLUNLGC-UHFFFAOYSA-N metronidazole Chemical compound CC1=NC=C([N+]([O-])=O)N1CCO VAOCPAMSLUNLGC-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 235000019364 tetracycline Nutrition 0.000 claims description 6
- 150000003522 tetracyclines Chemical class 0.000 claims description 6
- 229960003165 vancomycin Drugs 0.000 claims description 6
- 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 claims description 6
- 230000004543 DNA replication Effects 0.000 claims description 5
- 229960004099 azithromycin Drugs 0.000 claims description 5
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[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 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 claims description 5
- 229960004755 ceftriaxone Drugs 0.000 claims description 5
- VAAUVRVFOQPIGI-SPQHTLEESA-N ceftriaxone Chemical compound S([C@@H]1[C@@H](C(N1C=1C(O)=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1CSC1=NC(=O)C(=O)NN1C VAAUVRVFOQPIGI-SPQHTLEESA-N 0.000 claims description 5
- 229960001180 norfloxacin Drugs 0.000 claims description 5
- 238000001243 protein synthesis Methods 0.000 claims description 5
- 229960001225 rifampicin Drugs 0.000 claims description 5
- JQXXHWHPUNPDRT-WLSIYKJHSA-N rifampicin Chemical compound O([C@](C1=O)(C)O/C=C/[C@@H]([C@H]([C@@H](OC(C)=O)[C@H](C)[C@H](O)[C@H](C)[C@@H](O)[C@@H](C)\C=C\C=C(C)/C(=O)NC=2C(O)=C3C([O-])=C4C)C)OC)C4=C1C3=C(O)C=2\C=N\N1CC[NH+](C)CC1 JQXXHWHPUNPDRT-WLSIYKJHSA-N 0.000 claims description 5
- 229960002180 tetracycline Drugs 0.000 claims description 5
- 229930101283 tetracycline Natural products 0.000 claims description 5
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 claims description 4
- 229930182566 Gentamicin Natural products 0.000 claims description 4
- 108700021031 cdc Genes Proteins 0.000 claims description 4
- 229960002518 gentamicin Drugs 0.000 claims description 4
- 230000002829 reductive effect Effects 0.000 claims description 4
- 229960005322 streptomycin Drugs 0.000 claims description 4
- 229960000707 tobramycin Drugs 0.000 claims description 4
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 claims description 4
- NNRXCKZMQLFUPL-WBMZRJHASA-N (3r,4s,5s,6r,7r,9r,11r,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione;(2r,3 Chemical compound OC(=O)[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O.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 NNRXCKZMQLFUPL-WBMZRJHASA-N 0.000 claims description 3
- FFTVPQUHLQBXQZ-KVUCHLLUSA-N (4s,4as,5ar,12ar)-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=CC(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O FFTVPQUHLQBXQZ-KVUCHLLUSA-N 0.000 claims description 3
- MMRINLZOZVAPDZ-LSGRDSQZSA-N (6r,7r)-7-[[(2z)-2-(2-amino-1,3-thiazol-4-yl)-2-methoxyiminoacetyl]amino]-3-[(1-methylpyrrolidin-1-ium-1-yl)methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;chloride Chemical compound Cl.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC)C=2N=C(N)SC=2)CC=1C[N+]1(C)CCCC1 MMRINLZOZVAPDZ-LSGRDSQZSA-N 0.000 claims description 3
- MINDHVHHQZYEEK-UHFFFAOYSA-N (E)-(2S,3R,4R,5S)-5-[(2S,3S,4S,5S)-2,3-epoxy-5-hydroxy-4-methylhexyl]tetrahydro-3,4-dihydroxy-(beta)-methyl-2H-pyran-2-crotonic acid ester with 9-hydroxynonanoic acid Natural products CC(O)C(C)C1OC1CC1C(O)C(O)C(CC(C)=CC(=O)OCCCCCCCCC(O)=O)OC1 MINDHVHHQZYEEK-UHFFFAOYSA-N 0.000 claims description 3
- RXZBMPWDPOLZGW-XMRMVWPWSA-N (E)-roxithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=N/OCOCCOC)/[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 RXZBMPWDPOLZGW-XMRMVWPWSA-N 0.000 claims description 3
- 101710161460 3-oxoacyl-[acyl-carrier-protein] synthase Proteins 0.000 claims description 3
- 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 description 3
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 claims description 3
- 150000007513 acids Chemical class 0.000 claims description 3
- 229960004821 amikacin Drugs 0.000 claims description 3
- LKCWBDHBTVXHDL-RMDFUYIESA-N amikacin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O1)O)NC(=O)[C@@H](O)CCN)[C@H]1O[C@H](CN)[C@@H](O)[C@H](O)[C@H]1O LKCWBDHBTVXHDL-RMDFUYIESA-N 0.000 claims description 3
- 229960003669 carbenicillin Drugs 0.000 claims description 3
- FPPNZSSZRUTDAP-UWFZAAFLSA-N carbenicillin Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)C(C(O)=O)C1=CC=CC=C1 FPPNZSSZRUTDAP-UWFZAAFLSA-N 0.000 claims description 3
- 229960002100 cefepime Drugs 0.000 claims description 3
- 229960004041 cefetamet Drugs 0.000 claims description 3
- MQLRYUCJDNBWMV-GHXIOONMSA-N cefetamet Chemical compound N([C@@H]1C(N2C(=C(C)CS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 MQLRYUCJDNBWMV-GHXIOONMSA-N 0.000 claims description 3
- 229960004682 cefoperazone Drugs 0.000 claims description 3
- GCFBRXLSHGKWDP-XCGNWRKASA-N cefoperazone Chemical compound O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC(O)=CC=1)C(=O)N[C@@H]1C(=O)N2C(C(O)=O)=C(CSC=3N(N=NN=3)C)CS[C@@H]21 GCFBRXLSHGKWDP-XCGNWRKASA-N 0.000 claims description 3
- 229960004261 cefotaxime Drugs 0.000 claims description 3
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].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 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 claims description 3
- SRZNHPXWXCNNDU-RHBCBLIFSA-N cefotetan Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CS[C@@H]21)C(O)=O)=O)C(=O)C1SC(=C(C(N)=O)C(O)=O)S1 SRZNHPXWXCNNDU-RHBCBLIFSA-N 0.000 claims description 3
- 229960005495 cefotetan Drugs 0.000 claims description 3
- 229960005090 cefpodoxime Drugs 0.000 claims description 3
- WYUSVOMTXWRGEK-HBWVYFAYSA-N cefpodoxime Chemical compound N([C@H]1[C@@H]2N(C1=O)C(=C(CS2)COC)C(O)=O)C(=O)C(=N/OC)\C1=CSC(N)=N1 WYUSVOMTXWRGEK-HBWVYFAYSA-N 0.000 claims description 3
- 229940106164 cephalexin Drugs 0.000 claims description 3
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 claims description 3
- 229960002626 clarithromycin Drugs 0.000 claims description 3
- AGOYDEPGAOXOCK-KCBOHYOISA-N clarithromycin 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)([C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)OC)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 AGOYDEPGAOXOCK-KCBOHYOISA-N 0.000 claims description 3
- 229960002227 clindamycin Drugs 0.000 claims description 3
- KDLRVYVGXIQJDK-AWPVFWJPSA-N clindamycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@H](C)Cl)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 KDLRVYVGXIQJDK-AWPVFWJPSA-N 0.000 claims description 3
- 229960003326 cloxacillin Drugs 0.000 claims description 3
- LQOLIRLGBULYKD-JKIFEVAISA-N cloxacillin 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=CC=CC=C1Cl LQOLIRLGBULYKD-JKIFEVAISA-N 0.000 claims description 3
- 229960001585 dicloxacillin Drugs 0.000 claims description 3
- YFAGHNZHGGCZAX-JKIFEVAISA-N dicloxacillin 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(Cl)C=CC=C1Cl YFAGHNZHGGCZAX-JKIFEVAISA-N 0.000 claims description 3
- 229960000741 erythromycin ethylsuccinate Drugs 0.000 claims description 3
- NSYZCCDSJNWWJL-YXOIYICCSA-N erythromycin ethylsuccinate Chemical compound O1[C@H](C)C[C@H](N(C)C)[C@@H](OC(=O)CCC(=O)OCC)[C@@H]1O[C@H]1[C@@](O)(C)C[C@@H](C)C(=O)[C@H](C)[C@@H](O)[C@](C)(O)[C@@H](CC)OC(=O)[C@H](C)[C@@H](O[C@@H]2O[C@@H](C)[C@H](O)[C@](C)(OC)C2)[C@@H]1C NSYZCCDSJNWWJL-YXOIYICCSA-N 0.000 claims description 3
- 229960004213 erythromycin lactobionate Drugs 0.000 claims description 3
- 229960002182 imipenem Drugs 0.000 claims description 3
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 claims description 3
- 229960000318 kanamycin Drugs 0.000 claims description 3
- 229930027917 kanamycin Natural products 0.000 claims description 3
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 claims description 3
- 229930182823 kanamycin A Natural products 0.000 claims description 3
- 229960003085 meticillin Drugs 0.000 claims description 3
- 229960004023 minocycline Drugs 0.000 claims description 3
- 229960003128 mupirocin Drugs 0.000 claims description 3
- 229930187697 mupirocin Natural products 0.000 claims description 3
- DDHVILIIHBIMQU-YJGQQKNPSA-L mupirocin calcium hydrate Chemical compound O.O.[Ca+2].C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1.C[C@H](O)[C@H](C)[C@@H]1O[C@H]1C[C@@H]1[C@@H](O)[C@@H](O)[C@H](C\C(C)=C\C(=O)OCCCCCCCCC([O-])=O)OC1 DDHVILIIHBIMQU-YJGQQKNPSA-L 0.000 claims description 3
- 229960000515 nafcillin Drugs 0.000 claims description 3
- GPXLMGHLHQJAGZ-JTDSTZFVSA-N nafcillin Chemical compound C1=CC=CC2=C(C(=O)N[C@@H]3C(N4[C@H](C(C)(C)S[C@@H]43)C(O)=O)=O)C(OCC)=CC=C21 GPXLMGHLHQJAGZ-JTDSTZFVSA-N 0.000 claims description 3
- 229960000808 netilmicin Drugs 0.000 claims description 3
- ZBGPYVZLYBDXKO-HILBYHGXSA-N netilmycin Chemical compound O([C@@H]1[C@@H](N)C[C@H]([C@@H]([C@H]1O)O[C@@H]1[C@]([C@H](NC)[C@@H](O)CO1)(C)O)NCC)[C@H]1OC(CN)=CC[C@H]1N ZBGPYVZLYBDXKO-HILBYHGXSA-N 0.000 claims description 3
- NXFQHRVNIOXGAQ-YCRREMRBSA-N nitrofurantoin Chemical compound O1C([N+](=O)[O-])=CC=C1\C=N\N1C(=O)NC(=O)C1 NXFQHRVNIOXGAQ-YCRREMRBSA-N 0.000 claims description 3
- 229960000564 nitrofurantoin Drugs 0.000 claims description 3
- 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 description 3
- 229960001019 oxacillin Drugs 0.000 claims description 3
- UWYHMGVUTGAWSP-JKIFEVAISA-N oxacillin 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=CC=CC=C1 UWYHMGVUTGAWSP-JKIFEVAISA-N 0.000 claims description 3
- 229940056360 penicillin g Drugs 0.000 claims description 3
- 229960005224 roxithromycin Drugs 0.000 claims description 3
- 229960005404 sulfamethoxazole Drugs 0.000 claims description 3
- JLKIGFTWXXRPMT-UHFFFAOYSA-N sulphamethoxazole Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1 JLKIGFTWXXRPMT-UHFFFAOYSA-N 0.000 claims description 3
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 claims description 3
- 229960003865 tazobactam Drugs 0.000 claims description 3
- 229960004659 ticarcillin Drugs 0.000 claims description 3
- OHKOGUYZJXTSFX-KZFFXBSXSA-N ticarcillin Chemical compound C=1([C@@H](C(O)=O)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)C=CSC=1 OHKOGUYZJXTSFX-KZFFXBSXSA-N 0.000 claims description 3
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 claims description 3
- 229960001082 trimethoprim Drugs 0.000 claims description 3
- 108091033380 Coding strand Proteins 0.000 claims description 2
- YAVZHCFFUATPRK-YZPBMOCRSA-N Erythromycin stearate Chemical compound CCCCCCCCCCCCCCCCCC(O)=O.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 YAVZHCFFUATPRK-YZPBMOCRSA-N 0.000 claims description 2
- GSDSWSVVBLHKDQ-JTQLQIEISA-N Levofloxacin Chemical compound C([C@@H](N1C2=C(C(C(C(O)=O)=C1)=O)C=C1F)C)OC2=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-JTQLQIEISA-N 0.000 claims description 2
- 229960002129 cefixime Drugs 0.000 claims description 2
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 claims description 2
- 229960004142 erythromycin stearate Drugs 0.000 claims description 2
- 229960001977 loracarbef Drugs 0.000 claims description 2
- JAPHQRWPEGVNBT-UTUOFQBUSA-N loracarbef Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CC[C@@H]32)C([O-])=O)=O)[NH3+])=CC=CC=C1 JAPHQRWPEGVNBT-UTUOFQBUSA-N 0.000 claims description 2
- 229960000198 mezlocillin Drugs 0.000 claims description 2
- YPBATNHYBCGSSN-VWPFQQQWSA-N mezlocillin Chemical compound N([C@@H](C(=O)N[C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C=1C=CC=CC=1)C(=O)N1CCN(S(C)(=O)=O)C1=O YPBATNHYBCGSSN-VWPFQQQWSA-N 0.000 claims description 2
- MYPYJXKWCTUITO-LYRMYLQWSA-O vancomycin(1+) 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)[NH2+]C)[C@H]1C[C@](C)([NH3+])[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-O 0.000 claims 2
- ZXBDZLHAHGPXIG-VTXLJDRKSA-N (3r,4s,5s,6r,7r,9r,11r,12r,13s,14r)-6-[(2s,3r,4s,6r)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-14-ethyl-7,12,13-trihydroxy-4-[(2r,4r,5s,6s)-5-hydroxy-4-methoxy-4,6-dimethyloxan-2-yl]oxy-3,5,7,9,11,13-hexamethyl-oxacyclotetradecane-2,10-dione;(2r,3 Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)[C@@H](O)C(O)=O.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 ZXBDZLHAHGPXIG-VTXLJDRKSA-N 0.000 claims 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropanol Chemical compound CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 claims 1
- 229960000210 nalidixic acid Drugs 0.000 claims 1
- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 claims 1
- 125000003729 nucleotide group Chemical group 0.000 description 131
- 239000002773 nucleotide Substances 0.000 description 129
- 108091033319 polynucleotide Proteins 0.000 description 76
- 102000040430 polynucleotide Human genes 0.000 description 76
- 239000002157 polynucleotide Substances 0.000 description 76
- 241000894006 Bacteria Species 0.000 description 39
- 241000588724 Escherichia coli Species 0.000 description 25
- JLCPHMBAVCMARE-UHFFFAOYSA-N [3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[3-[[3-[[3-[[3-[[3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-[[5-(2-amino-6-oxo-1H-purin-9-yl)-3-hydroxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxyoxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(5-methyl-2,4-dioxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(6-aminopurin-9-yl)oxolan-2-yl]methoxy-hydroxyphosphoryl]oxy-5-(4-amino-2-oxopyrimidin-1-yl)oxolan-2-yl]methyl [5-(6-aminopurin-9-yl)-2-(hydroxymethyl)oxolan-3-yl] hydrogen phosphate Polymers Cc1cn(C2CC(OP(O)(=O)OCC3OC(CC3OP(O)(=O)OCC3OC(CC3O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c3nc(N)[nH]c4=O)C(COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3COP(O)(=O)OC3CC(OC3CO)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3ccc(N)nc3=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cc(C)c(=O)[nH]c3=O)n3cc(C)c(=O)[nH]c3=O)n3ccc(N)nc3=O)n3cc(C)c(=O)[nH]c3=O)n3cnc4c3nc(N)[nH]c4=O)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)n3cnc4c(N)ncnc34)O2)c(=O)[nH]c1=O JLCPHMBAVCMARE-UHFFFAOYSA-N 0.000 description 25
- 201000010099 disease Diseases 0.000 description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 25
- 150000007523 nucleic acids Chemical class 0.000 description 22
- 238000011282 treatment Methods 0.000 description 19
- 102000039446 nucleic acids Human genes 0.000 description 18
- 108020004707 nucleic acids Proteins 0.000 description 18
- 108020004999 messenger RNA Proteins 0.000 description 16
- 239000002245 particle Substances 0.000 description 16
- 125000006850 spacer group Chemical group 0.000 description 15
- 108020004414 DNA Proteins 0.000 description 14
- 230000027455 binding Effects 0.000 description 13
- 241001465754 Metazoa Species 0.000 description 12
- 108060001084 Luciferase Proteins 0.000 description 11
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 10
- 125000000217 alkyl group Chemical group 0.000 description 10
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 10
- 230000001965 increasing effect Effects 0.000 description 10
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 230000035945 sensitivity Effects 0.000 description 10
- 235000000346 sugar Nutrition 0.000 description 10
- 108020004465 16S ribosomal RNA Proteins 0.000 description 9
- 241000282412 Homo Species 0.000 description 9
- 150000001875 compounds Chemical class 0.000 description 9
- 230000034994 death Effects 0.000 description 9
- 231100000517 death Toxicity 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 241000894007 species Species 0.000 description 9
- 229930182555 Penicillin Natural products 0.000 description 8
- 230000015572 biosynthetic process Effects 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- 229940079593 drug Drugs 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 229910052760 oxygen Inorganic materials 0.000 description 8
- 229940049954 penicillin Drugs 0.000 description 8
- 239000008194 pharmaceutical composition Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 7
- 239000005089 Luciferase Substances 0.000 description 7
- 201000009906 Meningitis Diseases 0.000 description 7
- 206010035664 Pneumonia Diseases 0.000 description 7
- 230000000692 anti-sense effect Effects 0.000 description 7
- 230000005540 biological transmission Effects 0.000 description 7
- 239000003795 chemical substances by application Substances 0.000 description 7
- 235000013305 food Nutrition 0.000 description 7
- 238000003197 gene knockdown Methods 0.000 description 7
- 230000012010 growth Effects 0.000 description 7
- 230000004048 modification Effects 0.000 description 7
- 238000002360 preparation method Methods 0.000 description 7
- 229910052717 sulfur Inorganic materials 0.000 description 7
- 201000008827 tuberculosis Diseases 0.000 description 7
- 208000003732 Cat-scratch disease Diseases 0.000 description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 6
- 206010018612 Gonorrhoea Diseases 0.000 description 6
- ISAKRJDGNUQOIC-UHFFFAOYSA-N Uracil Chemical compound O=C1C=CNC(=O)N1 ISAKRJDGNUQOIC-UHFFFAOYSA-N 0.000 description 6
- 230000007423 decrease Effects 0.000 description 6
- 230000006870 function Effects 0.000 description 6
- 210000001035 gastrointestinal tract Anatomy 0.000 description 6
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 6
- 229910052737 gold Inorganic materials 0.000 description 6
- 239000010931 gold Substances 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- UHDGCWIWMRVCDJ-UHFFFAOYSA-N 1-beta-D-Xylofuranosyl-NH-Cytosine Natural products O=C1N=C(N)C=CN1C1C(O)C(O)C(CO)O1 UHDGCWIWMRVCDJ-UHFFFAOYSA-N 0.000 description 5
- UHDGCWIWMRVCDJ-PSQAKQOGSA-N Cytidine Natural products O=C1N=C(N)C=CN1[C@@H]1[C@@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-PSQAKQOGSA-N 0.000 description 5
- 206010037660 Pyrexia Diseases 0.000 description 5
- 241000607142 Salmonella Species 0.000 description 5
- 244000052616 bacterial pathogen Species 0.000 description 5
- UHDGCWIWMRVCDJ-ZAKLUEHWSA-N cytidine Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O1 UHDGCWIWMRVCDJ-ZAKLUEHWSA-N 0.000 description 5
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 125000004437 phosphorous atom Chemical group 0.000 description 5
- 229910052698 phosphorus Inorganic materials 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 5
- 208000024891 symptom Diseases 0.000 description 5
- 208000006379 syphilis Diseases 0.000 description 5
- 230000008685 targeting Effects 0.000 description 5
- PEHVGBZKEYRQSX-UHFFFAOYSA-N 7-deaza-adenine Chemical compound NC1=NC=NC2=C1C=CN2 PEHVGBZKEYRQSX-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical compound O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 description 4
- 229930024421 Adenine Natural products 0.000 description 4
- 208000031729 Bacteremia Diseases 0.000 description 4
- 241000606768 Haemophilus influenzae Species 0.000 description 4
- 206010033078 Otitis media Diseases 0.000 description 4
- 206010039438 Salmonella Infections Diseases 0.000 description 4
- 108091081021 Sense strand Proteins 0.000 description 4
- 206010040047 Sepsis Diseases 0.000 description 4
- 229960000643 adenine Drugs 0.000 description 4
- 125000000304 alkynyl group Chemical group 0.000 description 4
- 230000000844 anti-bacterial effect Effects 0.000 description 4
- 238000004113 cell culture Methods 0.000 description 4
- 210000002421 cell wall Anatomy 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 238000011161 development Methods 0.000 description 4
- 230000018109 developmental process Effects 0.000 description 4
- 231100000676 disease causative agent Toxicity 0.000 description 4
- 239000003623 enhancer Substances 0.000 description 4
- GNBHRKFJIUUOQI-UHFFFAOYSA-N fluorescein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC=C(O)C=C1OC1=CC(O)=CC=C21 GNBHRKFJIUUOQI-UHFFFAOYSA-N 0.000 description 4
- 101150002100 ftsK gene Proteins 0.000 description 4
- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical class O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- 244000144972 livestock Species 0.000 description 4
- 210000004072 lung Anatomy 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 239000012528 membrane Substances 0.000 description 4
- 239000000178 monomer Substances 0.000 description 4
- 230000004899 motility Effects 0.000 description 4
- 239000002777 nucleoside Substances 0.000 description 4
- 244000052769 pathogen Species 0.000 description 4
- 229920000642 polymer Polymers 0.000 description 4
- 230000008569 process Effects 0.000 description 4
- 206010039447 salmonellosis Diseases 0.000 description 4
- 239000002689 soil Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 4
- 229940035893 uracil Drugs 0.000 description 4
- 229960005486 vaccine Drugs 0.000 description 4
- 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 4
- SGKRLCUYIXIAHR-AKNGSSGZSA-N (4s,4ar,5s,5ar,6r,12ar)-4-(dimethylamino)-1,5,10,11,12a-pentahydroxy-6-methyl-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1=CC=C2[C@H](C)[C@@H]([C@H](O)[C@@H]3[C@](C(O)=C(C(N)=O)C(=O)[C@H]3N(C)C)(O)C3=O)C3=C(O)C2=C1O SGKRLCUYIXIAHR-AKNGSSGZSA-N 0.000 description 3
- WZRJTRPJURQBRM-UHFFFAOYSA-N 4-amino-n-(5-methyl-1,2-oxazol-3-yl)benzenesulfonamide;5-[(3,4,5-trimethoxyphenyl)methyl]pyrimidine-2,4-diamine Chemical compound O1C(C)=CC(NS(=O)(=O)C=2C=CC(N)=CC=2)=N1.COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 WZRJTRPJURQBRM-UHFFFAOYSA-N 0.000 description 3
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 3
- 208000030507 AIDS Diseases 0.000 description 3
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 3
- 241000193738 Bacillus anthracis Species 0.000 description 3
- 208000035143 Bacterial infection Diseases 0.000 description 3
- 241001518086 Bartonella henselae Species 0.000 description 3
- 241000589513 Burkholderia cepacia Species 0.000 description 3
- 208000007190 Chlamydia Infections Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 3
- 208000035473 Communicable disease Diseases 0.000 description 3
- 201000003883 Cystic fibrosis Diseases 0.000 description 3
- 108010054814 DNA Gyrase Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 206010016952 Food poisoning Diseases 0.000 description 3
- 208000019331 Foodborne disease Diseases 0.000 description 3
- 208000005577 Gastroenteritis Diseases 0.000 description 3
- 206010061598 Immunodeficiency Diseases 0.000 description 3
- 241000187479 Mycobacterium tuberculosis Species 0.000 description 3
- 108091093037 Peptide nucleic acid Proteins 0.000 description 3
- 241000242739 Renilla Species 0.000 description 3
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 3
- RYYWUUFWQRZTIU-UHFFFAOYSA-N Thiophosphoric acid Chemical class OP(O)(S)=O RYYWUUFWQRZTIU-UHFFFAOYSA-N 0.000 description 3
- 208000037386 Typhoid Diseases 0.000 description 3
- 241000607626 Vibrio cholerae Species 0.000 description 3
- 241000607479 Yersinia pestis Species 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 125000003342 alkenyl group Chemical group 0.000 description 3
- 238000013459 approach Methods 0.000 description 3
- 238000003556 assay Methods 0.000 description 3
- 229940092524 bartonella henselae Drugs 0.000 description 3
- 210000001124 body fluid Anatomy 0.000 description 3
- 239000010839 body fluid Substances 0.000 description 3
- 230000022131 cell cycle Effects 0.000 description 3
- 208000028512 chlamydia infectious disease Diseases 0.000 description 3
- 229960005091 chloramphenicol Drugs 0.000 description 3
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound 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 3
- 229940104302 cytosine Drugs 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 229960003722 doxycycline Drugs 0.000 description 3
- 239000000839 emulsion Substances 0.000 description 3
- 239000002158 endotoxin Substances 0.000 description 3
- 230000002068 genetic effect Effects 0.000 description 3
- 208000001786 gonorrhea Diseases 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 239000001257 hydrogen Substances 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 235000013372 meat Nutrition 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 150000002739 metals Chemical class 0.000 description 3
- 230000000813 microbial effect Effects 0.000 description 3
- 230000035772 mutation Effects 0.000 description 3
- 150000003833 nucleoside derivatives Chemical class 0.000 description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 3
- 244000039328 opportunistic pathogen Species 0.000 description 3
- 210000000056 organ Anatomy 0.000 description 3
- 230000001717 pathogenic effect Effects 0.000 description 3
- 238000012545 processing Methods 0.000 description 3
- 230000001105 regulatory effect Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 230000002441 reversible effect Effects 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 230000001225 therapeutic effect Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 201000008297 typhoid fever Diseases 0.000 description 3
- 208000019206 urinary tract infection Diseases 0.000 description 3
- WDLWHQDACQUCJR-ZAMMOSSLSA-N (6r,7r)-7-[[(2r)-2-azaniumyl-2-(4-hydroxyphenyl)acetyl]amino]-8-oxo-3-[(e)-prop-1-enyl]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)/C=C/C)C(O)=O)=CC=C(O)C=C1 WDLWHQDACQUCJR-ZAMMOSSLSA-N 0.000 description 2
- XQCZBXHVTFVIFE-UHFFFAOYSA-N 2-amino-4-hydroxypyrimidine Chemical compound NC1=NC=CC(O)=N1 XQCZBXHVTFVIFE-UHFFFAOYSA-N 0.000 description 2
- FZWGECJQACGGTI-UHFFFAOYSA-N 2-amino-7-methyl-1,7-dihydro-6H-purin-6-one Chemical compound NC1=NC(O)=C2N(C)C=NC2=N1 FZWGECJQACGGTI-UHFFFAOYSA-N 0.000 description 2
- ICSNLGPSRYBMBD-UHFFFAOYSA-N 2-aminopyridine Chemical compound NC1=CC=CC=N1 ICSNLGPSRYBMBD-UHFFFAOYSA-N 0.000 description 2
- OVONXEQGWXGFJD-UHFFFAOYSA-N 4-sulfanylidene-1h-pyrimidin-2-one Chemical compound SC=1C=CNC(=O)N=1 OVONXEQGWXGFJD-UHFFFAOYSA-N 0.000 description 2
- RYVNIFSIEDRLSJ-UHFFFAOYSA-N 5-(hydroxymethyl)cytosine Chemical compound NC=1NC(=O)N=CC=1CO RYVNIFSIEDRLSJ-UHFFFAOYSA-N 0.000 description 2
- UJBCLAXPPIDQEE-UHFFFAOYSA-N 5-prop-1-ynyl-1h-pyrimidine-2,4-dione Chemical compound CC#CC1=CNC(=O)NC1=O UJBCLAXPPIDQEE-UHFFFAOYSA-N 0.000 description 2
- LOSIULRWFAEMFL-UHFFFAOYSA-N 7-deazaguanine Chemical compound O=C1NC(N)=NC2=C1CC=N2 LOSIULRWFAEMFL-UHFFFAOYSA-N 0.000 description 2
- HCGHYQLFMPXSDU-UHFFFAOYSA-N 7-methyladenine Chemical compound C1=NC(N)=C2N(C)C=NC2=N1 HCGHYQLFMPXSDU-UHFFFAOYSA-N 0.000 description 2
- UJOBWOGCFQCDNV-UHFFFAOYSA-N 9H-carbazole Chemical compound C1=CC=C2C3=CC=CC=C3NC2=C1 UJOBWOGCFQCDNV-UHFFFAOYSA-N 0.000 description 2
- MSSXOMSJDRHRMC-UHFFFAOYSA-N 9H-purine-2,6-diamine Chemical compound NC1=NC(N)=C2NC=NC2=N1 MSSXOMSJDRHRMC-UHFFFAOYSA-N 0.000 description 2
- 101150004974 ACP3 gene Proteins 0.000 description 2
- 101710146995 Acyl carrier protein Proteins 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 101100366267 Bacillus subtilis (strain 168) spoIIIE gene Proteins 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 2
- 241001136175 Burkholderia pseudomallei Species 0.000 description 2
- 208000017667 Chronic Disease Diseases 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- 102000005636 Cyclic AMP Response Element-Binding Protein Human genes 0.000 description 2
- 108010045171 Cyclic AMP Response Element-Binding Protein Proteins 0.000 description 2
- 206010012735 Diarrhoea Diseases 0.000 description 2
- 101710146739 Enterotoxin Proteins 0.000 description 2
- 108700039887 Essential Genes Proteins 0.000 description 2
- 241000192125 Firmicutes Species 0.000 description 2
- 208000007882 Gastritis Diseases 0.000 description 2
- 206010017964 Gastrointestinal infection Diseases 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- UGQMRVRMYYASKQ-UHFFFAOYSA-N Hypoxanthine nucleoside Natural products OC1C(O)C(CO)OC1N1C(NC=NC2=O)=C2N=C1 UGQMRVRMYYASKQ-UHFFFAOYSA-N 0.000 description 2
- 206010024641 Listeriosis Diseases 0.000 description 2
- 208000019693 Lung disease Diseases 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108010052285 Membrane Proteins Proteins 0.000 description 2
- 102000018697 Membrane Proteins Human genes 0.000 description 2
- 241000588653 Neisseria Species 0.000 description 2
- 206010028980 Neoplasm Diseases 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 101710163270 Nuclease Proteins 0.000 description 2
- 108091028043 Nucleic acid sequence Proteins 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 208000029082 Pelvic Inflammatory Disease Diseases 0.000 description 2
- 206010035148 Plague Diseases 0.000 description 2
- 208000035109 Pneumococcal Infections Diseases 0.000 description 2
- 241000588770 Proteus mirabilis Species 0.000 description 2
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 2
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- 108091027981 Response element Proteins 0.000 description 2
- 241000293869 Salmonella enterica subsp. enterica serovar Typhimurium Species 0.000 description 2
- 241000607768 Shigella Species 0.000 description 2
- 241000191940 Staphylococcus Species 0.000 description 2
- 108700009124 Transcription Initiation Site Proteins 0.000 description 2
- 241000589884 Treponema pallidum Species 0.000 description 2
- XSQUKJJJFZCRTK-UHFFFAOYSA-N Urea Chemical compound NC(N)=O XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 2
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 229940126575 aminoglycoside Drugs 0.000 description 2
- 230000000890 antigenic effect Effects 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- UHYPYGJEEGLRJD-UHFFFAOYSA-N cadmium(2+);selenium(2-) Chemical compound [Se-2].[Cd+2] UHYPYGJEEGLRJD-UHFFFAOYSA-N 0.000 description 2
- 235000014633 carbohydrates Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 229910052799 carbon Inorganic materials 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229960002580 cefprozil Drugs 0.000 description 2
- 229960000484 ceftazidime Drugs 0.000 description 2
- NMVPEQXCMGEDNH-TZVUEUGBSA-N ceftazidime pentahydrate Chemical compound O.O.O.O.O.S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 NMVPEQXCMGEDNH-TZVUEUGBSA-N 0.000 description 2
- 230000004700 cellular uptake Effects 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 229940047766 co-trimoxazole Drugs 0.000 description 2
- 239000000084 colloidal system Substances 0.000 description 2
- 230000021615 conjugation Effects 0.000 description 2
- 230000008602 contraction Effects 0.000 description 2
- 238000013270 controlled release Methods 0.000 description 2
- 125000000753 cycloalkyl group Chemical group 0.000 description 2
- 230000006378 damage Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 230000018044 dehydration Effects 0.000 description 2
- 238000006297 dehydration reaction Methods 0.000 description 2
- 238000013461 design Methods 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 206010012601 diabetes mellitus Diseases 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 101150027005 divIB gene Proteins 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- 206010014599 encephalitis Diseases 0.000 description 2
- 230000000369 enteropathogenic effect Effects 0.000 description 2
- 231100000249 enterotoxic Toxicity 0.000 description 2
- 230000002242 enterotoxic effect Effects 0.000 description 2
- 239000000147 enterotoxin Substances 0.000 description 2
- 231100000655 enterotoxin Toxicity 0.000 description 2
- AEUTYOVWOVBAKS-UWVGGRQHSA-N ethambutol Chemical compound CC[C@@H](CO)NCCN[C@@H](CC)CO AEUTYOVWOVBAKS-UWVGGRQHSA-N 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 210000003608 fece Anatomy 0.000 description 2
- 244000078673 foodborn pathogen Species 0.000 description 2
- 101150101609 ftsA gene Proteins 0.000 description 2
- 101150005487 ftsI gene Proteins 0.000 description 2
- 101150071760 ftsL gene Proteins 0.000 description 2
- 101150069904 ftsN gene Proteins 0.000 description 2
- 101150026421 ftsQ gene Proteins 0.000 description 2
- 101150043569 ftsW gene Proteins 0.000 description 2
- 101150111615 ftsZ gene Proteins 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 125000001475 halogen functional group Chemical group 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 125000005842 heteroatom Chemical group 0.000 description 2
- 125000000623 heterocyclic group Chemical group 0.000 description 2
- 244000052637 human pathogen Species 0.000 description 2
- 239000000411 inducer Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- DRAVOWXCEBXPTN-UHFFFAOYSA-N isoguanine Chemical compound NC1=NC(=O)NC2=C1NC=N2 DRAVOWXCEBXPTN-UHFFFAOYSA-N 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- 229920006008 lipopolysaccharide Polymers 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000009630 liquid culture Methods 0.000 description 2
- 210000004962 mammalian cell Anatomy 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000011859 microparticle Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 239000000346 nonvolatile oil Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000037361 pathway Effects 0.000 description 2
- 101150060462 pbpB gene Proteins 0.000 description 2
- 210000000680 phagosome Anatomy 0.000 description 2
- 239000002953 phosphate buffered saline Substances 0.000 description 2
- 230000004962 physiological condition Effects 0.000 description 2
- BASFCYQUMIYNBI-UHFFFAOYSA-N platinum Chemical compound [Pt] BASFCYQUMIYNBI-UHFFFAOYSA-N 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 230000035755 proliferation Effects 0.000 description 2
- YNCMLFHHXWETLD-UHFFFAOYSA-N pyocyanin Chemical compound CN1C2=CC=CC=C2N=C2C1=CC=CC2=O YNCMLFHHXWETLD-UHFFFAOYSA-N 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 239000010865 sewage Substances 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- 229940114926 stearate Drugs 0.000 description 2
- 238000013268 sustained release Methods 0.000 description 2
- 239000012730 sustained-release form Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 230000009885 systemic effect Effects 0.000 description 2
- 229940113082 thymine Drugs 0.000 description 2
- 239000003053 toxin Substances 0.000 description 2
- 231100000765 toxin Toxicity 0.000 description 2
- 108700012359 toxins Proteins 0.000 description 2
- 238000011144 upstream manufacturing Methods 0.000 description 2
- 208000000143 urethritis Diseases 0.000 description 2
- 229920003169 water-soluble polymer Polymers 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- 229940075420 xanthine Drugs 0.000 description 2
- 101150096853 zipA gene Proteins 0.000 description 2
- YIMATHOGWXZHFX-WCTZXXKLSA-N (2r,3r,4r,5r)-5-(hydroxymethyl)-3-(2-methoxyethoxy)oxolane-2,4-diol Chemical compound COCCO[C@H]1[C@H](O)O[C@H](CO)[C@H]1O YIMATHOGWXZHFX-WCTZXXKLSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- DNIAPMSPPWPWGF-GSVOUGTGSA-N (R)-(-)-Propylene glycol Chemical compound C[C@@H](O)CO DNIAPMSPPWPWGF-GSVOUGTGSA-N 0.000 description 1
- PTFYZDMJTFMPQW-UHFFFAOYSA-N 1,10-dihydropyrimido[5,4-b][1,4]benzoxazin-2-one Chemical compound O1C2=CC=CC=C2N=C2C1=CNC(=O)N2 PTFYZDMJTFMPQW-UHFFFAOYSA-N 0.000 description 1
- FYADHXFMURLYQI-UHFFFAOYSA-N 1,2,4-triazine Chemical class C1=CN=NC=N1 FYADHXFMURLYQI-UHFFFAOYSA-N 0.000 description 1
- HASUWNAFLUMMFI-UHFFFAOYSA-N 1,7-dihydropyrrolo[2,3-d]pyrimidine-2,4-dione Chemical compound O=C1NC(=O)NC2=C1C=CN2 HASUWNAFLUMMFI-UHFFFAOYSA-N 0.000 description 1
- WJFKNYWRSNBZNX-UHFFFAOYSA-N 10H-phenothiazine Chemical compound C1=CC=C2NC3=CC=CC=C3SC2=C1 WJFKNYWRSNBZNX-UHFFFAOYSA-N 0.000 description 1
- TZMSYXZUNZXBOL-UHFFFAOYSA-N 10H-phenoxazine Chemical compound C1=CC=C2NC3=CC=CC=C3OC2=C1 TZMSYXZUNZXBOL-UHFFFAOYSA-N 0.000 description 1
- UHUHBFMZVCOEOV-UHFFFAOYSA-N 1h-imidazo[4,5-c]pyridin-4-amine Chemical compound NC1=NC=CC2=C1N=CN2 UHUHBFMZVCOEOV-UHFFFAOYSA-N 0.000 description 1
- QSHACTSJHMKXTE-UHFFFAOYSA-N 2-(2-aminopropyl)-7h-purin-6-amine Chemical compound CC(N)CC1=NC(N)=C2NC=NC2=N1 QSHACTSJHMKXTE-UHFFFAOYSA-N 0.000 description 1
- FBUTXZSKZCQABC-UHFFFAOYSA-N 2-amino-1-methyl-7h-purine-6-thione Chemical compound S=C1N(C)C(N)=NC2=C1NC=N2 FBUTXZSKZCQABC-UHFFFAOYSA-N 0.000 description 1
- JRYMOPZHXMVHTA-DAGMQNCNSA-N 2-amino-7-[(2r,3r,4s,5r)-3,4-dihydroxy-5-(hydroxymethyl)oxolan-2-yl]-1h-pyrrolo[2,3-d]pyrimidin-4-one Chemical compound C1=CC=2C(=O)NC(N)=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O JRYMOPZHXMVHTA-DAGMQNCNSA-N 0.000 description 1
- ZNQVEEAIQZEUHB-UHFFFAOYSA-N 2-ethoxyethanol Chemical compound CCOCCO ZNQVEEAIQZEUHB-UHFFFAOYSA-N 0.000 description 1
- WKMPTBDYDNUJLF-UHFFFAOYSA-N 2-fluoroadenine Chemical compound NC1=NC(F)=NC2=C1N=CN2 WKMPTBDYDNUJLF-UHFFFAOYSA-N 0.000 description 1
- 125000004200 2-methoxyethyl group Chemical group [H]C([H])([H])OC([H])([H])C([H])([H])* 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- LOJNBPNACKZWAI-UHFFFAOYSA-N 3-nitro-1h-pyrrole Chemical compound [O-][N+](=O)C=1C=CNC=1 LOJNBPNACKZWAI-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- LQLQRFGHAALLLE-UHFFFAOYSA-N 5-bromouracil Chemical compound BrC1=CNC(=O)NC1=O LQLQRFGHAALLLE-UHFFFAOYSA-N 0.000 description 1
- ZLAQATDNGLKIEV-UHFFFAOYSA-N 5-methyl-2-sulfanylidene-1h-pyrimidin-4-one Chemical compound CC1=CNC(=S)NC1=O ZLAQATDNGLKIEV-UHFFFAOYSA-N 0.000 description 1
- OZFPSOBLQZPIAV-UHFFFAOYSA-N 5-nitro-1h-indole Chemical compound [O-][N+](=O)C1=CC=C2NC=CC2=C1 OZFPSOBLQZPIAV-UHFFFAOYSA-N 0.000 description 1
- PLUDYDNNASPOEE-UHFFFAOYSA-N 6-(aziridin-1-yl)-1h-pyrimidin-2-one Chemical compound C1=CNC(=O)N=C1N1CC1 PLUDYDNNASPOEE-UHFFFAOYSA-N 0.000 description 1
- SXQMWXNOYLLRBY-UHFFFAOYSA-N 6-(methylamino)purin-8-one Chemical compound CNC1=NC=NC2=NC(=O)N=C12 SXQMWXNOYLLRBY-UHFFFAOYSA-N 0.000 description 1
- MVROVESVSXEPJL-UHFFFAOYSA-N 6-(prop-1-ynylamino)-1h-pyrimidin-2-one Chemical compound CC#CNC1=CC=NC(=O)N1 MVROVESVSXEPJL-UHFFFAOYSA-N 0.000 description 1
- KXBCLNRMQPRVTP-UHFFFAOYSA-N 6-amino-1,5-dihydroimidazo[4,5-c]pyridin-4-one Chemical compound O=C1NC(N)=CC2=C1N=CN2 KXBCLNRMQPRVTP-UHFFFAOYSA-N 0.000 description 1
- DCPSTSVLRXOYGS-UHFFFAOYSA-N 6-amino-1h-pyrimidine-2-thione Chemical compound NC1=CC=NC(S)=N1 DCPSTSVLRXOYGS-UHFFFAOYSA-N 0.000 description 1
- QNNARSZPGNJZIX-UHFFFAOYSA-N 6-amino-5-prop-1-ynyl-1h-pyrimidin-2-one Chemical compound CC#CC1=CNC(=O)N=C1N QNNARSZPGNJZIX-UHFFFAOYSA-N 0.000 description 1
- FVFVNNKYKYZTJU-UHFFFAOYSA-N 6-chloro-1,3,5-triazine-2,4-diamine Chemical group NC1=NC(N)=NC(Cl)=N1 FVFVNNKYKYZTJU-UHFFFAOYSA-N 0.000 description 1
- NJBMMMJOXRZENQ-UHFFFAOYSA-N 6H-pyrrolo[2,3-f]quinoline Chemical compound c1cc2ccc3[nH]cccc3c2n1 NJBMMMJOXRZENQ-UHFFFAOYSA-N 0.000 description 1
- VKKXEIQIGGPMHT-UHFFFAOYSA-N 7h-purine-2,8-diamine Chemical compound NC1=NC=C2NC(N)=NC2=N1 VKKXEIQIGGPMHT-UHFFFAOYSA-N 0.000 description 1
- HRYKDUPGBWLLHO-UHFFFAOYSA-N 8-azaadenine Chemical compound NC1=NC=NC2=NNN=C12 HRYKDUPGBWLLHO-UHFFFAOYSA-N 0.000 description 1
- LPXQRXLUHJKZIE-UHFFFAOYSA-N 8-azaguanine Chemical compound NC1=NC(O)=C2NN=NC2=N1 LPXQRXLUHJKZIE-UHFFFAOYSA-N 0.000 description 1
- 229960005508 8-azaguanine Drugs 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GSDSWSVVBLHKDQ-UHFFFAOYSA-N 9-fluoro-3-methyl-10-(4-methylpiperazin-1-yl)-7-oxo-2,3-dihydro-7H-[1,4]oxazino[2,3,4-ij]quinoline-6-carboxylic acid Chemical compound FC1=CC(C(C(C(O)=O)=C2)=O)=C3N2C(C)COC3=C1N1CCN(C)CC1 GSDSWSVVBLHKDQ-UHFFFAOYSA-N 0.000 description 1
- 208000004998 Abdominal Pain Diseases 0.000 description 1
- 206010000234 Abortion spontaneous Diseases 0.000 description 1
- 241000238876 Acari Species 0.000 description 1
- 102000007469 Actins Human genes 0.000 description 1
- 108010085238 Actins Proteins 0.000 description 1
- 208000030090 Acute Disease Diseases 0.000 description 1
- 241000351140 Allostoma pallidum Species 0.000 description 1
- 206010053555 Arthritis bacterial Diseases 0.000 description 1
- 206010060968 Arthritis infective Diseases 0.000 description 1
- 206010003399 Arthropod bite Diseases 0.000 description 1
- 208000004429 Bacillary Dysentery Diseases 0.000 description 1
- 101100000756 Bacillus subtilis (strain 168) acpA gene Proteins 0.000 description 1
- 108020000946 Bacterial DNA Proteins 0.000 description 1
- 108700003860 Bacterial Genes Proteins 0.000 description 1
- 108090000363 Bacterial Luciferases Proteins 0.000 description 1
- 201000001178 Bacterial Pneumonia Diseases 0.000 description 1
- 208000022844 Bacterial Sexually Transmitted disease Diseases 0.000 description 1
- 208000004926 Bacterial Vaginosis Diseases 0.000 description 1
- 201000004569 Blindness Diseases 0.000 description 1
- 208000007204 Brain death Diseases 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
- 241001453380 Burkholderia Species 0.000 description 1
- 241000722910 Burkholderia mallei Species 0.000 description 1
- 241000020731 Burkholderia multivorans Species 0.000 description 1
- 241000371422 Burkholderia stabilis Species 0.000 description 1
- 241000866606 Burkholderia vietnamiensis Species 0.000 description 1
- 241000589876 Campylobacter Species 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 102000053642 Catalytic RNA Human genes 0.000 description 1
- 108090000994 Catalytic RNA Proteins 0.000 description 1
- 108010031896 Cell Cycle Proteins Proteins 0.000 description 1
- 102000005483 Cell Cycle Proteins Human genes 0.000 description 1
- 206010007882 Cellulitis Diseases 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 241000606161 Chlamydia Species 0.000 description 1
- 241000606153 Chlamydia trachomatis Species 0.000 description 1
- 206010008631 Cholera Diseases 0.000 description 1
- 108020004705 Codon Proteins 0.000 description 1
- 208000002881 Colic Diseases 0.000 description 1
- 208000002330 Congenital Heart Defects Diseases 0.000 description 1
- RYGMFSIKBFXOCR-UHFFFAOYSA-N Copper Chemical compound [Cu] RYGMFSIKBFXOCR-UHFFFAOYSA-N 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- IVOMOUWHDPKRLL-KQYNXXCUSA-N Cyclic adenosine monophosphate Chemical compound C([C@H]1O2)OP(O)(=O)O[C@H]1[C@@H](O)[C@@H]2N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-KQYNXXCUSA-N 0.000 description 1
- 102000003915 DNA Topoisomerases Human genes 0.000 description 1
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 1
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 101100521984 Dictyostelium discoideum psiF gene Proteins 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010013654 Drug abuse Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 238000003718 Dual-Luciferase Reporter Assay System Methods 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010014561 Emphysema Diseases 0.000 description 1
- 208000032274 Encephalopathy Diseases 0.000 description 1
- 206010053025 Endemic syphilis Diseases 0.000 description 1
- 208000004232 Enteritis Diseases 0.000 description 1
- 206010014896 Enterocolitis haemorrhagic Diseases 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- 241000283074 Equus asinus Species 0.000 description 1
- 241001331845 Equus asinus x caballus Species 0.000 description 1
- 101100331542 Escherichia coli (strain K12) dicC gene Proteins 0.000 description 1
- 241001646719 Escherichia coli O157:H7 Species 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- GHASVSINZRGABV-UHFFFAOYSA-N Fluorouracil Chemical compound FC1=CNC(=O)NC1=O GHASVSINZRGABV-UHFFFAOYSA-N 0.000 description 1
- 235000016623 Fragaria vesca Nutrition 0.000 description 1
- 240000009088 Fragaria x ananassa Species 0.000 description 1
- 235000011363 Fragaria x ananassa Nutrition 0.000 description 1
- 241000589602 Francisella tularensis Species 0.000 description 1
- 102000013446 GTP Phosphohydrolases Human genes 0.000 description 1
- 108091006109 GTPases Proteins 0.000 description 1
- 241000287828 Gallus gallus Species 0.000 description 1
- 206010017914 Gastroenteritis salmonella Diseases 0.000 description 1
- 108010015899 Glycopeptides Proteins 0.000 description 1
- 102000002068 Glycopeptides Human genes 0.000 description 1
- 241000590002 Helicobacter pylori Species 0.000 description 1
- 208000004575 Infectious Arthritis Diseases 0.000 description 1
- UGQMRVRMYYASKQ-KQYNXXCUSA-N Inosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1N1C2=NC=NC(O)=C2N=C1 UGQMRVRMYYASKQ-KQYNXXCUSA-N 0.000 description 1
- 229930010555 Inosine Natural products 0.000 description 1
- 206010022678 Intestinal infections Diseases 0.000 description 1
- 241000589248 Legionella Species 0.000 description 1
- 208000007764 Legionnaires' Disease Diseases 0.000 description 1
- 241000186781 Listeria Species 0.000 description 1
- 206010024639 Listeria infections Diseases 0.000 description 1
- 241000186779 Listeria monocytogenes Species 0.000 description 1
- 208000032376 Lung infection Diseases 0.000 description 1
- 239000006137 Luria-Bertani broth Substances 0.000 description 1
- 206010025323 Lymphomas Diseases 0.000 description 1
- 206010026749 Mania Diseases 0.000 description 1
- 101100327514 Methanosarcina acetivorans (strain ATCC 35395 / DSM 2834 / JCM 12185 / C2A) cfbE gene Proteins 0.000 description 1
- 108091092878 Microsatellite Proteins 0.000 description 1
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 1
- 229910003849 O-Si Inorganic materials 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 206010053159 Organ failure Diseases 0.000 description 1
- 229910003872 O—Si Inorganic materials 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 108010013639 Peptidoglycan Proteins 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 241000286209 Phasianidae Species 0.000 description 1
- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 229920000954 Polyglycolide Polymers 0.000 description 1
- 108010093965 Polymyxin B Proteins 0.000 description 1
- 108010076504 Protein Sorting Signals Proteins 0.000 description 1
- 241000589516 Pseudomonas Species 0.000 description 1
- 206010037549 Purpura Diseases 0.000 description 1
- 241001672981 Purpura Species 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- 108091034057 RNA (poly(A)) Proteins 0.000 description 1
- 238000012228 RNA interference-mediated gene silencing Methods 0.000 description 1
- 206010037888 Rash pustular Diseases 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 206010038687 Respiratory distress Diseases 0.000 description 1
- 241000555745 Sciuridae Species 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 108700025832 Serum Response Element Proteins 0.000 description 1
- 208000019802 Sexually transmitted disease Diseases 0.000 description 1
- 108010079723 Shiga Toxin Proteins 0.000 description 1
- 241000607764 Shigella dysenteriae Species 0.000 description 1
- 206010040550 Shigella infections Diseases 0.000 description 1
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 241000589970 Spirochaetales Species 0.000 description 1
- 206010058339 Splenitis Diseases 0.000 description 1
- 241000191967 Staphylococcus aureus Species 0.000 description 1
- 108091081024 Start codon Proteins 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 101100095302 Streptococcus gordonii secA1 gene Proteins 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 241001455617 Sula Species 0.000 description 1
- 108700026226 TATA Box Proteins 0.000 description 1
- 108091023040 Transcription factor Proteins 0.000 description 1
- 102000040945 Transcription factor Human genes 0.000 description 1
- 208000034784 Tularaemia Diseases 0.000 description 1
- 108010069584 Type III Secretion Systems Proteins 0.000 description 1
- IVOMOUWHDPKRLL-UHFFFAOYSA-N UNPD107823 Natural products O1C2COP(O)(=O)OC2C(O)C1N1C(N=CN=C2N)=C2N=C1 IVOMOUWHDPKRLL-UHFFFAOYSA-N 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 108010046334 Urease Proteins 0.000 description 1
- 208000006374 Uterine Cervicitis Diseases 0.000 description 1
- 101100355952 Vibrio cholerae serotype O1 (strain ATCC 39315 / El Tor Inaba N16961) rcp gene Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 101150023061 acpP gene Proteins 0.000 description 1
- 101150051130 acpP1 gene Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 230000009603 aerobic growth Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 125000005083 alkoxyalkoxy group Chemical group 0.000 description 1
- 125000002877 alkyl aryl group Chemical group 0.000 description 1
- 125000005600 alkyl phosphonate group Chemical group 0.000 description 1
- 230000000172 allergic effect Effects 0.000 description 1
- 108010001818 alpha-sarcin Proteins 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 125000004103 aminoalkyl group Chemical group 0.000 description 1
- 125000005122 aminoalkylamino group Chemical group 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000001978 anti-ribosomal effect Effects 0.000 description 1
- 239000000427 antigen Substances 0.000 description 1
- 230000027645 antigenic variation Effects 0.000 description 1
- 108091007433 antigens Proteins 0.000 description 1
- 102000036639 antigens Human genes 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 229940041181 antineoplastic drug Drugs 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 208000010668 atopic eczema Diseases 0.000 description 1
- 229940065181 bacillus anthracis Drugs 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000002619 bicyclic group Chemical group 0.000 description 1
- 229920002988 biodegradable polymer Polymers 0.000 description 1
- 239000004621 biodegradable polymer Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 230000006696 biosynthetic metabolic pathway Effects 0.000 description 1
- 229910052797 bismuth Inorganic materials 0.000 description 1
- JCXGWMGPZLAOME-UHFFFAOYSA-N bismuth atom Chemical compound [Bi] JCXGWMGPZLAOME-UHFFFAOYSA-N 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 208000037815 bloodstream infection Diseases 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 206010006451 bronchitis Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 229940074375 burkholderia mallei Drugs 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 125000001369 canonical nucleoside group Chemical group 0.000 description 1
- JSVCEVCSANKFDY-SFYZADRCSA-N carbacephem Chemical compound C1CC(C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)C)[C@H]21 JSVCEVCSANKFDY-SFYZADRCSA-N 0.000 description 1
- 239000004202 carbamide Substances 0.000 description 1
- 229940041011 carbapenems Drugs 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- SNBUBQHDYVFSQF-HIFRSBDPSA-N cefmetazole Chemical compound S([C@@H]1[C@@](C(N1C=1C(O)=O)=O)(NC(=O)CSCC#N)OC)CC=1CSC1=NN=NN1C SNBUBQHDYVFSQF-HIFRSBDPSA-N 0.000 description 1
- 229960003585 cefmetazole Drugs 0.000 description 1
- 229960001991 ceftizoxime Drugs 0.000 description 1
- NNULBSISHYWZJU-LLKWHZGFSA-N ceftizoxime Chemical compound N([C@@H]1C(N2C(=CCS[C@@H]21)C(O)=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 NNULBSISHYWZJU-LLKWHZGFSA-N 0.000 description 1
- 230000006037 cell lysis Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 230000001413 cellular effect Effects 0.000 description 1
- 230000033077 cellular process Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- UCKZMPLVLCKKMO-LHLIQPBNSA-N cephamycin Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](C)[C@]21OC UCKZMPLVLCKKMO-LHLIQPBNSA-N 0.000 description 1
- 206010008323 cervicitis Diseases 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003638 chemical reducing agent Substances 0.000 description 1
- 235000013330 chicken meat Nutrition 0.000 description 1
- 229940038705 chlamydia trachomatis Drugs 0.000 description 1
- 230000002759 chromosomal effect Effects 0.000 description 1
- 208000016644 chronic atrophic gastritis Diseases 0.000 description 1
- 239000011248 coating agent Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229910017052 cobalt Inorganic materials 0.000 description 1
- 239000010941 cobalt Substances 0.000 description 1
- GUTLYIVDDKVIGB-UHFFFAOYSA-N cobalt atom Chemical compound [Co] GUTLYIVDDKVIGB-UHFFFAOYSA-N 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 108091036078 conserved sequence Proteins 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229910052802 copper Inorganic materials 0.000 description 1
- 239000010949 copper Substances 0.000 description 1
- 239000011258 core-shell material Substances 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 238000012258 culturing Methods 0.000 description 1
- 229940095074 cyclic amp Drugs 0.000 description 1
- 125000001995 cyclobutyl group Chemical group [H]C1([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 description 1
- 210000000805 cytoplasm Anatomy 0.000 description 1
- 210000000172 cytosol Anatomy 0.000 description 1
- 231100000433 cytotoxic Toxicity 0.000 description 1
- 230000001472 cytotoxic effect Effects 0.000 description 1
- 101150069320 ddl gene Proteins 0.000 description 1
- 101150109034 ddlA gene Proteins 0.000 description 1
- 101150046743 ddlB gene Proteins 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 101150064487 dicA gene Proteins 0.000 description 1
- 101150000034 dicB gene Proteins 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- LOKCTEFSRHRXRJ-UHFFFAOYSA-I dipotassium trisodium dihydrogen phosphate hydrogen phosphate dichloride Chemical compound P(=O)(O)(O)[O-].[K+].P(=O)(O)([O-])[O-].[Na+].[Na+].[Cl-].[K+].[Cl-].[Na+] LOKCTEFSRHRXRJ-UHFFFAOYSA-I 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- NAGJZTKCGNOGPW-UHFFFAOYSA-N dithiophosphoric acid Chemical class OP(O)(S)=S NAGJZTKCGNOGPW-UHFFFAOYSA-N 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000009510 drug design Methods 0.000 description 1
- 208000001848 dysentery Diseases 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- IDYZIJYBMGIQMJ-UHFFFAOYSA-N enoxacin Chemical compound N1=C2N(CC)C=C(C(O)=O)C(=O)C2=CC(F)=C1N1CCNCC1 IDYZIJYBMGIQMJ-UHFFFAOYSA-N 0.000 description 1
- 229960002549 enoxacin Drugs 0.000 description 1
- CHNUOJQWGUIOLD-NFZZJPOKSA-N epalrestat Chemical compound C=1C=CC=CC=1\C=C(/C)\C=C1/SC(=S)N(CC(O)=O)C1=O CHNUOJQWGUIOLD-NFZZJPOKSA-N 0.000 description 1
- 229960000285 ethambutol Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000002095 exotoxin Substances 0.000 description 1
- 231100000776 exotoxin Toxicity 0.000 description 1
- 235000013410 fast food Nutrition 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 230000001605 fetal effect Effects 0.000 description 1
- 229940124307 fluoroquinolone Drugs 0.000 description 1
- 229960002949 fluorouracil Drugs 0.000 description 1
- 229940118764 francisella tularensis Drugs 0.000 description 1
- 230000008014 freezing Effects 0.000 description 1
- 238000007710 freezing Methods 0.000 description 1
- 239000000446 fuel Substances 0.000 description 1
- 238000007306 functionalization reaction Methods 0.000 description 1
- 201000006585 gastric adenocarcinoma Diseases 0.000 description 1
- 108091008053 gene clusters Proteins 0.000 description 1
- 230000009368 gene silencing by RNA Effects 0.000 description 1
- 210000004392 genitalia Anatomy 0.000 description 1
- 230000035784 germination Effects 0.000 description 1
- 210000004907 gland Anatomy 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 101150070420 gyrA gene Proteins 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 235000015220 hamburgers Nutrition 0.000 description 1
- 230000003862 health status Effects 0.000 description 1
- 230000005831 heart abnormality Effects 0.000 description 1
- 229940037467 helicobacter pylori Drugs 0.000 description 1
- 208000007475 hemolytic anemia Diseases 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- 125000000592 heterocycloalkyl group Chemical group 0.000 description 1
- 229920013821 hydroxy alkyl cellulose Polymers 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000007235 immunity generation Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940124589 immunosuppressive drug Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 150000002475 indoles Chemical class 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 230000001939 inductive effect Effects 0.000 description 1
- 208000022760 infectious otitis media Diseases 0.000 description 1
- 230000028709 inflammatory response Effects 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 229940102213 injectable suspension Drugs 0.000 description 1
- 229960003786 inosine Drugs 0.000 description 1
- 238000003780 insertion Methods 0.000 description 1
- 230000037431 insertion Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 230000009545 invasion Effects 0.000 description 1
- 230000037427 ion transport Effects 0.000 description 1
- 229960003350 isoniazid Drugs 0.000 description 1
- QRXWMOHMRWLFEY-UHFFFAOYSA-N isoniazide Chemical compound NNC(=O)C1=CC=NC=C1 QRXWMOHMRWLFEY-UHFFFAOYSA-N 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000002502 liposome Substances 0.000 description 1
- 208000019423 liver disease Diseases 0.000 description 1
- 230000033001 locomotion Effects 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000004199 lung function Effects 0.000 description 1
- 210000001165 lymph node Anatomy 0.000 description 1
- 210000004324 lymphatic system Anatomy 0.000 description 1
- 239000008176 lyophilized powder Substances 0.000 description 1
- 239000003120 macrolide antibiotic agent Substances 0.000 description 1
- 229940041033 macrolides Drugs 0.000 description 1
- 229920002521 macromolecule Polymers 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 201000011475 meningoencephalitis Diseases 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 101150067055 minC gene Proteins 0.000 description 1
- 101150110189 minE gene Proteins 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- 229940041009 monobactams Drugs 0.000 description 1
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 1
- 125000004573 morpholin-4-yl group Chemical group N1(CCOCC1)* 0.000 description 1
- 101150074096 mraY gene Proteins 0.000 description 1
- 101150010079 mraZ gene Proteins 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 101150034514 murC gene Proteins 0.000 description 1
- 101150093075 murD gene Proteins 0.000 description 1
- 101150043597 murE gene Proteins 0.000 description 1
- 101150102210 murF gene Proteins 0.000 description 1
- 230000003533 narcotic effect Effects 0.000 description 1
- 230000000926 neurological effect Effects 0.000 description 1
- 231100000189 neurotoxic Toxicity 0.000 description 1
- 230000002887 neurotoxic effect Effects 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 230000006911 nucleation Effects 0.000 description 1
- 238000010899 nucleation Methods 0.000 description 1
- 230000000474 nursing effect Effects 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229960001699 ofloxacin Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 238000002515 oligonucleotide synthesis Methods 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- SBQLYHNEIUGQKH-UHFFFAOYSA-N omeprazole Chemical compound N1=C2[CH]C(OC)=CC=C2N=C1S(=O)CC1=NC=C(C)C(OC)=C1C SBQLYHNEIUGQKH-UHFFFAOYSA-N 0.000 description 1
- 238000005457 optimization Methods 0.000 description 1
- 230000005693 optoelectronics Effects 0.000 description 1
- 229940126578 oral vaccine Drugs 0.000 description 1
- 125000001181 organosilyl group Chemical group [SiH3]* 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- 239000006179 pH buffering agent Substances 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000000242 pagocytic effect Effects 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 208000011906 peptic ulcer disease Diseases 0.000 description 1
- 208000008494 pericarditis Diseases 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 229950000688 phenothiazine Drugs 0.000 description 1
- 150000002991 phenoxazines Chemical class 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001523 phosphate polymer Polymers 0.000 description 1
- 150000008298 phosphoramidates Chemical class 0.000 description 1
- 150000008300 phosphoramidites Chemical class 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 230000003169 placental effect Effects 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 229910052697 platinum Inorganic materials 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 239000004633 polyglycolic acid Substances 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 238000006116 polymerization reaction Methods 0.000 description 1
- 229920000024 polymyxin B Polymers 0.000 description 1
- 229960005266 polymyxin b Drugs 0.000 description 1
- 229920001184 polypeptide Polymers 0.000 description 1
- 208000015768 polyposis Diseases 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229960004063 propylene glycol Drugs 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000004952 protein activity Effects 0.000 description 1
- 208000020016 psychiatric disease Diseases 0.000 description 1
- 230000005180 public health Effects 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 150000003212 purines Chemical class 0.000 description 1
- 208000029561 pustule Diseases 0.000 description 1
- 229960005206 pyrazinamide Drugs 0.000 description 1
- IPEHBUMCGVEMRF-UHFFFAOYSA-N pyrazinecarboxamide Chemical compound NC(=O)C1=CN=CC=N1 IPEHBUMCGVEMRF-UHFFFAOYSA-N 0.000 description 1
- UBQKCCHYAOITMY-UHFFFAOYSA-N pyridin-2-ol Chemical compound OC1=CC=CC=N1 UBQKCCHYAOITMY-UHFFFAOYSA-N 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- RXTQGIIIYVEHBN-UHFFFAOYSA-N pyrimido[4,5-b]indol-2-one Chemical compound C1=CC=CC2=NC3=NC(=O)N=CC3=C21 RXTQGIIIYVEHBN-UHFFFAOYSA-N 0.000 description 1
- SRBUGYKMBLUTIS-UHFFFAOYSA-N pyrrolo[2,3-d]pyrimidin-2-one Chemical compound O=C1N=CC2=CC=NC2=N1 SRBUGYKMBLUTIS-UHFFFAOYSA-N 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 150000007660 quinolones Chemical class 0.000 description 1
- 230000006798 recombination Effects 0.000 description 1
- 238000005215 recombination Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000014493 regulation of gene expression Effects 0.000 description 1
- 125000006853 reporter group Chemical group 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 108091092562 ribozyme Proteins 0.000 description 1
- 101150014273 rsmH gene Proteins 0.000 description 1
- 101150108659 secA gene Proteins 0.000 description 1
- 239000004065 semiconductor Substances 0.000 description 1
- 201000001223 septic arthritis Diseases 0.000 description 1
- 230000036303 septic shock Effects 0.000 description 1
- 101150093914 seqA gene Proteins 0.000 description 1
- 230000009919 sequestration Effects 0.000 description 1
- 208000026775 severe diarrhea Diseases 0.000 description 1
- 230000009528 severe injury Effects 0.000 description 1
- 229940007046 shigella dysenteriae Drugs 0.000 description 1
- 229910052709 silver Inorganic materials 0.000 description 1
- 239000004332 silver Substances 0.000 description 1
- 201000009890 sinusitis Diseases 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010532 solid phase synthesis reaction Methods 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 229960000268 spectinomycin Drugs 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 238000002798 spectrophotometry method Methods 0.000 description 1
- 239000012798 spherical particle Substances 0.000 description 1
- 208000000995 spontaneous abortion Diseases 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000004544 sputter deposition Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 230000035882 stress Effects 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 101150073502 sulA gene Proteins 0.000 description 1
- 150000003456 sulfonamides Chemical group 0.000 description 1
- 125000001273 sulfonato group Chemical group [O-]S(*)(=O)=O 0.000 description 1
- 150000003457 sulfones Chemical group 0.000 description 1
- 150000003462 sulfoxides Chemical group 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229940042055 systemic antimycotics triazole derivative Drugs 0.000 description 1
- 206010056873 tertiary syphilis Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229940040944 tetracyclines Drugs 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 125000000101 thioether group Chemical group 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 230000008280 toxic mechanism Effects 0.000 description 1
- 230000005026 transcription initiation Effects 0.000 description 1
- 230000002103 transcriptional effect Effects 0.000 description 1
- 238000001890 transfection Methods 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 231100000397 ulcer Toxicity 0.000 description 1
- 210000003708 urethra Anatomy 0.000 description 1
- 238000005019 vapor deposition process Methods 0.000 description 1
- 108700026220 vif Genes Proteins 0.000 description 1
- 238000010792 warming Methods 0.000 description 1
- 238000009736 wetting Methods 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/15—Oximes (>C=N—O—); Hydrazines (>N—N<); Hydrazones (>N—N=) ; Imines (C—N=C)
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/424—Oxazoles condensed with heterocyclic ring systems, e.g. clavulanic acid
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
-
- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/436—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
-
- 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
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/7125—Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7088—Compounds having three or more nucleosides or nucleotides
- A61K31/713—Double-stranded nucleic acids or oligonucleotides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6921—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere
- A61K47/6923—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being a particulate, a powder, an adsorbate, a bead or a sphere the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Molecular Biology (AREA)
- Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Communicable Diseases (AREA)
- General Engineering & Computer Science (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- Inorganic Chemistry (AREA)
- Medical Informatics (AREA)
- Crystallography & Structural Chemistry (AREA)
- Ceramic Engineering (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
- Medicinal Preparation (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
本願は、米国特許法第119条(e)項の下、2009年1月8日に出願された米国仮特許出願第61/143,293号、および2009年4月15日に出願された米国仮特許出願第61/169,384号の利益を主張し、この米国仮特許出願の全体の内容は、本明細書中に参考として援用される。
本発明は、国立衛生研究所により授与された助成金番号5DP1OD000285の下、政府支援により成された。合衆国政府は、本発明に特定の権利を有する。
本発明は、オリゴヌクレオチド修飾ナノ粒子コンジュゲートおよび細菌タンパク質産生を阻害する方法に関する。
細菌増殖を調節するための新しい作用物質の開発は、最も重要なことである。抗生物質剤への分子的アプローチは有益な結果を生んでいるが、現行の抗生物質処置は、細菌が抗生物質抵抗性を構築するにつれて、より限定的になりつつある。無数の細菌機能を標的にする複数のクラスの抗生物質が存在する。網羅的な列挙ではないが、いくつかの様式として、細菌タンパク質産生を標的にする(翻訳ブロック、例えば、抗リボソーム剤)こと、細菌の細胞壁の完全性を標的にすること、およびゲノム完全性を標的にする(例えば、DNAジャイレース)ことが挙げられる。それにもかかわらず、これらの作用物質の大多数は、接合を介しての、細菌進化および伝達可能な抵抗性の発生によって中和されており、その上、その残りは、同じ運命に会うと予想される。場合によっては、細菌の抵抗性は、1つの細菌種から別の細菌種へと飛び越している。加えて、現行の抗生物質の広範な使用が、たいていの医療行為に抵抗する「スーパー株」の出現をもたらしている。したがって、細菌を標的にする新しいクラスの薬物が研究の優先事項である。
オリゴヌクレオチド修飾ナノ粒子およびキャリアーを含む抗生組成物であって、オリゴヌクレオチドが、原核生物遺伝子の標的非コード配列に対して、ハイブリダイゼーションを可能にする条件下でその標的配列にハイブリダイズするのに十分相補的である、抗生組成物が本明細書に記載されている。本明細書に記載された抗生組成物は、原核細胞に入り、原核生物遺伝子転写および/または翻訳を制御する。
抗生組成物およびその使用方法が本明細書に提供される。一態様において、抗生組成物は、オリゴヌクレオチドを含むように修飾されたナノ粒子を含み、オリゴヌクレオチドが、原核生物遺伝子の標的非コード配列に対して、ハイブリダイゼーションを可能にする条件下でオリゴヌクレオチドが標的配列にハイブリダイズするように十分相補的である。このハイブリダイゼーションを通して、抗生組成物は、標的原核細胞の増殖を阻害する。標的細胞において、ある特定の態様では、ハイブリダイゼーションは、標的にされた配列によってコードされる機能性タンパク質の発現を阻害する。様々な態様において、標的にされた配列によってコードされる原核生物タンパク質の転写、翻訳、または両方が阻害される。本開示は、細胞を抗生組成物と接触させる工程を含む、細胞において標的原核生物遺伝子産物の産生を阻害するための、本明細書に開示された抗生組成物を利用する方法であって、組成物のナノ粒子に会合したオリゴヌクレオチドが、ハイブリダイゼーションを可能にする条件下で細菌遺伝子の標的非コード配列に十分相補的であり、かつハイブリダイゼーションが結果として、標的遺伝子によってコードされる機能性原核生物遺伝子産物の阻害を生じる、方法をさらに提供する。標的原核生物配列の転写か翻訳のいずれか、または転写と翻訳の両方の阻害が、結果として、標的原核生物配列によってコードされる機能性タンパク質の産生の阻害を生じることは、当業者に理解されているであろう。
いくつかの実施形態において、本開示は、オリゴヌクレオチド修飾ナノ粒子およびキャリアーを含む抗生組成物であって、オリゴヌクレオチドが、原核生物遺伝子の標的非コード配列に対して、ハイブリダイゼーションを可能にする条件下でそれが標的配列にハイブリダイズするのに十分相補的である、抗生組成物を提供する。様々な実施形態において、抗生組成物は、原核細胞感染症処置のためのそれを必要する哺乳動物への治療的有効量での投与のために製剤化される。いくつかの態様において、哺乳動物はヒトである。
いくつかの実施形態において、オリゴヌクレオチド修飾ナノ粒子コンジュゲートを含む抗生組成物は、抗生物質剤と併用しての投与のために製剤化され、それぞれが治療的有効量である。
本明細書に用いられる場合、用語「治療的有効量」は、同定された疾患もしくは症状を処置するか、寛解させるか、もしくは予防するのに十分な、または検出可能な治療的、予防的、もしくは阻害的効果を示すのに十分な組成物の量を指す。効果は、例えば、臨床症状の改善、徴候の低下により、または本明細書に記載されたアッセイにより検出することができる。対象についての正確な有効量は、対象の体重、サイズ、および健康状態;症状の性質および程度;ならびに投与のために選択された抗生組成物または組成物の組合せに依存する。所定の状況についての治療的有効量は、臨床医の技能および判断の範囲内にある日常的実験によって決定することができる。
いくつかの態様において、本開示は、特定の核酸を標的にする方法を提供する。任意の型の原核生物核酸を標的にすることができ、その方法は、例えば、機能性原核生物遺伝子産物の産生の阻害のために用いることができる。本発明の方法によって標的にすることができる核酸の例には、遺伝子、および原核生物のRNAまたはDNAが挙げられるが、それらに限定されない。
本開示のオリゴヌクレオチドは、標的ポリヌクレオチド配列とハイブリダイズしたとき、少なくとも約45℃、典型的には、約50℃から60℃の間のTmを有するが、Tmはより高く、例えば、65℃であってもよい。原核生物標的ポリヌクレオチド配列および原核生物mRNA標的ポリヌクレオチド配列の選択を、本明細書の下記で考察する。
本開示のオリゴヌクレオチドは、必須原核生物遺伝子をコードする原核生物核酸の配列にハイブリダイズするように設計される。例示的な遺伝子として、細胞分裂タンパク質、細胞周期タンパク質に必要とされるもの、または脂質生合成もしくは核酸複製に必要とされる遺伝子が挙げられるが、それらに限定されない。いったん遺伝子の必須性が決定されたならば、いかなる必須細菌遺伝子も標的である。生物体におけるどの遺伝子が必須であるかを決定するための一つのアプローチは、記載されているように[Gerdesら、J Bacteriol.185(19):5673−84、2003(その全体が参照により本明細書に組み入れられている)]、遺伝子フットプリンティング技術を用いることである。この報告において、健全な好気性増殖のための培養条件下での増殖にとって、620個の大腸菌遺伝子が必須として、3,126個の遺伝子が不要として、同定された。進化関連分析により、かなりの数の必須大腸菌遺伝子、特に、DNA複製、細胞分裂、およびタンパク質合成などの重要な細胞過程についての遺伝子のサブセットが細菌界を通じて保存されていることが示された。
一実施形態において、本発明のオリゴヌクレオチドは、37℃よりかなり高い、例えば、少なくとも45℃、好ましくは60℃〜80℃のTmを有し、生理学的条件下で細菌16S rRNA核酸配列をコードする配列にハイブリダイズするように設計される。
家畜の胃腸管における健康な細菌叢は、健康、および対応する関連食品の生産にとって極めて重要である。ヒトと同様に、健康な動物の胃腸管は、多数の型の細菌(すなわち、大腸菌、Pseudomonas aeruginosa、およびSalmonella spp.)を含み、それらの細菌は、お互いに生態学的バランスの中で生きている。このバランスは、食事、ストレスの変化によって、または抗生物質もしくは他の治療的処置に応答して、乱される場合があり、その結果として、一般的にSalmonella、Campylobacter、Enterococci、Tularemia、および大腸菌などの細菌によって引き起こされる、動物における細菌性疾患を生じ得る。これらの動物における細菌感染は、治療的介入を必要とすることが多く、それは処置費用がかかり、加えて、生産性の減少を伴うことが多い。
ポリヌクレオチドが付着しているように官能基化されているナノ粒子が提供される。ナノ粒子のサイズ、形、および化学組成は、結果として生じるポリヌクレオチド官能基化ナノ粒子の性質に寄与する。これらの性質には、例えば、光学的性質、光電子工学的性質、電気化学的性質、電子工学的性質、様々な溶液における安定性、磁気的性質、ならびにポアおよびチャネルのサイズ変化が挙げられる。均一なサイズ、形、および/または化学組成を有するナノ粒子の使用に加えて、異なるサイズ、形、および/または化学組成を有するナノ粒子の混合物、ならびに、それにしたがって、性質の混合物が意図される。適切な粒子の例として、非限定的に、米国特許第7,238,472号および国際公開第2003/08539号(それらの特許の開示は、その全体が参照により組み入れられている)に記載されたものなどの、凝集粒子、等方性粒子(球状粒子など)、異方性粒子(非球状円柱、4面体、および/または角柱など)、およびコアシェル粒子が挙げられる。
本明細書に用いられる場合、用語「ヌクレオチド」またはその複数形は、本明細書に論じられているような、および当技術分野において他の形で公知のような修飾型と交換可能である。ある特定の場合、当技術分野は、天然のヌクレオチド、および修飾ヌクレオチドを含む非天然のヌクレオチドを包含する用語「核酸塩基」を用いる。したがって、ヌクレオチドまたは核酸塩基は、天然の核酸塩基のアデニン(A)、グアニン(G)、シトシン(C)、チミン(T)、およびウラシル(U)を意味する。非天然の核酸塩基には、例えば、非限定的に、キサンチン、ジアミノプリン、8−オキソ−N6−メチルアデニン、7−デアザキサンチン、7−デアザグアニン、N4,N4−エタノシトシン、N’,N’−エタノ−2,6−ジアミノプリン、5−メチルシトシン(mC)、5−(C3−C6)−アルキニル−シトシン、5−フルオロウラシル、5−ブロモウラシル、プソイドイソシトシン、2−ヒドロキシ−5−メチル−4−トリアゾロピリジン、イソシトシン、イソグアニン、イノシン、ならびにBennerら、米国特許第5,432,272号、Susan M.FreierおよびKarl−Heinz Altmann、1997、Nucleic Acids Research、25巻:4429−4443ページに記載された「非天然の」核酸塩基が挙げられる。用語「核酸塩基」はまた、公知のプリンおよびピリミジン複素環だけでなく、複素環類似体およびその互変異性体も含む。さらに天然および非天然の核酸塩基として、米国特許第3,687,808号(Meriganら)、Antisense Research and Application、S.T.CrookeおよびB.Lebleu編、CRC Press、1993のSanghviによる15章、Englischら、1991、Angewandte Chemie、International Edition、30:613−722(特に622ページおよび623ページ参照)、ならびにConcise Encyclopedia of Polymer Science and Engineering、J.I.Kroschwitz編、John Wiley & Sons、1990、858−859ページ、Cook、Anti−Cancer Drug Design 1991、6、585−607(それぞれは、その全体が参照により本明細書に組み入れられている)に開示されたものが挙げられる。様々な態様において、ポリヌクレオチドはまた、核酸塩基のように働くことができる複素環化合物などの化合物を含む非天然のヌクレオチドのカテゴリーである、1つ以上の「ヌクレオシド塩基」または「塩基単位」を含み、それらには、最も古典的な意味においてはヌクレオシド塩基ではないが、ヌクレオシド塩基として働く特定の「ユニバーサル塩基」が挙げられる。ユニバーサル塩基には、3−ニトロピロール、任意に置換されたインドール(例えば、5−ニトロインドール)、および任意に置換されたヒポキサンチンが挙げられる。他の望ましいユニバーサル塩基として、当技術分野において公知のユニバーサル塩基を含む、ピロール、ジアゾールまたはトリアゾール誘導体が挙げられる。
上記で論じられているように、ナノ粒子を官能基化するための修飾オリゴヌクレオチドが意図される。様々な態様において、ナノ粒子上に官能性付与するオリゴヌクレオチドは、完全に修飾されるか、または部分的に修飾されている。したがって、様々な態様において、ポリヌクレオチドにおけるヌクレオチド単位の1つもしくは複数、もしくは全部の糖、および/または1つもしくは複数もしくは全部のヌクレオチド間連結が、「非天然の」群で置き換えられている。
本方法に用いるために意図されるオリゴヌクレオチドには、任意の手段を通してナノ粒子に結合したものが挙げられる。どんな手段によってオリゴヌクレオチドがナノ粒子に付着していようと、様々な態様における付着は、5’連結、3’連結、いくつかの型の内部連結、またはこれらの付着の任意の組合せを通してもたらされる。
ある特定の態様において、オリゴヌクレオチドおよびドメインがスペーサーを通してナノ粒子に付着しているものを含む官能基化ナノ粒子が意図される。本明細書に用いられる場合、「スペーサー」は、それ自体、遺伝子発現を調節するのに関与しないが、ナノ粒子と官能基オリゴヌクレオチドとの間の距離を増加させるか、または複数コピーでナノ粒子に付着している場合、個々のオリゴヌクレオチド間の距離を増加させる働きをする部分を意味する。したがって、オリゴヌクレオチドが同じ配列を有しようと異なる配列を有しようと、スペーサーは、直列型での個々のオリゴヌクレオチドの間に位置することが意図される。ドメインがナノ粒子に直接付着している本発明の態様において、ドメインは、任意で、スペーサーを通してナノ粒子に官能性付与してもよい。直列型でのドメインがナノ粒子に官能性付与している態様において、スペーサーは、任意で、直列型構造におけるドメイン単位の一部または全部の間にあってもよい。一態様において、スペーサーは、存在する場合、有機質部分である。別の態様において、スペーサーはポリマーであり、それには、水溶性ポリマー、核酸、ポリペプチド、オリゴ糖、糖質、脂質、エチルグリコール、またはそれらの組合せが挙げられるが、それらに限定されない。
本明細書に提供されるナノ粒子は、様々な態様において、ナノ粒子間および単一のナノ粒子上のポリヌクレオチド鎖間で結果的に協調行動を生じるのに十分であるナノ粒子の表面上でのポリヌクレオチドのパッキング密度を有する。別の態様において、ナノ粒子間の協調行動は、ポリヌクレオチドのヌクレアーゼ分解に対する抵抗性を増加させる。さらに別の態様において、ナノ粒子の細胞による取り込みは、ナノ粒子に会合したポリヌクレオチドの密度によって影響される。全体が参照により本明細書に組み入れられているPCT/US2008/65366に記載されているように、ナノ粒子表面上のポリヌクレオチドのより高い密度は、ナノ粒子の細胞による取り込みの増加と関連している。
ナノ粒子の調製
クエン酸塩安定化金ナノ粒子(1〜250nm)を、公開された手順を用いて調製する[G.Frens、Nature Physical Science.1973、241、20]。この実施例において13nmおよび5nmのサイズを用いるが、他の実施例は、1nm〜500nmのサイズのナノ粒子を含む。簡単に述べると、テトラクロロ金酸を還流水中のクエン酸塩での処理によって還元する。粒子サイズおよび分散度は、透過型電子顕微鏡およびuv/vis分光光度法を用いて確認することができる。チオール化オリゴヌクレオチドを、標準固相ホスホラミダイト方法を用いて合成する[Pon,R.T.、Solid−phase supports for oligonucleotide synthesis.、Methods in Molecular Biology(Totowa、NJ、United States)(1993)、20(Protocols for Oligonucleotides and Analogs)、465−496]。チオール修飾オリゴヌクレオチドを次に、10nMコロイドの1mLあたり3nmolのオリゴヌクレオチドの濃度で13±1nmおよび5nmの金コロイドに加え、一晩、振盪する。12時間後、ドデシル硫酸ナトリウム(SDS)溶液(10%)をその混合物に、0.1%SDS濃度に達するように加え、リン酸緩衝液(0.1M;pH=7.4)をその混合物に、0.01リン酸濃度に達するように加え、塩化ナトリウム溶液(2.0M)をその混合物に、0.1M塩化ナトリウム濃度に達するように加える。その後、6つの塩化ナトリウム溶液(2.0M)のアリコートをその混合物に、0.3Mの最終塩化ナトリウム濃度に達するように8時間かけて加え、一晩、振盪して、官能基化過程を完了する。その溶液を遠心分離し(13,000rpm、20分)、滅菌リン酸緩衝食塩水中に3回、再懸濁して、精製されたコンジュゲートを作製する。
オリゴヌクレオチド修飾ナノ粒子コンジュゲート方法
この実施例におけるオリゴヌクレオチド設計は、2つの可能な作用機構を含む。第1に、アンピシリン抵抗性(AmpR)遺伝子β−ラクタマーゼについてのプロモーター部位のセンス鎖に優先的にハイブリダイズする公開されたプラスミド配列を用いて、配列を設計した。これは、細菌ゲノムにおけるAmpRのプロモーター配列への(粒子のより好ましい結合定数および/または細胞内濃度を与えられた)コンジュゲートの優先的ハイブリダイゼーションを利用することによって、細菌のアンピシリンに対する感受性を増加させるであろう。これは、プロモーター複合体がその標的部位に結合するのを阻止して、mRNA転写産物(Amp抵抗性遺伝子)の転写を阻止し、それにしたがって、細菌のアンピシリンに対する感受性を増加させるであろう。用いられる配列は、5’−AT TGT CTC ATG AGC GGA TAC ATA TTT GAA AAA AAA AAA A−SH−3’(配列番号1)および5’−AT TGT CTC ATG AGC GGA TAC AAA AAA AAA A−SH−3’(配列番号2)であった。
オリゴヌクレオチド修飾ナノ粒子コンジュゲートは転写ノックダウンを達成する
追加のストラテジーを用いて、プラスミド由来ルシフェラーゼ遺伝子における転写ノックダウンを調べた。このモデルを用いて、ルシフェラーゼノックダウンを、ウミシイタケ(Renilla)発現をコードするプラスミド上の別途の領域と区別することによって部位選択的遺伝子ノックダウンを実証した。この効果をアッセイするために、二重ルシフェラーゼレポーターアッセイ系(Dual−Luciferase Reporter Assay System)(Promega)を用いた。このモデルについて用いられるストラテジーは、ルシフェラーゼ遺伝子の完全mRNA転写産物の形成をブロックすることであった。これは、結果としてウミシイタケに関連したルシフェラーゼシグナルの減少を生じる。これに用いられる配列は、5’−CCC GAG CAA CGC AAA CGC AAA AAA AAA AA−SH−3’(配列番号4)であった。あるいは、プロモーター複合体がその標的部位に結合するのをブロックするために、上記で用いられたものと類似したストラテジーを用いることができた。この実施例において、5nm粒子を用いた。12時間後の生じたノックダウンは、300nM濃度の粒子を用いて、59%であった(p値=0.0004)。これらの結果は、転写レベルで遺伝子制御を達成する別の方法を実証している。データの要約は図3に示されている。
オリゴヌクレオチド修飾ナノ粒子コンジュゲートの転写のブロック
二本鎖ゲノムDNAとハイブリダイズすることによって転写およびその後のタンパク質産生をブロックするこれらのコンジュゲートの能力の実証として、インビトロ転写アッセイを行った。ルシフェラーゼ遺伝子をコードする二本鎖プラスミドDNAを含むインビトロ転写反応(Promega)にオリゴヌクレオチド官能基化金ナノ粒子を加えた。オリゴヌクレオチド配列は、ルシフェラーゼ遺伝子のセンス鎖を標的にし、それにしたがって、転写だけでなく、翻訳もブロックすることができた。対照として、非相補的配列で官能基化されたナノ粒子コンジュゲートもまた、同一の様式で用いた。転写反応を進行させ、ルシフェラーゼ活性を市販のキット(Promega)を用いて測定した。ルシフェラーゼ遺伝子を標的にするナノ粒子コンジュゲートを含む試料において、非相補的配列でのナノ粒子コンジュゲートを含む対照反応物と比較して、ルシフェラーゼ活性の有意な低下(>75%)が観察された。
Claims (25)
- オリゴヌクレオチド修飾ナノ粒子を含む抗生組成物であって、該オリゴヌクレオチドが、原核生物遺伝子の標的非コード配列に対して、ハイブリダイゼーションを可能にする条件下で該標的非コード配列にハイブリダイズするのに十分相補的である、抗生組成物。
- 原核生物遺伝子へのハイブリダイゼーションが原核細胞の増殖を阻害する、請求項1に記載の抗生組成物。
- オリゴヌクレオチドのハイブリダイゼーションが、原核生物遺伝子によってコードされる機能性原核生物タンパク質の発現を阻害する、請求項1または請求項2に記載の抗生組成物。
- 前記機能性原核生物タンパク質の発現が、前記オリゴヌクレオチド修飾ナノ粒子と接触されない細胞と比較して、約75%阻害される、請求項3に記載の抗生組成物。
- ハイブリダイゼーションが、変化した活性を有する、原核生物遺伝子によってコードされるタンパク質の発現をもたらす、請求項1〜4のいずれか一項に記載の抗生組成物。
- 前記活性が、前記オリゴヌクレオチド修飾ナノ粒子と接触されない細胞と比較して、約10%低下している、請求項5に記載の抗生組成物。
- ハイブリダイゼーションが、前記原核生物遺伝子の転写を阻害する、請求項1〜6のいずれか一項に記載の抗生組成物。
- ハイブリダイゼーションが、前記原核生物遺伝子によってコードされる機能性タンパク質の翻訳を阻害する、請求項1〜7のいずれか一項に記載の抗生組成物。
- 前記オリゴヌクレオチドのハイブリダイゼーションが、前記原核細胞増殖に必須の機能性タンパク質の発現を阻害する、請求項1〜8のいずれか一項に記載の抗生組成物。
- 前記オリゴヌクレオチドのハイブリダイゼーションが、原核細胞増殖に必須の機能性タンパク質の発現を阻害し、該原核細胞増殖に必須の機能性タンパク質が、グラム陰性遺伝子産物、グラム陽性遺伝子産物、細胞周期遺伝子産物、DNA複製に関与する遺伝子産物、細胞分裂遺伝子産物、タンパク質合成に関与する遺伝子産物、細菌ジャイレース、およびアシルキャリアー遺伝子産物からなる群から選択される、請求項9に記載の抗生組成物。
- 前記原核生物遺伝子が、抗生物質抵抗性を与えるタンパク質をコードする、請求項1〜10のいずれか一項に記載の抗生組成物。
- 抗生物質剤をさらに含む、請求項1〜11のいずれか一項に記載の抗生組成物。
- 前記抗生物質剤が、ペニシリンG、メチシリン、ナフシリン、オキサシリン、クロキサシリン、ジクロキサシリン、アンピシリン、アモキシシリン、チカルシリン、カルベニシリン、メズロシリン、アズロシリン、ピペラシリン、イミペネム、アズトレオナム、セファロチン、セファクロール、セフォキシチン、セフロキシム、セフォニシド、セフメタゾール、セフォテタン、セフプロジル、ロラカルベフ、セフェタメット、セフォペラゾン、セフォタキシム、セフチゾキシム、セフトリアキソン、セフタジジム、セフェピム、セフィキシム、セフポドキシム、セフスロジン、フレロキサシン、ナリジキシン酸、ノルフロキサシン、シプロフロキサシン、オフロキサシン、エノキサシン、ロメフロキサシン、シノキサシン、ドキシサイクリン、ミノサイクリン、テトラサイクリン、アミカシン、ゲンタマイシン、カナマイシン、ネチルマイシン、トブラマイシン、ストレプトマイシン、アジスロマイシン、クラリスロマイシン、エリスロマイシン、エリスロマイシンエストレート、エチルコハク酸エリスロマイシン、グルコヘプトン酸エリスロマイシン、ラクトビオン酸エリスロマイシン、ステアリン酸エリスロマイシン、バンコマイシン、テイコプラニン、クロラムフェニコール、クリンダマイシン、トリメトプリム、スルファメトキサゾール、ニトロフラントイン、リファンピン、ムピロシン、メトロニダゾール、セファレキシン、ロキシスロマイシン、コ−アモキシクラブアネート(Co−amoxiclavuanate)、ピペラシリンとタゾバクタムとの組合せ、ならびにそれらの様々な塩、酸、塩基、および他の誘導体からなる群から選択される、請求項12に記載の抗生組成物。
- 前記オリゴヌクレオチドが、前記原核生物遺伝子の非コード鎖内の配列に十分相補的である、請求項1〜13のいずれか一項に記載の抗生組成物。
- 前記オリゴヌクレオチドが、前記原核生物遺伝子の非コード配列内の配列に対して、三重鎖構造を形成するのに十分相補的である、請求項1〜14のいずれか一項に記載の抗生組成物。
- ハイブリダイゼーションが、前記オリゴヌクレオチドと、前記非コード配列と、該非コード配列に対して相補的なコード配列との間で三本鎖構造を形成する、請求項1〜15のいずれか一項に記載の抗生組成物。
- 前記オリゴヌクレオチドが、前記原核生物遺伝子の非コード配列内の配列に対して、該オリゴヌクレオチドと該非コード配列との間で二本鎖構造を形成するのに十分相補的である、請求項1〜16のいずれか一項に記載の抗生組成物。
- 前記非コード配列がプロモーター配列である、請求項1〜17のいずれか一項に記載の抗生組成物。
- 前記オリゴヌクレオチドが3’非コード配列にハイブリダイズする、請求項1〜18のいずれか一項に記載の抗生組成物。
- 前記オリゴヌクレオチドが5’非コード配列にハイブリダイズする、請求項1〜19のいずれか一項に記載の抗生組成物。
- インビトロで標的配列にハイブリダイズする、請求項1〜20のいずれか一項に記載の抗生組成物。
- インビボで標的配列にハイブリダイズする、請求項1〜21のいずれか一項に記載の抗生組成物。
- 細胞において標的遺伝子産物の産生を阻害する方法であって、
ハイブリダイゼーションが結果として、標的遺伝子によってコードされる機能性タンパク質の産生の阻害を生じる条件下で、該細胞を請求項1〜22のいずれか一項に記載の抗生組成物と接触させる工程を含む、方法。 - 原核生物感染症を処置する方法であって、請求項1〜22のいずれか一項に記載のナノ粒子を含む治療的有効量の組成物を細胞に投与する工程を含む、方法。
- 抗生物質および請求項1〜22のいずれか一項に記載のナノ粒子を含むキット。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US14329309P | 2009-01-08 | 2009-01-08 | |
US61/143,293 | 2009-01-08 | ||
US16938409P | 2009-04-15 | 2009-04-15 | |
US61/169,384 | 2009-04-15 | ||
PCT/US2010/020558 WO2010081049A1 (en) | 2009-01-08 | 2010-01-08 | Inhibition of bacterial protein production by polyvalent oligonucleotide modified nanoparticle conjugates |
Publications (3)
Publication Number | Publication Date |
---|---|
JP2012514656A true JP2012514656A (ja) | 2012-06-28 |
JP2012514656A5 JP2012514656A5 (ja) | 2013-02-28 |
JP5801205B2 JP5801205B2 (ja) | 2015-10-28 |
Family
ID=42316849
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2011545476A Expired - Fee Related JP5801205B2 (ja) | 2009-01-08 | 2010-01-08 | 多価オリゴヌクレオチド修飾ナノ粒子コンジュゲートによる細菌タンパク質産生の阻害 |
Country Status (9)
Country | Link |
---|---|
US (1) | US20100184844A1 (ja) |
EP (1) | EP2385760A4 (ja) |
JP (1) | JP5801205B2 (ja) |
KR (1) | KR20110102492A (ja) |
CN (1) | CN102307470B (ja) |
AU (1) | AU2010203474B2 (ja) |
CA (1) | CA2749536A1 (ja) |
MX (1) | MX2011007350A (ja) |
WO (1) | WO2010081049A1 (ja) |
Families Citing this family (26)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8252756B2 (en) | 2005-06-14 | 2012-08-28 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
MX2009008470A (es) | 2007-02-09 | 2009-11-26 | Univ Northwestern | Particulas para detectar objetivos intracelulares. |
MX2010011680A (es) | 2008-04-25 | 2011-05-03 | Univ Northwestern | Nanoestructuras adecuadas para secuestrar colesterol y otras moleculas. |
WO2010060110A1 (en) | 2008-11-24 | 2010-05-27 | Northwestern University | Polyvalent rna-nanoparticle compositions |
US20100233270A1 (en) | 2009-01-08 | 2010-09-16 | Northwestern University | Delivery of Oligonucleotide-Functionalized Nanoparticles |
KR20120022938A (ko) | 2009-04-15 | 2012-03-12 | 노오쓰웨스턴 유니버시티 | 올리고뉴클레오티드 관능화된 나노입자의 전달 |
KR20120136345A (ko) | 2009-10-30 | 2012-12-18 | 노오쓰웨스턴 유니버시티 | 주형화된 나노컨쥬게이트 |
WO2011091065A2 (en) | 2010-01-19 | 2011-07-28 | Northwestern University | Synthetic nanostructures including nucleic acids and/or other entities |
CN104024854A (zh) | 2011-09-11 | 2014-09-03 | 奥拉森斯有限责任公司 | 细胞摄取对照系统 |
EP2755692B1 (en) | 2011-09-14 | 2020-11-25 | Northwestern University | Nanoconjugates able to cross the blood-brain barrier |
US10260089B2 (en) | 2012-10-29 | 2019-04-16 | The Research Foundation Of The State University Of New York | Compositions and methods for recognition of RNA using triple helical peptide nucleic acids |
AU2014292928A1 (en) | 2013-07-25 | 2016-03-03 | Exicure, Inc. | Spherical nucleic acid-based constructs as immunoregulatory agents |
ES2750608T3 (es) | 2013-07-25 | 2020-03-26 | Exicure Inc | Construcciones esféricas a base de ácido nucleico como agentes inmunoestimulantes para uso profiláctico y terapéutico |
US10568898B2 (en) | 2013-08-13 | 2020-02-25 | Northwestern University | Lipophilic nanoparticles for drug delivery |
KR102290205B1 (ko) | 2014-06-04 | 2021-08-20 | 엑시큐어, 인크. | 예방 또는 치료 용도를 위한 리포솜성 구형 핵산에 의한 면역 조절인자의 다가 전달 |
MX2017004448A (es) | 2014-10-06 | 2017-10-23 | Exicure Inc | Compuestos anti-factor de necrosis tumoral (tnf). |
WO2016081911A2 (en) | 2014-11-21 | 2016-05-26 | Northwestern University | The sequence-specific cellular uptake of spherical nucleic acid nanoparticle conjugates |
US10517924B2 (en) | 2014-11-24 | 2019-12-31 | Northwestern University | High density lipoprotein nanoparticles for inflammation |
US10078092B2 (en) | 2015-03-18 | 2018-09-18 | Northwestern University | Assays for measuring binding kinetics and binding capacity of acceptors for lipophilic or amphiphilic molecules |
DE102016000865A1 (de) * | 2016-01-28 | 2017-08-03 | Friz Biochem Gesellschaft Für Bioanalytik Mbh | Funktionalisierte metallische Nanopartikel |
EP3452598A4 (en) | 2016-05-06 | 2020-04-29 | Exicure, Inc. | LIPOSOMAL SPHERIC NUCLEIC ACID (SNA) CONSTRUCTS WITH ANTISENSE OLIGONUCLEOTIDES (ASO) FOR THE SPECIFIC KNOCKDOWN OF INTERLEUKIN-17 RECEPTOR MRNA |
WO2018039629A2 (en) | 2016-08-25 | 2018-03-01 | Northwestern University | Micellar spherical nucleic acids from thermoresponsive, traceless templates |
US11696954B2 (en) | 2017-04-28 | 2023-07-11 | Exicure Operating Company | Synthesis of spherical nucleic acids using lipophilic moieties |
US10973927B2 (en) | 2017-08-28 | 2021-04-13 | The Chinese University Of Hong Kong | Materials and methods for effective in vivo delivery of DNA nanostructures to atherosclerotic plaques |
CN109045056A (zh) * | 2018-07-04 | 2018-12-21 | 重庆第二师范学院 | 多药载药靶向纳米颗粒及其制备方法和应用 |
WO2020072976A1 (en) * | 2018-10-04 | 2020-04-09 | The Regents Of The University Of California | Discovery of novel anti-infectives for gram negative pathogens |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6144820A (ja) * | 1984-07-25 | 1986-03-04 | サントル ナシオナル ド ラ ルシエルシユ シアンテイフイク | 遺伝子発現の選択的阻害剤 |
JP2001516724A (ja) * | 1997-09-16 | 2001-10-02 | ペーター・エー・ニールセン | 抗菌活性を有するペプチド核酸 |
WO2006138145A1 (en) * | 2005-06-14 | 2006-12-28 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
Family Cites Families (99)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5023243A (en) * | 1981-10-23 | 1991-06-11 | Molecular Biosystems, Inc. | Oligonucleotide therapeutic agent and method of making same |
US4640835A (en) * | 1981-10-30 | 1987-02-03 | Nippon Chemiphar Company, Ltd. | Plasminogen activator derivatives |
JPS5927900A (ja) * | 1982-08-09 | 1984-02-14 | Wakunaga Seiyaku Kk | 固定化オリゴヌクレオチド |
FR2540122B1 (fr) * | 1983-01-27 | 1985-11-29 | Centre Nat Rech Scient | Nouveaux composes comportant une sequence d'oligonucleotide liee a un agent d'intercalation, leur procede de synthese et leur application |
US4824941A (en) * | 1983-03-10 | 1989-04-25 | Julian Gordon | Specific antibody to the native form of 2'5'-oligonucleotides, the method of preparation and the use as reagents in immunoassays or for binding 2'5'-oligonucleotides in biological systems |
US4587044A (en) * | 1983-09-01 | 1986-05-06 | The Johns Hopkins University | Linkage of proteins to nucleic acids |
US5118802A (en) * | 1983-12-20 | 1992-06-02 | California Institute Of Technology | DNA-reporter conjugates linked via the 2' or 5'-primary amino group of the 5'-terminal nucleoside |
US5118800A (en) * | 1983-12-20 | 1992-06-02 | California Institute Of Technology | Oligonucleotides possessing a primary amino group in the terminal nucleotide |
US4496689A (en) * | 1983-12-27 | 1985-01-29 | Miles Laboratories, Inc. | Covalently attached complex of alpha-1-proteinase inhibitor with a water soluble polymer |
FR2567892B1 (fr) * | 1984-07-19 | 1989-02-17 | Centre Nat Rech Scient | Nouveaux oligonucleotides, leur procede de preparation et leurs applications comme mediateurs dans le developpement des effets des interferons |
US4828979A (en) * | 1984-11-08 | 1989-05-09 | Life Technologies, Inc. | Nucleotide analogs for nucleic acid labeling and detection |
US5405938A (en) * | 1989-12-20 | 1995-04-11 | Anti-Gene Development Group | Sequence-specific binding polymers for duplex nucleic acids |
US5185444A (en) * | 1985-03-15 | 1993-02-09 | Anti-Gene Deveopment Group | Uncharged morpolino-based polymers having phosphorous containing chiral intersubunit linkages |
DE3675588D1 (de) * | 1985-06-19 | 1990-12-20 | Ajinomoto Kk | Haemoglobin, das an ein poly(alkenylenoxid) gebunden ist. |
US5317098A (en) * | 1986-03-17 | 1994-05-31 | Hiroaki Shizuya | Non-radioisotope tagging of fragments |
EP0260032B1 (en) * | 1986-09-08 | 1994-01-26 | Ajinomoto Co., Inc. | Compounds for the cleavage at a specific position of RNA, oligomers employed for the formation of said compounds, and starting materials for the synthesis of said oligomers |
US5276019A (en) * | 1987-03-25 | 1994-01-04 | The United States Of America As Represented By The Department Of Health And Human Services | Inhibitors for replication of retroviruses and for the expression of oncogene products |
US4904582A (en) * | 1987-06-11 | 1990-02-27 | Synthetic Genetics | Novel amphiphilic nucleic acid conjugates |
US5188897A (en) * | 1987-10-22 | 1993-02-23 | Temple University Of The Commonwealth System Of Higher Education | Encapsulated 2',5'-phosphorothioate oligoadenylates |
US4924624A (en) * | 1987-10-22 | 1990-05-15 | Temple University-Of The Commonwealth System Of Higher Education | 2,',5'-phosphorothioate oligoadenylates and plant antiviral uses thereof |
US5525465A (en) * | 1987-10-28 | 1996-06-11 | Howard Florey Institute Of Experimental Physiology And Medicine | Oligonucleotide-polyamide conjugates and methods of production and applications of the same |
DE3738460A1 (de) * | 1987-11-12 | 1989-05-24 | Max Planck Gesellschaft | Modifizierte oligonukleotide |
EP0348458B1 (en) * | 1987-11-30 | 1997-04-09 | University Of Iowa Research Foundation | Dna molecules stabilized by modifications of the 3'-terminal phosphodiester linkage and their use as nucleic acid probes and as therapeutic agents to block the expression of specifically targeted genes |
US5403711A (en) * | 1987-11-30 | 1995-04-04 | University Of Iowa Research Foundation | Nucleic acid hybridization and amplification method for detection of specific sequences in which a complementary labeled nucleic acid probe is cleaved |
US5082830A (en) * | 1988-02-26 | 1992-01-21 | Enzo Biochem, Inc. | End labeled nucleotide probe |
JPH03503894A (ja) * | 1988-03-25 | 1991-08-29 | ユニバーシィティ オブ バージニア アランミ パテンツ ファウンデイション | オリゴヌクレオチド n‐アルキルホスホラミデート |
US5278302A (en) * | 1988-05-26 | 1994-01-11 | University Patents, Inc. | Polynucleotide phosphorodithioates |
US5109124A (en) * | 1988-06-01 | 1992-04-28 | Biogen, Inc. | Nucleic acid probe linked to a label having a terminal cysteine |
US5216141A (en) * | 1988-06-06 | 1993-06-01 | Benner Steven A | Oligonucleotide analogs containing sulfur linkages |
US5194599A (en) * | 1988-09-23 | 1993-03-16 | Gilead Sciences, Inc. | Hydrogen phosphonodithioate compositions |
US5512439A (en) * | 1988-11-21 | 1996-04-30 | Dynal As | Oligonucleotide-linked magnetic particles and uses thereof |
US5599923A (en) * | 1989-03-06 | 1997-02-04 | Board Of Regents, University Of Tx | Texaphyrin metal complexes having improved functionalization |
US5391723A (en) * | 1989-05-31 | 1995-02-21 | Neorx Corporation | Oligonucleotide conjugates |
US4958013A (en) * | 1989-06-06 | 1990-09-18 | Northwestern University | Cholesteryl modified oligonucleotides |
US5591722A (en) * | 1989-09-15 | 1997-01-07 | Southern Research Institute | 2'-deoxy-4'-thioribonucleosides and their antiviral activity |
US5721218A (en) * | 1989-10-23 | 1998-02-24 | Gilead Sciences, Inc. | Oligonucleotides with inverted polarity |
US5399676A (en) * | 1989-10-23 | 1995-03-21 | Gilead Sciences | Oligonucleotides with inverted polarity |
US5292873A (en) * | 1989-11-29 | 1994-03-08 | The Research Foundation Of State University Of New York | Nucleic acids labeled with naphthoquinone probe |
US5486603A (en) * | 1990-01-08 | 1996-01-23 | Gilead Sciences, Inc. | Oligonucleotide having enhanced binding affinity |
US5623065A (en) * | 1990-08-13 | 1997-04-22 | Isis Pharmaceuticals, Inc. | Gapped 2' modified oligonucleotides |
US5587470A (en) * | 1990-01-11 | 1996-12-24 | Isis Pharmaceuticals, Inc. | 3-deazapurines |
US5220007A (en) * | 1990-02-15 | 1993-06-15 | The Worcester Foundation For Experimental Biology | Method of site-specific alteration of RNA and production of encoded polypeptides |
WO1991013080A1 (en) * | 1990-02-20 | 1991-09-05 | Gilead Sciences, Inc. | Pseudonucleosides and pseudonucleotides and their polymers |
US5214136A (en) * | 1990-02-20 | 1993-05-25 | Gilead Sciences, Inc. | Anthraquinone-derivatives oligonucleotides |
US5321131A (en) * | 1990-03-08 | 1994-06-14 | Hybridon, Inc. | Site-specific functionalization of oligodeoxynucleotides for non-radioactive labelling |
DE69032425T2 (de) * | 1990-05-11 | 1998-11-26 | Microprobe Corp., Bothell, Wash. | Teststreifen zum Eintauchen für Nukleinsäure-Hybridisierungsassays und Verfahren zur kovalenten Immobilisierung von Oligonucleotiden |
US5637459A (en) * | 1990-06-11 | 1997-06-10 | Nexstar Pharmaceuticals, Inc. | Systematic evolution of ligands by exponential enrichment: chimeric selex |
US5218105A (en) * | 1990-07-27 | 1993-06-08 | Isis Pharmaceuticals | Polyamine conjugated oligonucleotides |
US5602240A (en) * | 1990-07-27 | 1997-02-11 | Ciba Geigy Ag. | Backbone modified oligonucleotide analogs |
ATE154246T1 (de) * | 1990-07-27 | 1997-06-15 | Isis Pharmaceuticals Inc | Nuklease resistente, pyrimidin modifizierte oligonukleotide, die die gen-expression detektieren und modulieren |
US5618704A (en) * | 1990-07-27 | 1997-04-08 | Isis Pharmacueticals, Inc. | Backbone-modified oligonucleotide analogs and preparation thereof through radical coupling |
US5489677A (en) * | 1990-07-27 | 1996-02-06 | Isis Pharmaceuticals, Inc. | Oligonucleoside linkages containing adjacent oxygen and nitrogen atoms |
US5608046A (en) * | 1990-07-27 | 1997-03-04 | Isis Pharmaceuticals, Inc. | Conjugated 4'-desmethyl nucleoside analog compounds |
US5610289A (en) * | 1990-07-27 | 1997-03-11 | Isis Pharmaceuticals, Inc. | Backbone modified oligonucleotide analogues |
US5623070A (en) * | 1990-07-27 | 1997-04-22 | Isis Pharmaceuticals, Inc. | Heteroatomic oligonucleoside linkages |
US5177196A (en) * | 1990-08-16 | 1993-01-05 | Microprobe Corporation | Oligo (α-arabinofuranosyl nucleotides) and α-arabinofuranosyl precursors thereof |
US5512667A (en) * | 1990-08-28 | 1996-04-30 | Reed; Michael W. | Trifunctional intermediates for preparing 3'-tailed oligonucleotides |
US5214134A (en) * | 1990-09-12 | 1993-05-25 | Sterling Winthrop Inc. | Process of linking nucleosides with a siloxane bridge |
CA2092002A1 (en) * | 1990-09-20 | 1992-03-21 | Mark Matteucci | Modified internucleoside linkages |
CA2095212A1 (en) * | 1990-11-08 | 1992-05-09 | Sudhir Agrawal | Incorporation of multiple reporter groups on synthetic oligonucleotides |
US7223833B1 (en) * | 1991-05-24 | 2007-05-29 | Isis Pharmaceuticals, Inc. | Peptide nucleic acid conjugates |
US5714331A (en) * | 1991-05-24 | 1998-02-03 | Buchardt, Deceased; Ole | Peptide nucleic acids having enhanced binding affinity, sequence specificity and solubility |
US5719262A (en) * | 1993-11-22 | 1998-02-17 | Buchardt, Deceased; Ole | Peptide nucleic acids having amino acid side chains |
EP0538194B1 (de) * | 1991-10-17 | 1997-06-04 | Novartis AG | Bicyclische Nukleoside, Oligonukleotide, Verfahren zu deren Herstellung und Zwischenprodukte |
US5594121A (en) * | 1991-11-07 | 1997-01-14 | Gilead Sciences, Inc. | Enhanced triple-helix and double-helix formation with oligomers containing modified purines |
US5484908A (en) * | 1991-11-26 | 1996-01-16 | Gilead Sciences, Inc. | Oligonucleotides containing 5-propynyl pyrimidines |
US5595726A (en) * | 1992-01-21 | 1997-01-21 | Pharmacyclics, Inc. | Chromophore probe for detection of nucleic acid |
FR2687679B1 (fr) * | 1992-02-05 | 1994-10-28 | Centre Nat Rech Scient | Oligothionucleotides. |
US5633360A (en) * | 1992-04-14 | 1997-05-27 | Gilead Sciences, Inc. | Oligonucleotide analogs capable of passive cell membrane permeation |
EP0577558A2 (de) * | 1992-07-01 | 1994-01-05 | Ciba-Geigy Ag | Carbocyclische Nukleoside mit bicyclischen Ringen, Oligonukleotide daraus, Verfahren zu deren Herstellung, deren Verwendung und Zwischenproduckte |
US5759571A (en) * | 1993-05-11 | 1998-06-02 | Nexstar Pharmaceuticals, Inc. | Antibiotic formulation and use for drug resistant infections |
US5502177A (en) * | 1993-09-17 | 1996-03-26 | Gilead Sciences, Inc. | Pyrimidine derivatives for labeled binding partners |
US5519134A (en) * | 1994-01-11 | 1996-05-21 | Isis Pharmaceuticals, Inc. | Pyrrolidine-containing monomers and oligomers |
US5596091A (en) * | 1994-03-18 | 1997-01-21 | The Regents Of The University Of California | Antisense oligonucleotides comprising 5-aminoalkyl pyrimidine nucleotides |
US5627053A (en) * | 1994-03-29 | 1997-05-06 | Ribozyme Pharmaceuticals, Inc. | 2'deoxy-2'-alkylnucleotide containing nucleic acid |
US5625050A (en) * | 1994-03-31 | 1997-04-29 | Amgen Inc. | Modified oligonucleotides and intermediates useful in nucleic acid therapeutics |
US5525711A (en) * | 1994-05-18 | 1996-06-11 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Pteridine nucleotide analogs as fluorescent DNA probes |
US5597696A (en) * | 1994-07-18 | 1997-01-28 | Becton Dickinson And Company | Covalent cyanine dye oligonucleotide conjugates |
US5580731A (en) * | 1994-08-25 | 1996-12-03 | Chiron Corporation | N-4 modified pyrimidine deoxynucleotides and oligonucleotide probes synthesized therewith |
US5597909A (en) * | 1994-08-25 | 1997-01-28 | Chiron Corporation | Polynucleotide reagents containing modified deoxyribose moieties, and associated methods of synthesis and use |
US5652356A (en) * | 1995-08-17 | 1997-07-29 | Hybridon, Inc. | Inverted chimeric and hybrid oligonucleotides |
US6361944B1 (en) * | 1996-07-29 | 2002-03-26 | Nanosphere, Inc. | Nanoparticles having oligonucleotides attached thereto and uses therefor |
US6506564B1 (en) * | 1996-07-29 | 2003-01-14 | Nanosphere, Inc. | Nanoparticles having oligonucleotides attached thereto and uses therefor |
US20060002949A1 (en) * | 1996-11-14 | 2006-01-05 | Army Govt. Of The Usa, As Rep. By Secretary Of The Office Of The Command Judge Advocate, Hq Usamrmc. | Transcutaneous immunization without heterologous adjuvant |
WO1999011655A1 (en) * | 1997-09-04 | 1999-03-11 | Gryphon Sciences | Modular protein libraries and methods of preparation |
US6242246B1 (en) * | 1997-12-15 | 2001-06-05 | Somalogic, Inc. | Nucleic acid ligand diagnostic Biochip |
US6506559B1 (en) * | 1997-12-23 | 2003-01-14 | Carnegie Institute Of Washington | Genetic inhibition by double-stranded RNA |
KR20020064915A (ko) * | 1999-11-29 | 2002-08-10 | 에이브이아이 바이오파마 인코포레이티드 | 안티센스 항박테리아 방법 및 조성물 |
US20030181412A1 (en) * | 1999-12-21 | 2003-09-25 | Ingeneus Corporation | Method for modifying transcription and/or translation in an organism for therapeutic, prophylactic and/or analytic uses |
US6991900B2 (en) * | 2000-06-28 | 2006-01-31 | California Institute Of Technology | Methods for identifying an essential gene in a prokaryotic microorganism |
ATE388691T1 (de) * | 2001-07-10 | 2008-03-15 | Univ North Carolina State | Träger zur freisetzung von nanopartikeln |
US20060035344A1 (en) * | 2002-10-18 | 2006-02-16 | Pachuk Catherine J | Double-stranded rna structures and constructs, and methods for generating and using the same |
US20060105343A1 (en) * | 2003-01-09 | 2006-05-18 | Children's Medical Center Corporation | Methods for diagnosis and prognosis of cancer |
EP1771583A2 (en) * | 2004-07-26 | 2007-04-11 | Nanosphere, Inc. | Method for distinguishing methicillin resistant s. aureus from methicillin sensitive s. aureus in a mixed culture |
US8246995B2 (en) * | 2005-05-10 | 2012-08-21 | The Board Of Trustees Of The Leland Stanford Junior University | Hydrophobic nanotubes and nanoparticles as transporters for the delivery of drugs into cells |
JP2007101498A (ja) * | 2005-10-07 | 2007-04-19 | Fujifilm Corp | 蛍光プローブ及び蛍光検出方法 |
WO2008030624A2 (en) * | 2006-09-08 | 2008-03-13 | The Research Foundation Of State University Of New York | Nanoparticles for two-photon activated photodynamic therapy and imaging |
EP2826863B1 (en) * | 2007-05-30 | 2017-08-23 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
WO2010060110A1 (en) * | 2008-11-24 | 2010-05-27 | Northwestern University | Polyvalent rna-nanoparticle compositions |
-
2010
- 2010-01-08 EP EP10729603.0A patent/EP2385760A4/en not_active Withdrawn
- 2010-01-08 JP JP2011545476A patent/JP5801205B2/ja not_active Expired - Fee Related
- 2010-01-08 WO PCT/US2010/020558 patent/WO2010081049A1/en active Application Filing
- 2010-01-08 KR KR1020117018020A patent/KR20110102492A/ko not_active Application Discontinuation
- 2010-01-08 MX MX2011007350A patent/MX2011007350A/es active IP Right Grant
- 2010-01-08 AU AU2010203474A patent/AU2010203474B2/en not_active Ceased
- 2010-01-08 US US12/684,836 patent/US20100184844A1/en not_active Abandoned
- 2010-01-08 CA CA2749536A patent/CA2749536A1/en not_active Abandoned
- 2010-01-08 CN CN201080007013.1A patent/CN102307470B/zh not_active Expired - Fee Related
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS6144820A (ja) * | 1984-07-25 | 1986-03-04 | サントル ナシオナル ド ラ ルシエルシユ シアンテイフイク | 遺伝子発現の選択的阻害剤 |
JP2001516724A (ja) * | 1997-09-16 | 2001-10-02 | ペーター・エー・ニールセン | 抗菌活性を有するペプチド核酸 |
WO2006138145A1 (en) * | 2005-06-14 | 2006-12-28 | Northwestern University | Nucleic acid functionalized nanoparticles for therapeutic applications |
Also Published As
Publication number | Publication date |
---|---|
WO2010081049A1 (en) | 2010-07-15 |
KR20110102492A (ko) | 2011-09-16 |
CN102307470A (zh) | 2012-01-04 |
JP5801205B2 (ja) | 2015-10-28 |
AU2010203474B2 (en) | 2015-11-19 |
EP2385760A4 (en) | 2015-09-30 |
CN102307470B (zh) | 2015-05-20 |
US20100184844A1 (en) | 2010-07-22 |
AU2010203474A1 (en) | 2011-07-28 |
EP2385760A1 (en) | 2011-11-16 |
MX2011007350A (es) | 2011-09-06 |
CA2749536A1 (en) | 2010-07-15 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5801205B2 (ja) | 多価オリゴヌクレオチド修飾ナノ粒子コンジュゲートによる細菌タンパク質産生の阻害 | |
US11633503B2 (en) | Delivery of oligonucleotide-functionalized nanoparticles | |
AU2016238902B2 (en) | Delivery of Oligonucleotide-Functionalized Nanoparticles | |
EP1238071B1 (en) | Uncharged antisense oligonucleotides targeted to bacterial 16s and 23s rrnas and their uses | |
ES2367289T3 (es) | Método y compuesto antibacteriano antisentido. | |
JP2003518946A (ja) | アンチセンス抗細菌性細胞分裂組成物、およびその方法 | |
JP5906508B2 (ja) | Rna干渉効果が高い2本鎖脂質修飾rna | |
JP2017522044A (ja) | アンチセンス抗菌化合物および方法 | |
JP2022040131A (ja) | アンチセンス抗細菌性化合物および方法 | |
WO2016004168A1 (en) | Spherical nanoparticles as antibacterial agents | |
Bai et al. | Antisense antibacterials: from proof-of-concept to therapeutic perspectives | |
WO2021173986A1 (en) | Chemically modified transfer rna-derived small rnas (tsrnas) to target pathogenic bacteria |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20130107 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20130107 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140305 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140605 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20140605 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20150109 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20150511 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20150526 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20150616 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150803 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150826 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5801205 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
LAPS | Cancellation because of no payment of annual fees |