JP6873939B2 - バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 - Google Patents
バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 Download PDFInfo
- Publication number
- JP6873939B2 JP6873939B2 JP2018031017A JP2018031017A JP6873939B2 JP 6873939 B2 JP6873939 B2 JP 6873939B2 JP 2018031017 A JP2018031017 A JP 2018031017A JP 2018031017 A JP2018031017 A JP 2018031017A JP 6873939 B2 JP6873939 B2 JP 6873939B2
- Authority
- JP
- Japan
- Prior art keywords
- streptococcus
- biofilm
- pharmaceutical composition
- composition according
- plyss2
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 238000011282 treatment Methods 0.000 title description 64
- 230000002265 prevention Effects 0.000 title description 21
- 241001515965 unidentified phage Species 0.000 title description 20
- 230000006378 damage Effects 0.000 title description 8
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 167
- 102000004196 processed proteins & peptides Human genes 0.000 claims description 156
- 229920001184 polypeptide Polymers 0.000 claims description 147
- 241000894006 Bacteria Species 0.000 claims description 117
- KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 81
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 81
- 239000000203 mixture Substances 0.000 claims description 81
- 239000003242 anti bacterial agent Substances 0.000 claims description 76
- 229940088710 antibiotic agent Drugs 0.000 claims description 68
- 108010013198 Daptomycin Proteins 0.000 claims description 66
- DOAKLVKFURWEDJ-QCMAZARJSA-N daptomycin Chemical compound C([C@H]1C(=O)O[C@H](C)[C@@H](C(NCC(=O)N[C@@H](CCCN)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@H](C)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@H](CO)C(=O)N[C@H](C(=O)N1)[C@H](C)CC(O)=O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](CC(N)=O)NC(=O)[C@H](CC=1C2=CC=CC=C2NC=1)NC(=O)CCCCCCCCC)C(=O)C1=CC=CC=C1N DOAKLVKFURWEDJ-QCMAZARJSA-N 0.000 claims description 66
- 229960005484 daptomycin Drugs 0.000 claims description 66
- 239000006166 lysate Substances 0.000 claims description 60
- 241000191967 Staphylococcus aureus Species 0.000 claims description 48
- 150000001413 amino acids Chemical group 0.000 claims description 46
- 230000002147 killing effect Effects 0.000 claims description 44
- 208000015181 infectious disease Diseases 0.000 claims description 42
- 241000192125 Firmicutes Species 0.000 claims description 38
- 230000003115 biocidal effect Effects 0.000 claims description 38
- 108010059993 Vancomycin Proteins 0.000 claims description 36
- 229960003165 vancomycin Drugs 0.000 claims description 36
- 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 claims description 36
- 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 36
- 239000008194 pharmaceutical composition Substances 0.000 claims description 35
- 241000194017 Streptococcus Species 0.000 claims description 32
- 239000003814 drug Substances 0.000 claims description 25
- TYZROVQLWOKYKF-ZDUSSCGKSA-N linezolid Chemical compound O=C1O[C@@H](CNC(=O)C)CN1C(C=C1F)=CC=C1N1CCOCC1 TYZROVQLWOKYKF-ZDUSSCGKSA-N 0.000 claims description 24
- 229960003907 linezolid Drugs 0.000 claims description 24
- 241000295644 Staphylococcaceae Species 0.000 claims description 22
- 229940079593 drug Drugs 0.000 claims description 22
- 241000191940 Staphylococcus Species 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 15
- 230000035945 sensitivity Effects 0.000 claims description 12
- 229930182555 Penicillin Natural products 0.000 claims description 11
- 241000194021 Streptococcus suis Species 0.000 claims description 11
- 239000006185 dispersion Substances 0.000 claims description 11
- 208000035143 Bacterial infection Diseases 0.000 claims description 10
- 230000015572 biosynthetic process Effects 0.000 claims description 10
- 150000002960 penicillins Chemical class 0.000 claims description 10
- 241000193996 Streptococcus pyogenes Species 0.000 claims description 9
- 108010015899 Glycopeptides Proteins 0.000 claims description 8
- 102000002068 Glycopeptides Human genes 0.000 claims description 8
- 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 7
- 239000003120 macrolide antibiotic agent Substances 0.000 claims description 7
- 229960003085 meticillin Drugs 0.000 claims description 7
- 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 6
- 241000193985 Streptococcus agalactiae Species 0.000 claims description 6
- 206010014665 endocarditis Diseases 0.000 claims description 6
- 241000193998 Streptococcus pneumoniae Species 0.000 claims description 5
- 241000191978 Staphylococcus simulans Species 0.000 claims description 4
- 241000194042 Streptococcus dysgalactiae Species 0.000 claims description 4
- 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 4
- 229960001019 oxacillin Drugs 0.000 claims description 4
- 229940037648 staphylococcus simulans Drugs 0.000 claims description 4
- 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
- 206010031252 Osteomyelitis Diseases 0.000 claims description 3
- 241000194048 Streptococcus equi Species 0.000 claims description 3
- 241000194026 Streptococcus gordonii Species 0.000 claims description 3
- 241000194023 Streptococcus sanguinis Species 0.000 claims description 3
- 108010053950 Teicoplanin Proteins 0.000 claims description 3
- 229960000723 ampicillin Drugs 0.000 claims description 3
- 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 3
- 229960004099 azithromycin Drugs 0.000 claims description 3
- 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 3
- DDTDNCYHLGRFBM-YZEKDTGTSA-N chembl2367892 Chemical compound CC(=O)N[C@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1O[C@@H]([C@H]1C(N[C@@H](C2=CC(O)=CC(O[C@@H]3[C@H]([C@H](O)[C@H](O)[C@@H](CO)O3)O)=C2C=2C(O)=CC=C(C=2)[C@@H](NC(=O)[C@@H]2NC(=O)[C@@H]3C=4C=C(O)C=C(C=4)OC=4C(O)=CC=C(C=4)[C@@H](N)C(=O)N[C@H](CC=4C=C(Cl)C(O5)=CC=4)C(=O)N3)C(=O)N1)C(O)=O)=O)C(C=C1Cl)=CC=C1OC1=C(O[C@H]3[C@H]([C@@H](O)[C@H](O)[C@H](CO)O3)NC(C)=O)C5=CC2=C1 DDTDNCYHLGRFBM-YZEKDTGTSA-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
- 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
- 229960003326 cloxacillin Drugs 0.000 claims description 3
- 229960003276 erythromycin Drugs 0.000 claims description 3
- 229960005224 roxithromycin Drugs 0.000 claims description 3
- 229940115920 streptococcus dysgalactiae Drugs 0.000 claims description 3
- 229960001608 teicoplanin Drugs 0.000 claims description 3
- 229930186147 Cephalosporin Natural products 0.000 claims description 2
- 229940124587 cephalosporin Drugs 0.000 claims description 2
- 150000001780 cephalosporins Chemical class 0.000 claims description 2
- 230000000399 orthopedic effect Effects 0.000 claims description 2
- 229940041033 macrolides Drugs 0.000 claims 6
- 241000174295 Episcius Species 0.000 claims 5
- 241000120569 Streptococcus equi subsp. zooepidemicus Species 0.000 claims 4
- 201000005010 Streptococcus pneumonia Diseases 0.000 claims 3
- 206010060968 Arthritis infective Diseases 0.000 claims 2
- 241000194005 Streptococcus sp. 'group G' Species 0.000 claims 2
- 210000000748 cardiovascular system Anatomy 0.000 claims 1
- 238000007493 shaping process Methods 0.000 claims 1
- 102000004190 Enzymes Human genes 0.000 description 106
- 108090000790 Enzymes Proteins 0.000 description 106
- 229940088598 enzyme Drugs 0.000 description 106
- 238000000034 method Methods 0.000 description 104
- 108090000623 proteins and genes Proteins 0.000 description 99
- 102000004169 proteins and genes Human genes 0.000 description 76
- 235000018102 proteins Nutrition 0.000 description 75
- 101710126949 Lysin Proteins 0.000 description 64
- 230000001580 bacterial effect Effects 0.000 description 57
- 230000000694 effects Effects 0.000 description 53
- 235000001014 amino acid Nutrition 0.000 description 52
- 229940024606 amino acid Drugs 0.000 description 45
- 230000001320 lysogenic effect Effects 0.000 description 43
- 210000004027 cell Anatomy 0.000 description 42
- 108020004414 DNA Proteins 0.000 description 41
- 125000003275 alpha amino acid group Chemical group 0.000 description 41
- 108091028043 Nucleic acid sequence Proteins 0.000 description 32
- 239000002953 phosphate buffered saline Substances 0.000 description 28
- 238000006467 substitution reaction Methods 0.000 description 26
- 210000002421 cell wall Anatomy 0.000 description 24
- 239000003795 chemical substances by application Substances 0.000 description 24
- 150000007523 nucleic acids Chemical class 0.000 description 22
- 101000925662 Enterobacteria phage PRD1 Endolysin Proteins 0.000 description 19
- 230000002934 lysing effect Effects 0.000 description 18
- 102000039446 nucleic acids Human genes 0.000 description 18
- 108020004707 nucleic acids Proteins 0.000 description 18
- 230000001225 therapeutic effect Effects 0.000 description 18
- 108020001507 fusion proteins Proteins 0.000 description 17
- 102000037865 fusion proteins Human genes 0.000 description 17
- CXKWCBBOMKCUKX-UHFFFAOYSA-M methylene blue Chemical compound [Cl-].C1=CC(N(C)C)=CC2=[S+]C3=CC(N(C)C)=CC=C3N=C21 CXKWCBBOMKCUKX-UHFFFAOYSA-M 0.000 description 17
- 229960000907 methylthioninium chloride Drugs 0.000 description 17
- 239000000872 buffer Substances 0.000 description 16
- 150000001875 compounds Chemical class 0.000 description 16
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 16
- 241000194033 Enterococcus Species 0.000 description 15
- 239000004472 Lysine Substances 0.000 description 15
- 230000032770 biofilm formation Effects 0.000 description 15
- BJQHLKABXJIVAM-UHFFFAOYSA-N bis(2-ethylhexyl) phthalate Chemical compound CCCCC(CC)COC(=O)C1=CC=CC=C1C(=O)OCC(CC)CCCC BJQHLKABXJIVAM-UHFFFAOYSA-N 0.000 description 15
- 201000010099 disease Diseases 0.000 description 15
- 239000012528 membrane Substances 0.000 description 15
- 210000004379 membrane Anatomy 0.000 description 15
- 241000186781 Listeria Species 0.000 description 14
- 239000012891 Ringer solution Substances 0.000 description 14
- 239000000969 carrier Substances 0.000 description 14
- 239000013078 crystal Substances 0.000 description 14
- 230000006870 function Effects 0.000 description 14
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 13
- 241000699670 Mus sp. Species 0.000 description 13
- 239000000853 adhesive Substances 0.000 description 13
- 230000001070 adhesive effect Effects 0.000 description 13
- 230000027455 binding Effects 0.000 description 13
- 230000012010 growth Effects 0.000 description 13
- 239000002773 nucleotide Substances 0.000 description 13
- 125000003729 nucleotide group Chemical group 0.000 description 13
- 241000894007 species Species 0.000 description 13
- 238000010186 staining Methods 0.000 description 13
- 108091026890 Coding region Proteins 0.000 description 12
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 12
- 108010013639 Peptidoglycan Proteins 0.000 description 12
- 239000007943 implant Substances 0.000 description 12
- 238000000338 in vitro Methods 0.000 description 12
- 230000002101 lytic effect Effects 0.000 description 12
- 239000002609 medium Substances 0.000 description 12
- 210000001519 tissue Anatomy 0.000 description 12
- 102000053602 DNA Human genes 0.000 description 11
- 238000004458 analytical method Methods 0.000 description 11
- 239000008103 glucose Substances 0.000 description 11
- 238000001727 in vivo Methods 0.000 description 11
- 238000004448 titration Methods 0.000 description 11
- 239000013598 vector Substances 0.000 description 11
- 108020004705 Codon Proteins 0.000 description 10
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 10
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 10
- 102000004503 Perforin Human genes 0.000 description 10
- 108010056995 Perforin Proteins 0.000 description 10
- 230000000844 anti-bacterial effect Effects 0.000 description 10
- 239000004599 antimicrobial Substances 0.000 description 10
- 238000000576 coating method Methods 0.000 description 10
- 230000008029 eradication Effects 0.000 description 10
- 238000002474 experimental method Methods 0.000 description 10
- 229920000642 polymer Polymers 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- 239000000126 substance Substances 0.000 description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 9
- 241000282414 Homo sapiens Species 0.000 description 9
- 238000013459 approach Methods 0.000 description 9
- 230000002829 reductive effect Effects 0.000 description 9
- 238000007920 subcutaneous administration Methods 0.000 description 9
- 241000282412 Homo Species 0.000 description 8
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 8
- 108010014251 Muramidase Proteins 0.000 description 8
- 102000016943 Muramidase Human genes 0.000 description 8
- 102000007079 Peptide Fragments Human genes 0.000 description 8
- 108010033276 Peptide Fragments Proteins 0.000 description 8
- 238000003556 assay Methods 0.000 description 8
- 239000003153 chemical reaction reagent Substances 0.000 description 8
- 235000010335 lysozyme Nutrition 0.000 description 8
- 230000004048 modification Effects 0.000 description 8
- 238000012986 modification Methods 0.000 description 8
- 230000035772 mutation Effects 0.000 description 8
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 7
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 7
- 239000004793 Polystyrene Substances 0.000 description 7
- 108010076504 Protein Sorting Signals Proteins 0.000 description 7
- MTCFGRXMJLQNBG-UHFFFAOYSA-N Serine Natural products OCC(N)C(O)=O MTCFGRXMJLQNBG-UHFFFAOYSA-N 0.000 description 7
- 239000003570 air Substances 0.000 description 7
- 125000000539 amino acid group Chemical group 0.000 description 7
- 239000000427 antigen Substances 0.000 description 7
- 102000036639 antigens Human genes 0.000 description 7
- 108091007433 antigens Proteins 0.000 description 7
- 230000000295 complement effect Effects 0.000 description 7
- 230000009089 cytolysis Effects 0.000 description 7
- 238000012217 deletion Methods 0.000 description 7
- 230000037430 deletion Effects 0.000 description 7
- 239000013604 expression vector Substances 0.000 description 7
- 238000007667 floating Methods 0.000 description 7
- 239000012634 fragment Substances 0.000 description 7
- 230000002401 inhibitory effect Effects 0.000 description 7
- 238000001990 intravenous administration Methods 0.000 description 7
- 239000004325 lysozyme Substances 0.000 description 7
- 229960000274 lysozyme Drugs 0.000 description 7
- 244000005700 microbiome Species 0.000 description 7
- 229920002223 polystyrene Polymers 0.000 description 7
- 230000009467 reduction Effects 0.000 description 7
- 230000001105 regulatory effect Effects 0.000 description 7
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 7
- 239000003981 vehicle Substances 0.000 description 7
- 230000035899 viability Effects 0.000 description 7
- 241000194032 Enterococcus faecalis Species 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- 108060003951 Immunoglobulin Proteins 0.000 description 6
- XUJNEKJLAYXESH-REOHCLBHSA-N L-Cysteine Chemical compound SC[C@H](N)C(O)=O XUJNEKJLAYXESH-REOHCLBHSA-N 0.000 description 6
- ROHFNLRQFUQHCH-YFKPBYRVSA-N L-leucine Chemical compound CC(C)C[C@H](N)C(O)=O ROHFNLRQFUQHCH-YFKPBYRVSA-N 0.000 description 6
- ROHFNLRQFUQHCH-UHFFFAOYSA-N Leucine Natural products CC(C)CC(N)C(O)=O ROHFNLRQFUQHCH-UHFFFAOYSA-N 0.000 description 6
- 108060001084 Luciferase Proteins 0.000 description 6
- 239000005089 Luciferase Substances 0.000 description 6
- 108090000988 Lysostaphin Proteins 0.000 description 6
- 241000191963 Staphylococcus epidermidis Species 0.000 description 6
- 238000002835 absorbance Methods 0.000 description 6
- 238000007792 addition Methods 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 235000003704 aspartic acid Nutrition 0.000 description 6
- 208000022362 bacterial infectious disease Diseases 0.000 description 6
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 description 6
- 108091006116 chimeric peptides Proteins 0.000 description 6
- 230000000875 corresponding effect Effects 0.000 description 6
- 230000002068 genetic effect Effects 0.000 description 6
- 235000013922 glutamic acid Nutrition 0.000 description 6
- 239000004220 glutamic acid Substances 0.000 description 6
- 102000018358 immunoglobulin Human genes 0.000 description 6
- 230000002458 infectious effect Effects 0.000 description 6
- 238000007912 intraperitoneal administration Methods 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000000813 microbial effect Effects 0.000 description 6
- 244000052769 pathogen Species 0.000 description 6
- 239000013612 plasmid Substances 0.000 description 6
- 239000002157 polynucleotide Substances 0.000 description 6
- 102000040430 polynucleotide Human genes 0.000 description 6
- 108091033319 polynucleotide Proteins 0.000 description 6
- 230000003389 potentiating effect Effects 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 238000012216 screening Methods 0.000 description 6
- 238000012731 temporal analysis Methods 0.000 description 6
- MTCFGRXMJLQNBG-REOHCLBHSA-N (2S)-2-Amino-3-hydroxypropansäure Chemical compound OC[C@H](N)C(O)=O MTCFGRXMJLQNBG-REOHCLBHSA-N 0.000 description 5
- 108700023418 Amidases Proteins 0.000 description 5
- 102100028188 Cystatin-F Human genes 0.000 description 5
- 101710169749 Cystatin-F Proteins 0.000 description 5
- 101700012268 Holin Proteins 0.000 description 5
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 5
- ZDXPYRJPNDTMRX-VKHMYHEASA-N L-glutamine Chemical compound OC(=O)[C@@H](N)CCC(N)=O ZDXPYRJPNDTMRX-VKHMYHEASA-N 0.000 description 5
- AGPKZVBTJJNPAG-WHFBIAKZSA-N L-isoleucine Chemical compound CC[C@H](C)[C@H](N)C(O)=O AGPKZVBTJJNPAG-WHFBIAKZSA-N 0.000 description 5
- COLNVLDHVKWLRT-QMMMGPOBSA-N L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=CC=C1 COLNVLDHVKWLRT-QMMMGPOBSA-N 0.000 description 5
- AYFVYJQAPQTCCC-GBXIJSLDSA-N L-threonine Chemical compound C[C@@H](O)[C@H](N)C(O)=O AYFVYJQAPQTCCC-GBXIJSLDSA-N 0.000 description 5
- 241000699666 Mus <mouse, genus> Species 0.000 description 5
- 108091034117 Oligonucleotide Proteins 0.000 description 5
- 108020004511 Recombinant DNA Proteins 0.000 description 5
- 108090000631 Trypsin Proteins 0.000 description 5
- 102000004142 Trypsin Human genes 0.000 description 5
- 102000005922 amidase Human genes 0.000 description 5
- 238000002815 broth microdilution Methods 0.000 description 5
- 239000002299 complementary DNA Substances 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229960000310 isoleucine Drugs 0.000 description 5
- AGPKZVBTJJNPAG-UHFFFAOYSA-N isoleucine Natural products CCC(C)C(N)C(O)=O AGPKZVBTJJNPAG-UHFFFAOYSA-N 0.000 description 5
- 239000012139 lysis buffer Substances 0.000 description 5
- 229930182817 methionine Natural products 0.000 description 5
- -1 methionine Amino acids Chemical class 0.000 description 5
- 239000002674 ointment Substances 0.000 description 5
- 230000001717 pathogenic effect Effects 0.000 description 5
- COLNVLDHVKWLRT-UHFFFAOYSA-N phenylalanine Natural products OC(=O)C(N)CC1=CC=CC=C1 COLNVLDHVKWLRT-UHFFFAOYSA-N 0.000 description 5
- 239000004800 polyvinyl chloride Substances 0.000 description 5
- 229920000915 polyvinyl chloride Polymers 0.000 description 5
- 230000004044 response Effects 0.000 description 5
- 238000003786 synthesis reaction Methods 0.000 description 5
- 238000012360 testing method Methods 0.000 description 5
- 239000012588 trypsin Substances 0.000 description 5
- 239000004475 Arginine Substances 0.000 description 4
- 241000193830 Bacillus <bacterium> Species 0.000 description 4
- 241000186216 Corynebacterium Species 0.000 description 4
- 206010014684 Endocarditis staphylococcal Diseases 0.000 description 4
- QIVBCDIJIAJPQS-VIFPVBQESA-N L-tryptophane Chemical compound C1=CC=C2C(C[C@H](N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-VIFPVBQESA-N 0.000 description 4
- KZSNJWFQEVHDMF-BYPYZUCNSA-N L-valine Chemical compound CC(C)[C@H](N)C(O)=O KZSNJWFQEVHDMF-BYPYZUCNSA-N 0.000 description 4
- 241001465754 Metazoa Species 0.000 description 4
- BQCADISMDOOEFD-UHFFFAOYSA-N Silver Chemical compound [Ag] BQCADISMDOOEFD-UHFFFAOYSA-N 0.000 description 4
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 4
- KZSNJWFQEVHDMF-UHFFFAOYSA-N Valine Natural products CC(C)C(N)C(O)=O KZSNJWFQEVHDMF-UHFFFAOYSA-N 0.000 description 4
- 230000009471 action Effects 0.000 description 4
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 description 4
- 230000010065 bacterial adhesion Effects 0.000 description 4
- 230000009286 beneficial effect Effects 0.000 description 4
- 230000004071 biological effect Effects 0.000 description 4
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 4
- 230000008859 change Effects 0.000 description 4
- 239000003638 chemical reducing agent Substances 0.000 description 4
- 239000003085 diluting agent Substances 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- ZDXPYRJPNDTMRX-UHFFFAOYSA-N glutamine Natural products OC(=O)C(N)CCC(N)=O ZDXPYRJPNDTMRX-UHFFFAOYSA-N 0.000 description 4
- 238000002513 implantation Methods 0.000 description 4
- 238000003780 insertion Methods 0.000 description 4
- 230000037431 insertion Effects 0.000 description 4
- 239000003446 ligand Substances 0.000 description 4
- 239000004014 plasticizer Substances 0.000 description 4
- 239000003755 preservative agent Substances 0.000 description 4
- 238000012545 processing Methods 0.000 description 4
- 238000011002 quantification Methods 0.000 description 4
- 230000000717 retained effect Effects 0.000 description 4
- 229910052709 silver Inorganic materials 0.000 description 4
- 239000004332 silver Substances 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 230000000699 topical effect Effects 0.000 description 4
- 230000014616 translation Effects 0.000 description 4
- 239000004474 valine Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 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 3
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Chemical compound OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 3
- IGXWBGJHJZYPQS-SSDOTTSWSA-N D-Luciferin Chemical compound OC(=O)[C@H]1CSC(C=2SC3=CC=C(O)C=C3N=2)=N1 IGXWBGJHJZYPQS-SSDOTTSWSA-N 0.000 description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 3
- QNAYBMKLOCPYGJ-UHFFFAOYSA-N D-alpha-Ala Natural products CC([NH3+])C([O-])=O QNAYBMKLOCPYGJ-UHFFFAOYSA-N 0.000 description 3
- 230000006820 DNA synthesis Effects 0.000 description 3
- 102000004163 DNA-directed RNA polymerases Human genes 0.000 description 3
- 108090000626 DNA-directed RNA polymerases Proteins 0.000 description 3
- CYCGRDQQIOGCKX-UHFFFAOYSA-N Dehydro-luciferin Natural products OC(=O)C1=CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 CYCGRDQQIOGCKX-UHFFFAOYSA-N 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- BJGNCJDXODQBOB-UHFFFAOYSA-N Fivefly Luciferin Natural products OC(=O)C1CSC(C=2SC3=CC(O)=CC=C3N=2)=N1 BJGNCJDXODQBOB-UHFFFAOYSA-N 0.000 description 3
- 108010010803 Gelatin Proteins 0.000 description 3
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 description 3
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 3
- DDWFXDSYGUXRAY-UHFFFAOYSA-N Luciferin Natural products CCc1c(C)c(CC2NC(=O)C(=C2C=C)C)[nH]c1Cc3[nH]c4C(=C5/NC(CC(=O)O)C(C)C5CC(=O)O)CC(=O)c4c3C DDWFXDSYGUXRAY-UHFFFAOYSA-N 0.000 description 3
- 229930195725 Mannitol Natural products 0.000 description 3
- ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Natural products OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 241001505901 Streptococcus sp. 'group A' Species 0.000 description 3
- AYFVYJQAPQTCCC-UHFFFAOYSA-N Threonine Natural products CC(O)C(N)C(O)=O AYFVYJQAPQTCCC-UHFFFAOYSA-N 0.000 description 3
- 239000004473 Threonine Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 230000002411 adverse Effects 0.000 description 3
- 230000004075 alteration Effects 0.000 description 3
- 238000010171 animal model Methods 0.000 description 3
- 239000005557 antagonist Substances 0.000 description 3
- 230000000845 anti-microbial effect Effects 0.000 description 3
- 230000003385 bacteriostatic effect Effects 0.000 description 3
- 239000007853 buffer solution Substances 0.000 description 3
- 238000004113 cell culture Methods 0.000 description 3
- 210000000170 cell membrane Anatomy 0.000 description 3
- 239000012707 chemical precursor Substances 0.000 description 3
- 230000002759 chromosomal effect Effects 0.000 description 3
- 210000000349 chromosome Anatomy 0.000 description 3
- 238000010367 cloning Methods 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 230000002596 correlated effect Effects 0.000 description 3
- 238000003235 crystal violet staining Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 229940032049 enterococcus faecalis Drugs 0.000 description 3
- 239000008273 gelatin Substances 0.000 description 3
- 229920000159 gelatin Polymers 0.000 description 3
- 235000019322 gelatine Nutrition 0.000 description 3
- 235000011852 gelatine desserts Nutrition 0.000 description 3
- 210000003709 heart valve Anatomy 0.000 description 3
- HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 238000001802 infusion Methods 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000000968 intestinal effect Effects 0.000 description 3
- 210000004731 jugular vein Anatomy 0.000 description 3
- 230000000670 limiting effect Effects 0.000 description 3
- 238000004020 luminiscence type Methods 0.000 description 3
- 239000000594 mannitol Substances 0.000 description 3
- 235000010355 mannitol Nutrition 0.000 description 3
- 239000011159 matrix material Substances 0.000 description 3
- 108020004999 messenger RNA Proteins 0.000 description 3
- 239000000693 micelle Substances 0.000 description 3
- 238000002703 mutagenesis Methods 0.000 description 3
- 231100000350 mutagenesis Toxicity 0.000 description 3
- 239000007922 nasal spray Substances 0.000 description 3
- 230000036961 partial effect Effects 0.000 description 3
- 229920003023 plastic Polymers 0.000 description 3
- 239000004033 plastic Substances 0.000 description 3
- 238000003752 polymerase chain reaction Methods 0.000 description 3
- 230000008569 process Effects 0.000 description 3
- 230000000069 prophylactic effect Effects 0.000 description 3
- 230000010076 replication Effects 0.000 description 3
- 238000004626 scanning electron microscopy Methods 0.000 description 3
- 238000004904 shortening Methods 0.000 description 3
- 230000009870 specific binding Effects 0.000 description 3
- 239000007921 spray Substances 0.000 description 3
- 230000001954 sterilising effect Effects 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- 230000002195 synergetic effect Effects 0.000 description 3
- 229940124597 therapeutic agent Drugs 0.000 description 3
- 238000013518 transcription Methods 0.000 description 3
- 230000035897 transcription Effects 0.000 description 3
- 238000012546 transfer Methods 0.000 description 3
- 238000000108 ultra-filtration Methods 0.000 description 3
- 238000011144 upstream manufacturing Methods 0.000 description 3
- 208000019206 urinary tract infection Diseases 0.000 description 3
- 230000003612 virological effect Effects 0.000 description 3
- ZKHQWZAMYRWXGA-KQYNXXCUSA-J ATP(4-) Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](COP([O-])(=O)OP([O-])(=O)OP([O-])([O-])=O)[C@@H](O)[C@H]1O ZKHQWZAMYRWXGA-KQYNXXCUSA-J 0.000 description 2
- ZKHQWZAMYRWXGA-UHFFFAOYSA-N Adenosine triphosphate Natural products C1=NC=2C(N)=NC=NC=2N1C1OC(COP(O)(=O)OP(O)(=O)OP(O)(O)=O)C(O)C1O ZKHQWZAMYRWXGA-UHFFFAOYSA-N 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 108010032595 Antibody Binding Sites Proteins 0.000 description 2
- 208000034309 Bacterial disease carrier Diseases 0.000 description 2
- QFOHBWFCKVYLES-UHFFFAOYSA-N Butylparaben Chemical compound CCCCOC(=O)C1=CC=C(O)C=C1 QFOHBWFCKVYLES-UHFFFAOYSA-N 0.000 description 2
- 241000193403 Clostridium Species 0.000 description 2
- 108091035707 Consensus sequence Proteins 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 108010059378 Endopeptidases Proteins 0.000 description 2
- 102000005593 Endopeptidases Human genes 0.000 description 2
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 2
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004471 Glycine Substances 0.000 description 2
- QNAYBMKLOCPYGJ-REOHCLBHSA-N L-alanine Chemical compound C[C@H](N)C(O)=O QNAYBMKLOCPYGJ-REOHCLBHSA-N 0.000 description 2
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 description 2
- HNDVDQJCIGZPNO-YFKPBYRVSA-N L-histidine Chemical compound OC(=O)[C@@H](N)CC1=CN=CN1 HNDVDQJCIGZPNO-YFKPBYRVSA-N 0.000 description 2
- 241000186779 Listeria monocytogenes Species 0.000 description 2
- 241000186359 Mycobacterium Species 0.000 description 2
- OVRNDRQMDRJTHS-UHFFFAOYSA-N N-acelyl-D-glucosamine Natural products CC(=O)NC1C(O)OC(CO)C(O)C1O OVRNDRQMDRJTHS-UHFFFAOYSA-N 0.000 description 2
- MNLRQHMNZILYPY-MDMHTWEWSA-N N-acetyl-alpha-D-muramic acid Chemical compound OC(=O)[C@@H](C)O[C@H]1[C@H](O)[C@@H](CO)O[C@H](O)[C@@H]1NC(C)=O MNLRQHMNZILYPY-MDMHTWEWSA-N 0.000 description 2
- OVRNDRQMDRJTHS-FMDGEEDCSA-N N-acetyl-beta-D-glucosamine Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O OVRNDRQMDRJTHS-FMDGEEDCSA-N 0.000 description 2
- MBLBDJOUHNCFQT-LXGUWJNJSA-N N-acetylglucosamine Natural products CC(=O)N[C@@H](C=O)[C@@H](O)[C@H](O)[C@H](O)CO MBLBDJOUHNCFQT-LXGUWJNJSA-N 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 206010033078 Otitis media Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 206010035664 Pneumonia Diseases 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- 206010037660 Pyrexia Diseases 0.000 description 2
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 2
- 241001522306 Serinus serinus Species 0.000 description 2
- 102000007562 Serum Albumin Human genes 0.000 description 2
- 108010071390 Serum Albumin Proteins 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 206010041925 Staphylococcal infections Diseases 0.000 description 2
- 108091081024 Start codon Proteins 0.000 description 2
- 108700009124 Transcription Initiation Site Proteins 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 208000000260 Warts Diseases 0.000 description 2
- 206010000059 abdominal discomfort Diseases 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 238000005273 aeration Methods 0.000 description 2
- 229960003767 alanine Drugs 0.000 description 2
- 235000004279 alanine Nutrition 0.000 description 2
- 230000000172 allergic effect Effects 0.000 description 2
- 239000012080 ambient air Substances 0.000 description 2
- 230000003214 anti-biofilm Effects 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 210000001765 aortic valve Anatomy 0.000 description 2
- 229960001230 asparagine Drugs 0.000 description 2
- 235000009582 asparagine Nutrition 0.000 description 2
- 208000010668 atopic eczema Diseases 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- 239000003139 biocide Substances 0.000 description 2
- 230000036760 body temperature Effects 0.000 description 2
- 210000004899 c-terminal region Anatomy 0.000 description 2
- 238000011088 calibration curve Methods 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 230000003197 catalytic effect Effects 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 230000001276 controlling effect Effects 0.000 description 2
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 2
- 235000018417 cysteine Nutrition 0.000 description 2
- OPTASPLRGRRNAP-UHFFFAOYSA-N cytosine Chemical compound NC=1C=CNC(=O)N=1 OPTASPLRGRRNAP-UHFFFAOYSA-N 0.000 description 2
- 230000002354 daily effect Effects 0.000 description 2
- 238000005202 decontamination Methods 0.000 description 2
- 230000003588 decontaminative effect Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 208000002173 dizziness Diseases 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 239000003937 drug carrier Substances 0.000 description 2
- 239000000975 dye Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 230000002255 enzymatic effect Effects 0.000 description 2
- 210000003527 eukaryotic cell Anatomy 0.000 description 2
- 230000001747 exhibiting effect Effects 0.000 description 2
- 210000002744 extracellular matrix Anatomy 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
- 230000005714 functional activity Effects 0.000 description 2
- 230000002538 fungal effect Effects 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 244000000059 gram-positive pathogen Species 0.000 description 2
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000009396 hybridization Methods 0.000 description 2
- 230000002209 hydrophobic effect Effects 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 230000002452 interceptive effect Effects 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 238000002955 isolation Methods 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 230000001665 lethal effect Effects 0.000 description 2
- 210000000265 leukocyte Anatomy 0.000 description 2
- 239000002502 liposome Substances 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 201000004792 malaria Diseases 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- LXCFILQKKLGQFO-UHFFFAOYSA-N methylparaben Chemical compound COC(=O)C1=CC=C(O)C=C1 LXCFILQKKLGQFO-UHFFFAOYSA-N 0.000 description 2
- 238000001471 micro-filtration Methods 0.000 description 2
- 239000002480 mineral oil Substances 0.000 description 2
- 239000002324 mouth wash Substances 0.000 description 2
- 210000003205 muscle Anatomy 0.000 description 2
- 229950006780 n-acetylglucosamine Drugs 0.000 description 2
- 239000013642 negative control Substances 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 238000005373 pervaporation Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 230000008488 polyadenylation Effects 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229920000136 polysorbate Polymers 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- QELSKZZBTMNZEB-UHFFFAOYSA-N propylparaben Chemical compound CCCOC(=O)C1=CC=C(O)C=C1 QELSKZZBTMNZEB-UHFFFAOYSA-N 0.000 description 2
- 238000010188 recombinant method Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 108091008146 restriction endonucleases Proteins 0.000 description 2
- 238000001223 reverse osmosis Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 201000010153 skin papilloma Diseases 0.000 description 2
- 150000003384 small molecules Chemical class 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- 230000002623 sporogenic effect Effects 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 230000000087 stabilizing effect Effects 0.000 description 2
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- 230000008685 targeting Effects 0.000 description 2
- 239000002562 thickening agent Substances 0.000 description 2
- RWQNBRDOKXIBIV-UHFFFAOYSA-N thymine Chemical compound CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 description 2
- 230000002103 transcriptional effect Effects 0.000 description 2
- 230000001052 transient effect Effects 0.000 description 2
- 238000013519 translation Methods 0.000 description 2
- 210000000689 upper leg Anatomy 0.000 description 2
- 230000002792 vascular Effects 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- DGVVWUTYPXICAM-UHFFFAOYSA-N β‐Mercaptoethanol Chemical compound OCCS DGVVWUTYPXICAM-UHFFFAOYSA-N 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- OIXLLKLZKCBCPS-RZVRUWJTSA-N (2s)-2-azanyl-5-[bis(azanyl)methylideneamino]pentanoic acid Chemical compound OC(=O)[C@@H](N)CCCNC(N)=N.OC(=O)[C@@H](N)CCCNC(N)=N OIXLLKLZKCBCPS-RZVRUWJTSA-N 0.000 description 1
- WHTVZRBIWZFKQO-AWEZNQCLSA-N (S)-chloroquine Chemical compound ClC1=CC=C2C(N[C@@H](C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-AWEZNQCLSA-N 0.000 description 1
- CHHHXKFHOYLYRE-UHFFFAOYSA-M 2,4-Hexadienoic acid, potassium salt (1:1), (2E,4E)- Chemical compound [K+].CC=CC=CC([O-])=O CHHHXKFHOYLYRE-UHFFFAOYSA-M 0.000 description 1
- GDMDOMRUYVLLHM-UHFFFAOYSA-N 2-(1-iodoethyl)pentyl carbamate Chemical compound CCCC(C(C)I)COC(N)=O GDMDOMRUYVLLHM-UHFFFAOYSA-N 0.000 description 1
- GHCZTIFQWKKGSB-UHFFFAOYSA-N 2-hydroxypropane-1,2,3-tricarboxylic acid;phosphoric acid Chemical compound OP(O)(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O GHCZTIFQWKKGSB-UHFFFAOYSA-N 0.000 description 1
- OSDLLIBGSJNGJE-UHFFFAOYSA-N 4-chloro-3,5-dimethylphenol Chemical compound CC1=CC(O)=CC(C)=C1Cl OSDLLIBGSJNGJE-UHFFFAOYSA-N 0.000 description 1
- HUKUZLFKFIUNLE-UHFFFAOYSA-N 4-ethenyl-1-hexyl-2H-pyridine Chemical compound CCCCCCN1CC=C(C=C)C=C1 HUKUZLFKFIUNLE-UHFFFAOYSA-N 0.000 description 1
- 241000186046 Actinomyces Species 0.000 description 1
- 229930024421 Adenine Natural products 0.000 description 1
- GFFGJBXGBJISGV-UHFFFAOYSA-N Adenine Chemical compound NC1=NC=NC2=C1N=CN2 GFFGJBXGBJISGV-UHFFFAOYSA-N 0.000 description 1
- 102000009027 Albumins Human genes 0.000 description 1
- 108010088751 Albumins Proteins 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 108090000531 Amidohydrolases Proteins 0.000 description 1
- 102000004092 Amidohydrolases Human genes 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 241000193738 Bacillus anthracis Species 0.000 description 1
- 108010001478 Bacitracin Proteins 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-M Bromide Chemical compound [Br-] CPELXLSAUQHCOX-UHFFFAOYSA-M 0.000 description 1
- VZHHNDCSESIXJW-UHFFFAOYSA-N C(=CC(C)=C)OP(=O)(O)OP(=O)(O)O Chemical compound C(=CC(C)=C)OP(=O)(O)OP(=O)(O)O VZHHNDCSESIXJW-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 241000700198 Cavia Species 0.000 description 1
- 206010057248 Cell death Diseases 0.000 description 1
- 229940123982 Cell wall synthesis inhibitor Drugs 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- 206010009657 Clostridium difficile colitis Diseases 0.000 description 1
- 108020004635 Complementary DNA Proteins 0.000 description 1
- 241000195493 Cryptophyta Species 0.000 description 1
- 201000003883 Cystic fibrosis Diseases 0.000 description 1
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 description 1
- 238000012270 DNA recombination Methods 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- BWGNESOTFCXPMA-UHFFFAOYSA-N Dihydrogen disulfide Chemical compound SS BWGNESOTFCXPMA-UHFFFAOYSA-N 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- ZGTMUACCHSMWAC-UHFFFAOYSA-L EDTA disodium salt (anhydrous) Chemical compound [Na+].[Na+].OC(=O)CN(CC([O-])=O)CCN(CC(O)=O)CC([O-])=O ZGTMUACCHSMWAC-UHFFFAOYSA-L 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010067770 Endopeptidase K Proteins 0.000 description 1
- 241000792859 Enema Species 0.000 description 1
- 241001053330 Enterobacteria phage C-1 Species 0.000 description 1
- 241000194031 Enterococcus faecium Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000233866 Fungi Species 0.000 description 1
- 230000005526 G1 to G0 transition Effects 0.000 description 1
- 201000000628 Gas Gangrene Diseases 0.000 description 1
- 208000005577 Gastroenteritis Diseases 0.000 description 1
- SXRSQZLOMIGNAQ-UHFFFAOYSA-N Glutaraldehyde Chemical compound O=CCCCC=O SXRSQZLOMIGNAQ-UHFFFAOYSA-N 0.000 description 1
- 108010000540 Hexosaminidases Proteins 0.000 description 1
- 102000002268 Hexosaminidases Human genes 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 108010044467 Isoenzymes Proteins 0.000 description 1
- YQEZLKZALYSWHR-UHFFFAOYSA-N Ketamine Chemical compound C=1C=CC=C(Cl)C=1C1(NC)CCCCC1=O YQEZLKZALYSWHR-UHFFFAOYSA-N 0.000 description 1
- 150000008575 L-amino acids Chemical group 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 description 1
- 241000194036 Lactococcus Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 239000004166 Lanolin Substances 0.000 description 1
- 108010090665 Mannosyl-Glycoprotein Endo-beta-N-Acetylglucosaminidase Proteins 0.000 description 1
- 102000018697 Membrane Proteins Human genes 0.000 description 1
- 108010052285 Membrane Proteins Proteins 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- XUYPXLNMDZIRQH-LURJTMIESA-N N-acetyl-L-methionine Chemical compound CSCC[C@@H](C(O)=O)NC(C)=O XUYPXLNMDZIRQH-LURJTMIESA-N 0.000 description 1
- 102100030397 N-acetylmuramoyl-L-alanine amidase Human genes 0.000 description 1
- IABBAGAOMDWOCW-UHFFFAOYSA-N Nicametate citrate Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O.CCN(CC)CCOC(=O)C1=CC=CN=C1 IABBAGAOMDWOCW-UHFFFAOYSA-N 0.000 description 1
- 101710149086 Nuclease S1 Proteins 0.000 description 1
- 108091005461 Nucleic proteins Proteins 0.000 description 1
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 101710202686 Penicillin-sensitive transpeptidase Proteins 0.000 description 1
- 201000007100 Pharyngitis Diseases 0.000 description 1
- 229920001214 Polysorbate 60 Polymers 0.000 description 1
- 241000982698 Prorodonopsis coli Species 0.000 description 1
- 208000003100 Pseudomembranous Enterocolitis Diseases 0.000 description 1
- 206010037128 Pseudomembranous colitis Diseases 0.000 description 1
- 208000032536 Pseudomonas Infections Diseases 0.000 description 1
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 108091028664 Ribonucleotide Proteins 0.000 description 1
- 230000018199 S phase Effects 0.000 description 1
- 102100037205 Sal-like protein 2 Human genes 0.000 description 1
- 101710192308 Sal-like protein 2 Proteins 0.000 description 1
- 229920002125 Sokalan® Polymers 0.000 description 1
- 238000002105 Southern blotting Methods 0.000 description 1
- 241000193990 Streptococcus sp. 'group B' Species 0.000 description 1
- 241000187747 Streptomyces Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- 206010043376 Tetanus Diseases 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 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 1
- 206010000269 abscess Diseases 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 229960000643 adenine Drugs 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000009435 amidation Effects 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 208000022338 anthrax infection Diseases 0.000 description 1
- 229940126573 antibacterial therapeutic Drugs 0.000 description 1
- 239000003430 antimalarial agent Substances 0.000 description 1
- 238000011203 antimicrobial therapy Methods 0.000 description 1
- 239000000010 aprotic solvent Substances 0.000 description 1
- 229940009098 aspartate Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 229960003071 bacitracin Drugs 0.000 description 1
- 229930184125 bacitracin Natural products 0.000 description 1
- CLKOFPXJLQSYAH-ABRJDSQDSA-N bacitracin A Chemical compound C1SC([C@@H](N)[C@@H](C)CC)=N[C@@H]1C(=O)N[C@@H](CC(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H]1C(=O)N[C@H](CCCN)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@H](CC=2C=CC=CC=2)C(=O)N[C@@H](CC=2N=CNC=2)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)NCCCC1 CLKOFPXJLQSYAH-ABRJDSQDSA-N 0.000 description 1
- 244000052616 bacterial pathogen Species 0.000 description 1
- 230000004888 barrier function Effects 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 239000003519 biomedical and dental material Substances 0.000 description 1
- 229920001222 biopolymer Polymers 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000004820 blood count Methods 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 210000000988 bone and bone Anatomy 0.000 description 1
- 239000008366 buffered solution Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- 229940067596 butylparaben Drugs 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 108020001778 catalytic domains Proteins 0.000 description 1
- 230000030833 cell death Effects 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000010307 cell transformation Effects 0.000 description 1
- 238000012200 cell viability kit Methods 0.000 description 1
- 230000005754 cellular signaling Effects 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000007385 chemical modification Methods 0.000 description 1
- 235000015218 chewing gum Nutrition 0.000 description 1
- 229960003677 chloroquine Drugs 0.000 description 1
- WHTVZRBIWZFKQO-UHFFFAOYSA-N chloroquine Natural products ClC1=CC=C2C(NC(C)CCCN(CC)CC)=CC=NC2=C1 WHTVZRBIWZFKQO-UHFFFAOYSA-N 0.000 description 1
- 229960005443 chloroxylenol Drugs 0.000 description 1
- 230000001713 cholinergic effect Effects 0.000 description 1
- 239000013611 chromosomal DNA Substances 0.000 description 1
- 238000003776 cleavage reaction Methods 0.000 description 1
- 229960002227 clindamycin Drugs 0.000 description 1
- 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 description 1
- 230000001332 colony forming effect Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002742 combinatorial mutagenesis Methods 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 235000009508 confectionery Nutrition 0.000 description 1
- 238000010276 construction Methods 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 229940104302 cytosine Drugs 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- JDRSMPFHFNXQRB-IBEHDNSVSA-N decyl glucoside Chemical compound CCCCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O JDRSMPFHFNXQRB-IBEHDNSVSA-N 0.000 description 1
- 230000000593 degrading effect Effects 0.000 description 1
- KXGVEGMKQFWNSR-LLQZFEROSA-N deoxycholic acid Chemical class C([C@H]1CC2)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 KXGVEGMKQFWNSR-LLQZFEROSA-N 0.000 description 1
- 239000005547 deoxyribonucleotide Substances 0.000 description 1
- 125000002637 deoxyribonucleotide group Chemical group 0.000 description 1
- 230000030609 dephosphorylation Effects 0.000 description 1
- 238000006209 dephosphorylation reaction Methods 0.000 description 1
- 230000001066 destructive effect Effects 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000011026 diafiltration Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000000502 dialysis Methods 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 206010013023 diphtheria Diseases 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
- 150000002016 disaccharides Chemical class 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- VHJLVAABSRFDPM-QWWZWVQMSA-N dithiothreitol Chemical compound SC[C@@H](O)[C@H](O)CS VHJLVAABSRFDPM-QWWZWVQMSA-N 0.000 description 1
- WSDISUOETYTPRL-UHFFFAOYSA-N dmdm hydantoin Chemical compound CC1(C)N(CO)C(=O)N(CO)C1=O WSDISUOETYTPRL-UHFFFAOYSA-N 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002500 effect on skin Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 239000007920 enema Substances 0.000 description 1
- 229940079360 enema for constipation Drugs 0.000 description 1
- 239000003623 enhancer Substances 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 230000006862 enzymatic digestion Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 230000007717 exclusion Effects 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229930195712 glutamate Natural products 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 229920000578 graft copolymer Polymers 0.000 description 1
- 210000005255 gram-positive cell Anatomy 0.000 description 1
- 230000009036 growth inhibition Effects 0.000 description 1
- 208000019622 heart disease Diseases 0.000 description 1
- 230000013632 homeostatic process Effects 0.000 description 1
- 229920001477 hydrophilic polymer Polymers 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 239000008235 industrial water Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 239000000644 isotonic solution Substances 0.000 description 1
- 229960003299 ketamine Drugs 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- PYIDGJJWBIBVIA-UYTYNIKBSA-N lauryl glucoside Chemical compound CCCCCCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O PYIDGJJWBIBVIA-UYTYNIKBSA-N 0.000 description 1
- 238000002386 leaching Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 239000003055 low molecular weight heparin Substances 0.000 description 1
- 229940127215 low-molecular weight heparin Drugs 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 210000004962 mammalian cell Anatomy 0.000 description 1
- 238000013507 mapping Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000012567 medical material Substances 0.000 description 1
- 230000007102 metabolic function Effects 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 239000004292 methyl p-hydroxybenzoate Substances 0.000 description 1
- 235000010270 methyl p-hydroxybenzoate Nutrition 0.000 description 1
- 229960002216 methylparaben Drugs 0.000 description 1
- 238000001000 micrograph Methods 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 230000011278 mitosis Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000010369 molecular cloning Methods 0.000 description 1
- NJTGANWAUPEOAX-UHFFFAOYSA-N molport-023-220-454 Chemical compound OCC(O)CO.OCC(O)CO NJTGANWAUPEOAX-UHFFFAOYSA-N 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 230000003232 mucoadhesive effect Effects 0.000 description 1
- 210000004400 mucous membrane Anatomy 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 229940051921 muramidase Drugs 0.000 description 1
- HEGSGKPQLMEBJL-UHFFFAOYSA-N n-octyl beta-D-glucopyranoside Natural products CCCCCCCCOC1OC(CO)C(O)C(O)C1O HEGSGKPQLMEBJL-UHFFFAOYSA-N 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- 239000007923 nasal drop Substances 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229940097496 nasal spray Drugs 0.000 description 1
- 239000008239 natural water Substances 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 238000007899 nucleic acid hybridization Methods 0.000 description 1
- 235000015097 nutrients Nutrition 0.000 description 1
- 229920002113 octoxynol Polymers 0.000 description 1
- HEGSGKPQLMEBJL-RKQHYHRCSA-N octyl beta-D-glucopyranoside Chemical compound CCCCCCCCO[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O HEGSGKPQLMEBJL-RKQHYHRCSA-N 0.000 description 1
- UYDLBVPAAFVANX-UHFFFAOYSA-N octylphenoxy polyethoxyethanol Chemical compound CC(C)(C)CC(C)(C)C1=CC=C(OCCOCCOCCOCCO)C=C1 UYDLBVPAAFVANX-UHFFFAOYSA-N 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- RARSHUDCJQSEFJ-UHFFFAOYSA-N p-Hydroxypropiophenone Chemical compound CCC(=O)C1=CC=C(O)C=C1 RARSHUDCJQSEFJ-UHFFFAOYSA-N 0.000 description 1
- 238000012856 packing Methods 0.000 description 1
- 230000008506 pathogenesis Effects 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 230000000737 periodic effect Effects 0.000 description 1
- 229940021222 peritoneal dialysis isotonic solution Drugs 0.000 description 1
- 230000002688 persistence Effects 0.000 description 1
- 108700010839 phage proteins Proteins 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 230000004260 plant-type cell wall biogenesis Effects 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 108010094020 polyglycine Proteins 0.000 description 1
- 229920000232 polyglycine polymer Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 239000004302 potassium sorbate Substances 0.000 description 1
- 235000010241 potassium sorbate Nutrition 0.000 description 1
- 229940069338 potassium sorbate Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 238000011533 pre-incubation Methods 0.000 description 1
- REQCZEXYDRLIBE-UHFFFAOYSA-N procainamide Chemical compound CCN(CC)CCNC(=O)C1=CC=C(N)C=C1 REQCZEXYDRLIBE-UHFFFAOYSA-N 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000010232 propyl p-hydroxybenzoate Nutrition 0.000 description 1
- 239000004405 propyl p-hydroxybenzoate Substances 0.000 description 1
- 229960003415 propylparaben Drugs 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000002797 proteolythic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 239000002336 ribonucleotide Substances 0.000 description 1
- 125000002652 ribonucleotide group Chemical group 0.000 description 1
- 238000011808 rodent model Methods 0.000 description 1
- 210000003296 saliva Anatomy 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000007423 screening assay Methods 0.000 description 1
- 239000006152 selective media Substances 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 229960003885 sodium benzoate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000000475 sunscreen effect Effects 0.000 description 1
- 239000000516 sunscreening agent Substances 0.000 description 1
- 238000010897 surface acoustic wave method Methods 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229940113082 thymine Drugs 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000005030 transcription termination Effects 0.000 description 1
- 238000011277 treatment modality Methods 0.000 description 1
- 229960005486 vaccine Drugs 0.000 description 1
- 229940099259 vaseline Drugs 0.000 description 1
- 239000005526 vasoconstrictor agent Substances 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
- 238000012800 visualization Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 230000003442 weekly effect Effects 0.000 description 1
- BPICBUSOMSTKRF-UHFFFAOYSA-N xylazine Chemical compound CC1=CC=CC(C)=C1NC1=NCCCS1 BPICBUSOMSTKRF-UHFFFAOYSA-N 0.000 description 1
- 229960001600 xylazine Drugs 0.000 description 1
- 210000005253 yeast cell Anatomy 0.000 description 1
- 150000003952 β-lactams Chemical group 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/164—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
- A01N63/40—Viruses, e.g. bacteriophages
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
- A01N63/00—Biocides, pest repellants or attractants, or plant growth regulators containing microorganisms, viruses, microbial fungi, animals or substances produced by, or obtained from, microorganisms, viruses, microbial fungi or animals, e.g. enzymes or fermentates
- A01N63/50—Isolated enzymes; Isolated proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/02—Bacterial antigens
- A61K39/085—Staphylococcus
-
- 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
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2/00—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor
- A61L2/16—Methods or apparatus for disinfecting or sterilising materials or objects other than foodstuffs or contact lenses; Accessories therefor using chemical substances
- A61L2/18—Liquid substances or solutions comprising solids or dissolved gases
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/08—Materials for coatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L29/00—Materials for catheters, medical tubing, cannulae, or endoscopes or for coating catheters
- A61L29/14—Materials characterised by their function or physical properties, e.g. lubricating compositions
- A61L29/16—Biologically active materials, e.g. therapeutic substances
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/195—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria
- C07K14/315—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Streptococcus (G), e.g. Enterococci
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/503—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from viruses
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/52—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from bacteria or Archaea
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
- C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
- C12Y302/01017—Lysozyme (3.2.1.17)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2202/00—Aspects relating to methods or apparatus for disinfecting or sterilising materials or objects
- A61L2202/20—Targets to be treated
- A61L2202/24—Medical instruments, e.g. endoscopes, catheters, sharps
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2300/00—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices
- A61L2300/40—Biologically active materials used in bandages, wound dressings, absorbent pads or medical devices characterised by a specific therapeutic activity or mode of action
- A61L2300/404—Biocides, antimicrobial agents, antiseptic agents
- A61L2300/406—Antibiotics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
- A61L2420/00—Materials or methods for coatings medical devices
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Gastroenterology & Hepatology (AREA)
- Immunology (AREA)
- Microbiology (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Virology (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- Biomedical Technology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Agronomy & Crop Science (AREA)
- Environmental Sciences (AREA)
- Dentistry (AREA)
- Plant Pathology (AREA)
- Pest Control & Pesticides (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Biophysics (AREA)
- Mycology (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
本発明は、概して、溶解素、特に、薬物耐性Staphylococcus aureusを含むブドウ球菌を殺滅する能力を有する溶解素、特に、溶解素PlySs2を用いた、細菌バイオフィルムの防止、制御、破壊および処置に関する。本発明は、細菌バイオフィルム(複数可)およびバイオフィルム形成を調整するための組成物および方法にも関する。
多種多様の疾病および他の状態に対して使用する抗生物質が増えるにつれ、薬物耐性菌が発生することが、医療における大きな問題である。より多くの抗生物質を使用することおよび耐性を示す細菌の数のせいで、処置時間が長くなる。さらに、広域の非特異的抗生物質が、現在、頻繁に使用されているが、そのうちのいくつかは、患者に有害作用を及ぼす。この使用の増加に関連する問題は、多くの抗生物質が、粘液内層(mucus lining)を容易に透過しないということである。
本明細書中の参考文献の引用は、それらが本発明に対する先行技術であることを認めるものとして解釈されるものではない。
本発明によると、細菌バイオフィルムの防止、破壊および処置のための組成物および方法が提供される。その最も広範な態様において、本発明は、バイオフィルムの防止、破壊および処置における、複数の細菌、特に、Staphylococcus、Streptococcus、特に、Streptococcus pyogenes(A群連鎖球菌)およびStreptococcus agalactiae(B群連鎖球菌)の菌株を含む、特にグラム陽性菌に対して広範な殺滅活性を有する溶解素の使用および適用を提供する。本発明の溶解素および組成物は、EnterococcusおよびListeriaの菌株ならびにそれらの適用可能なバイオフィルムの殺滅において有用かつ適用可能である。本発明は、バイオフィルム内の細菌を効果的かつ効率的に殺滅することができるバクテリオファージ溶解素を利用して細菌バイオフィルムを除菌するため、分散させるためおよび除去するための方法を提供する。したがって、本発明は、細菌バイオフィルムの処置、除菌および/または除染、ならびにバイオフィルム(複数可)の分散後の感染症の防止を企図し、ここで、1つまたは複数のグラム陽性菌、特に、Staphylococcus、Streptococcus、EnterococcusおよびListeria菌のうちの1つまたは複数が、存在すると疑われるかまたは存在する。
(項目1)
グラム陽性菌のバイオフィルムの防止、破壊または処置のための方法であって、該方法は、ブドウ球菌を殺滅することができる溶解素ポリペプチドを含む組成物とバイオフィルムとを接触させる工程を含み、ここで、該バイオフィルムは、効果的に防止されるか、分散されるか、または処置される、方法。
(項目2)
前記溶解素ポリペプチドが、PlySs2である、項目1に記載の方法。
(項目3)
前記溶解素ポリペプチドが、図5に示されているようなアミノ酸配列(配列番号1)、または図5のポリペプチド(配列番号1)に対して少なくとも80%の同一性を有し、前記バイオフィルム内の前記グラム陽性菌を殺滅するのに有効である、そのバリアントを含む、項目2に記載の方法。
(項目4)
前記組成物が、1つまたは複数の抗生物質をさらに含む、項目1に記載の方法。
(項目5)
前記抗生物質が、ダプトマイシン、バンコマイシンおよびリネゾリドから選択される、項目4に記載の方法。
(項目6)
前記バイオフィルムを1つまたは複数の抗生物質と接触させる工程をさらに含む、項目1に記載の方法。
(項目7)
グラム陽性菌のバイオフィルム形成を防止するまたは減少させる方法であって、該方法は、ブドウ球菌を殺滅することができる溶解素ポリペプチドを含む組成物と医療用デバイス、カテーテルまたは埋め込み物を接触させる工程を含み、ここで、該溶解素は、PlySs2である、方法。
(項目8)
前記溶解素ポリペプチドが、図5に示されているようなアミノ酸配列(配列番号1)、または図5のポリペプチド(配列番号1)に対して少なくとも80%の同一性を有し、前記医療用デバイス、カテーテルもしくは埋め込み物における細菌バイオフィルムの形成もしくは細菌の付着および増殖を防止するかまたは減少させるのに有効である、そのバリアントを含む、項目7に記載の方法。
(項目9)
前記組成物が、抗生物質をさらに含む、項目7に記載の方法。
(項目10)
前記抗生物質が、ダプトマイシン、バンコマイシンおよびリネゾリドまたは関連化合物から選択される、項目9に記載の方法。
(項目11)
図5に示されているようなアミノ酸配列(配列番号1)、または図5のポリペプチド(配列番号1)に対して少なくとも80%の同一性を有し、グラム陽性菌のバイオフィルム内のグラム陽性菌を殺滅するのに有効である、そのバリアントを含む溶解素ポリペプチドを含む、該バイオフィルムの防止、破壊または処置において使用するための組成物。
(項目12)
1つまたは複数の抗生物質をさらに含む、項目11に記載の組成物。
(項目13)
前記抗生物質が、ダプトマイシン、バンコマイシンおよびリネゾリドまたは関連化合物から選択される、項目12に記載の組成物。
(項目14)
図5に示されているようなアミノ酸配列(配列番号1)、または図5のポリペプチド(配列番号1)に対して少なくとも80%の同一性を有し、ブドウ球菌もしくは連鎖球菌を殺滅するのに有効である、そのバリアントを含む溶解素ポリペプチドを含む、該連鎖球菌またはブドウ球菌のバイオフィルムの防止、破壊または処置のための組成物。
(項目15)
1つまたは複数の抗生物質をさらに含む、項目14に記載の組成物。
他の目的および利点は、以下の例証的な図面を参照して進められる以下の記載の精査から当業者に明らかになる。
本発明によると、当該分野の技術範囲内の従来の分子生物学、微生物学および組換えDNAの技法が使用されることがある。そのような技法は、文献に十分に説明されている。例えば、Sambrookら、“Molecular Cloning:A Laboratory Manual”(1989);“Current Protocols in Molecular Biology”Volumes I−III[Ausubel,R.M.,ed.(1994)];“Cell Biology:A Laboratory Handbook”Volumes I−III[J.E.Celis,ed.(1994))];“Current Protocols in Immunology”Volumes I−III[Coligan,J.E.,ed.(1994)];“Oligonucleotide Synthesis”(M.J.Gait ed.1984);“Nucleic Acid Hybridization”[B.D.Hames & S.J.Higgins eds.(1985)];“Transcription And Translation”[B.D.Hames & S.J.Higgins,eds.(1984)];“Animal Cell Culture”[R.I.Freshney,ed.(1986)];“Immobilized Cells And Enzymes”[IRL Press,(1986)];B.Perbal,“A Practical Guide To Molecular Cloning”(1984)を参照のこと。
対応表
記号 アミノ酸
1文字 3文字
Y Tyr チロシン
G Gly グリシン
F Phe フェニルアラニン
M Met メチオニン
A Ala アラニン
S Ser セリン
I Ile イソロイシン
L Leu ロイシン
T Thr トレオニン
V Val バリン
P Pro プロリン
K Lys リジン
H His ヒスチジン
Q Gln グルタミン
E Glu グルタミン酸
W Trp トリプトファン
R Arg アルギニン
D Asp アスパラギン酸
N Asn アスパラギン
C Cys システイン
非極性のR基を有するアミノ酸
アラニン、バリン、ロイシン、イソロイシン、プロリン、フェニルアラニン、トリプトファン、メチオニン
無電荷極性のR基を有するアミノ酸
グリシン、セリン、トレオニン、システイン、チロシン、アスパラギン、グルタミン
荷電極性R基を有するアミノ酸(Ph6.0において負に帯電)
アスパラギン酸、グルタミン酸
塩基性アミノ酸(pH6.0において正に帯電)
リジン、アルギニン、ヒスチジン(pH6.0において)
フェニルアラニン、トリプトファン、チロシン
グリシン 75 アラニン 89
セリン 105 プロリン 115
バリン 117 トレオニン 119
システイン 121 ロイシン 131
イソロイシン 131 アスパラギン 132
アスパラギン酸 133 グルタミン 146
リジン 146 グルタミン酸 147
メチオニン 149 ヒスチジン(pH6.0において) 155
フェニルアラニン 165 アルギニン 174
チロシン 181 トリプトファン 204
正電荷が維持され得るような、Argの代わりのLysおよびその逆;
負電荷が維持され得るような、Aspの代わりのGluおよびその逆;
遊離−OHが維持され得るような、Thrの代わりのSer;および
遊離NH2が維持され得るような、Asnの代わりのGln。
表1
PlySs2による種々の細菌の増殖の低減(部分的な列挙)
感受性菌株および非感受性菌株
抗生物質耐性Staphylococcus aureusに対するPlySs2の活性
PlySs2溶解素は、Staphylococcus aureusのメチシリンおよびバンコマイシン耐性および感性の菌株(MRSA、MSSA、VRSAおよびVISA)を含む臨床的に重要なグラム陽性菌の様々な菌株を殺滅する能力を明らかに示す。PlySs2は、広範な種殺滅活性を有する点において独特の溶解素であり、複数の種の細菌、特に、グラム陽性菌、極めて様々な抗生物質感性および抗生物質耐性のStaphylococcus、ならびにまたA群およびB群連鎖球菌を含むStreptococcusを殺滅し得る。他のPlySs2感性細菌としては、EnterococcusおよびListeriaの菌株が挙げられる。PlySs2溶解素に対する、ブドウ球菌および連鎖球菌を含む様々な細菌の感性の作表を、表2および3を含む上記に提供する。
表4
S.aureus菌株に対するPlySs2および抗生物質の活性*
*赤色/太字=薬物失敗(MIC値が、S.aureusにおいて、示されている薬物についてのEUCASTブレイクポイントより高い)
表5
PlySs2に対する腸細菌の感性
BAA−42のバイオフィルムに対して評価した。バイオフィルムを、より低いMIC未満の用量のPlySs2で、0.5時間、1時間、4時間および24時間処理した。上に記載されたように、BAA−42バイオフィルムを24ウェルディッシュに生成し、そのウェルをPlySs2溶解素またはダプトマイシン抗生物質で処理した(適切な培地コントロールとともに)。PlySs2の場合、MIC未満の用量の3.2μg/mL(1/10×MIC値)または0.32μg/mL(1/100×MIC値)のいずれかを使用した。ダプトマイシンの場合、1μg/mL(1×MIC値)または10μg/mL(10×MIC値)のいずれかを使用した。それらのウェルを、最長24時間までインキュベートし、洗浄し、固定し、染色した。結果を図4に示す。1/100 MICのPlySs2溶解素でさえも、バイオフィルムの溶解が観察される。PlySs2溶解素3.2μg/ml(1/10×MIC)を用いた4時間後に有意な溶解が実証され、0.32μg/ml(1/100×MIC)を用いた4時間後でさえ、一部の溶解が観察される。最大10×MICのダプトマイシン濃度をを用いても、溶解は認められない。
実施例2
実施例3
インビトロでの混合バイオフィルム研究
I.Staphylococcus/Enterococcus混合バイオフィルム−上に記載されたように溶解素+抗生物質で処理。
II.S.aureus/S.epidermidis混合バイオフィルム、またはS.epidermidisのみのバイオフィルムを生成し、評価する。S.aureusおよびS.epidermidis菌から形成されたバイオフィルムを使用して、上記のように実験を行う。
III.Staph+Strep菌バイオフィルムの組み合わせ、PlySs2およびダプトマイシンまたは他の抗生物質で処理。
S.aureusとS.pyogenes(またはS.dysgalactiae)の両方から形成されるバイオフィルムを使用して、上記のように実験を行う。S.pyogenes(A群連鎖球菌属)とS.dysgalactiae(B群連鎖球菌)の両方が、PlySs2に感性であるので、これらの実験は、ダプトマイシンを使用しない。むしろ、ブドウ球菌および連鎖球菌からなる混合バイオフィルム内の細菌を破壊するおよび殺滅するPlySs2溶解素を単独で評価する。
実施例4
インビボのカテーテルベースのバイオフィルムモデル
実施例5
実施例6
実施例7
実施例8
実施例9
表6
乳酸加リンガー溶液中の37℃におけるPlySs2の安定性
実施例10
実施例11
表7
BEC=PlySs2のバイオフィルム根絶濃度(単位はμg/ml)は、示されている菌株の24時間のバイオフィルムを完全に破壊する希釈範囲の最低濃度である。
実施例12
実施例13
実施例14
バイオフィルムを、上記のようにカテーテルチューブ(可塑剤としてDEHPを含むPVC)上に生成し、走査型電子顕微鏡法(SEM)によってPlySs2感性について評価した。カテーテル表面上のMRSA菌株CFS218(MRSA菌株ATCC BAA−42)の3日経過したバイオフィルムを、乳酸加リンガー溶液中の1×MIC濃度(すなわち、32μg/ml)のPlySs2で30秒間または15分間のいずれかで処理した後、その処理物を洗浄し、残存しているバイオフィルムをグルタルアルデヒド(gluteraldehyde)で固定した。カテーテル表面上での固定の後、サンプルをさらに処理し、5000×倍率の走査型電子顕微鏡法によって解析した(図21)。緩衝液のみ(すなわち、乳酸加リンガー溶液のみ)による処理をコントロールとして含める。図21に示されているように、PlySs2処理は、MRSAバイオフィルムを迅速に減少させ(30秒以内)、15分までに、バイオフィルムをほぼ完全に除去する。
Claims (34)
- ブドウ球菌および/または連鎖球菌を含むバイオフィルムを含む表面上で該ブドウ球菌および/または連鎖球菌による新たなバイオフィルムの後続形成を防止するための組成物であって、
溶解素ポリペプチドを含み、該溶解素ポリペプチドは、配列番号1に示されるアミノ酸配列、または、配列番号1のポリペプチドに対して少なくとも80%の同一性を有し、かつ、バイオフィルム内のブドウ球菌および連鎖球菌を殺滅するのに有効であるそのバリアントを含む、組成物。 - 前記表面が医療用デバイスの表面を含む、請求項1に記載の組成物。
- 前記医療用デバイスが、カテーテル、バルブ、補綴デバイス、薬物のポンプ、ステント、または、整形材料である、請求項2に記載の組成物。
- 前記ブドウ球菌および/または連鎖球菌がスタフィロコッカス・アウレウス(Staphylococcus aureus)、スタフィロコッカス・シムランス(Staphylococcus simulans)、ストレプトコッカス・スイス(Streptococcus suis)、スタフィロコッカス・エピデルミディス(Staphylococcus epidermidis)、ストレプトコッカス・エクイ(Streptococcus equi)、ストレプトコッカス・エクイ・ズーエピデミカス(Streptococcus equi zooepidemicus)、ストレプトコッカス・アガラクティエ(Streptococcus agalactiae)、ストレプトコッカス・ピオゲネス(Streptococcus pyogenes)、ストレプトコッカス・サンギニス(Streptococcus sanguinis)、ストレプトコッカス・ゴルドニ(Streptococcus gordonii)、ストレプトコッカス・ディスガラクティエ(Streptococcus dysgalactiae)、G群ストレプトコッカス(Streptococcus)、E群ストレプトコッカス(Streptococcus)、およびストレプトコッカス・ニューモニア(Streptococcus pneumonia)から選択される、請求項1〜3のいずれか一項に記載の組成物。
- 前記バイオフィルム内の細菌が、抗生物質耐性菌、および/または、抗生物質に対する感性が変更された菌を含む、請求項1〜4のいずれか一項に記載の組成物。
- 前記抗生物質耐性菌が、メチシリン耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)(MRSA)、バンコマイシン耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)(VRSA)、ダプトマイシン耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)(DRSA)、および/または、リネゾリド耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)(LRSA)を含み、前記抗生物質に対する感受性が変更された菌が、バンコマイシン中間感性スタフィロコッカス・アウレウス(Staphylococcus aureus)(VISA)を含む、請求項5に記載の組成物。
- 1または複数の抗生物質をさらに含む、請求項1〜6のいずれか一項に記載の組成物。
- 前記1または複数の抗生物質が、グリコペプチド類、セファロスポリン類、マクロライド類および/またはペニシリン類を含む、請求項7に記載の組成物。
- 前記1または複数の抗生物質がペニシリン類を含み、該ペニシリン類が、オキサシリン、アンピシリンおよび/またはクロキサシリンを含む、請求項7に記載の組成物。
- 前記1または複数の抗生物質がグリコペプチド類を含み、該グリコペプチド類が、バンコマイシンおよび/またはテイコプラニンを含む、請求項7に記載の組成物。
- 前記1または複数の抗生物質がマクロライド類を含み、該マクロライド類が、エリスロマイシン、クラリスロマイシン、アジスロマイシンおよび/またはロキシスロマイシンを含む、請求項7に記載の組成物。
- 前記1または複数の抗生物質がダプトマイシン、バンコマイシン、および/または、リネゾリドを含む、請求項7に記載の組成物。
- 薬学的組成物である、請求項1〜12のいずれか一項に記載の組成物。
- 前記溶解素ポリペプチドが配列番号1に示されるアミノ酸配列を含む、請求項1〜13のいずれか一項に記載の組成物。
- 被験体において、グラム陽性菌を含むバイオフィルムの分散後のグラム陽性菌の感染症を処置又は予防するための薬学的組成物であって、
前記グラム陽性菌はブドウ球菌および/または連鎖球菌を含み、
前記薬学的組成物は溶解素ポリペプチドを含み、該溶解素ポリペプチドは、配列番号1に示されるアミノ酸配列、または、配列番号1のポリペプチドに対して少なくとも80%の同一性を有し、かつ、バイオフィルム内のブドウ球菌および/または連鎖球菌を殺滅するのに有効であるそのバリアントを含む、薬学的組成物。 - 前記被験体において、前記被験体内に埋め込まれた医療用デバイスの表面の前記バイオフィルムの分散後のグラム陽性菌の感染症を処置又は予防するための、請求項15に記載の薬学的組成物。
- 前記埋め込まれた医療用デバイスが、カテーテル、バルブ、補綴デバイス、薬物のポンプ、ステント、または、整形材料である、請求項16に記載の薬学的組成物。
- 前記グラム陽性菌の感染症が、心内膜炎、骨髄炎、または、置換関節の感染症を含む、請求項15〜17のいずれか一項に記載の薬学的組成物。
- 前記グラム陽性菌の感染症が心内膜炎を含む、請求項15〜18のいずれか一項に記載の薬学的組成物。
- 前記医療用デバイスが、前記被験体の心臓または心臓血管に埋め込まれる、請求項19に記載の薬学的組成物。
- 前記医療用デバイスがステントである、請求項20に記載の薬学的組成物。
- 前記グラム陽性菌の感染症が骨髄炎を含む、請求項15〜18のいずれか一項に記載の薬学的組成物。
- 前記グラム陽性菌の感染症が、置換関節の感染症を含む、請求項15〜18のいずれか一項に記載の薬学的組成物。
- 前記バイオフィルムがスタフィロコッカス・アウレウス(Staphylococcus aureus)、スタフィロコッカス・シムランス(Staphylococcus simulans)、ストレプトコッカス・スイス(Streptococcus suis)、スタフィロコッカス・エピデルミディス(Staphylococcus epidermidis)、ストレプトコッカス・エクイ(Streptococcus equi)、ストレプトコッカス・エクイ・ズーエピデミカス(Streptococcus equi zooepidemicus)、ストレプトコッカス・アガラクティエ(Streptococcus agalactiae)、ストレプトコッカス・ピオゲネス(Streptococcus pyogenes)、ストレプトコッカス・サンギニス(Streptococcus sanguinis)、ストレプトコッカス・ゴルドニ(Streptococcus gordonii)、ストレプトコッカス・ディスガラクティエ(Streptococcus dysgalactiae)、G群ストレプトコッカス(Streptococcus)、E群ストレプトコッカス(Streptococcus)、およびストレプトコッカス・ニューモニア(Streptococcus pneumonia)から選択される1または複数のブドウ球菌または連鎖球菌を含む、請求項15〜23のいずれか一項に記載の薬学的組成物。
- 前記バイオフィルム内の細菌が、抗生物質耐性菌、および/または、抗生物質に対する感性が変更された菌を含む、請求項15〜24のいずれか一項に記載の薬学的組成物。
- 前記抗生物質耐性菌が、メチシリン耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)(MRSA)、バンコマイシン耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)(VRSA)、ダプトマイシン耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)(DRSA)、および/または、リネゾリド耐性スタフィロコッカス・アウレウス(Staphylococcus aureus)(LRSA)を含み、前記抗生物質に対する感受性が変更された菌が、バンコマイシン中間感性スタフィロコッカス・アウレウス(Staphylococcus aureus)(VISA)を含む、請求項25に記載の薬学的組成物。
- 1または複数の抗生物質をさらに含む、請求項15〜26のいずれか一項に記載の薬学的組成物。
- 前記組成物が、1または複数の抗生物質と組み合わせて、該抗生物質の前、または、該抗生物質の後に、前記被験体に投与される、請求項15〜26のいずれか一項に記載の薬学的組成物。
- 前記1または複数の抗生物質が、グリコペプチド類、マクロライド類および/またはペニシリン類を含む、請求項27または28に記載の薬学的組成物。
- 前記1または複数の抗生物質がペニシリン類を含み、該ペニシリン類が、オキサシリン、アンピシリンおよび/またはクロキサシリンを含む、請求項27または28に記載の薬学的組成物。
- 前記1または複数の抗生物質がグリコペプチド類を含み、該グリコペプチド類が、バンコマイシンおよび/またはテイコプラニンを含む、請求項27または28に記載の薬学的組成物。
- 前記1または複数の抗生物質がダプトマイシン、バンコマイシン、および/または、リネゾリドを含む、請求項27または28に記載の薬学的組成物。
- 前記1または複数の抗生物質がマクロライド類を含み、該マクロライド類が、エリスロマイシン、クラリスロマイシン、アジスロマイシンおよび/またはロキシスロマイシンを含む、請求項27または28に記載の薬学的組成物。
- 前記溶解素ポリペプチドが配列番号1に示されるアミノ酸配列を含む、請求項15〜33のいずれか一項に記載の薬学的組成物。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201261644799P | 2012-05-09 | 2012-05-09 | |
US61/644,799 | 2012-05-09 | ||
US201261736813P | 2012-12-13 | 2012-12-13 | |
US61/736,813 | 2012-12-13 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015511701A Division JP6348901B2 (ja) | 2012-05-09 | 2013-05-09 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020134278A Division JP2020189860A (ja) | 2012-05-09 | 2020-08-07 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2018087242A JP2018087242A (ja) | 2018-06-07 |
JP6873939B2 true JP6873939B2 (ja) | 2021-05-19 |
Family
ID=49551275
Family Applications (4)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015511701A Active JP6348901B2 (ja) | 2012-05-09 | 2013-05-09 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
JP2018031017A Active JP6873939B2 (ja) | 2012-05-09 | 2018-02-23 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
JP2020134278A Pending JP2020189860A (ja) | 2012-05-09 | 2020-08-07 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
JP2022130371A Active JP7368018B2 (ja) | 2012-05-09 | 2022-08-18 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015511701A Active JP6348901B2 (ja) | 2012-05-09 | 2013-05-09 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
Family Applications After (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2020134278A Pending JP2020189860A (ja) | 2012-05-09 | 2020-08-07 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
JP2022130371A Active JP7368018B2 (ja) | 2012-05-09 | 2022-08-18 | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 |
Country Status (16)
Country | Link |
---|---|
US (4) | US9499594B2 (ja) |
EP (2) | EP2846827B1 (ja) |
JP (4) | JP6348901B2 (ja) |
KR (4) | KR20210118980A (ja) |
CN (2) | CN111803620A (ja) |
AU (3) | AU2013259427B2 (ja) |
BR (1) | BR112014027818B1 (ja) |
CA (2) | CA3187222A1 (ja) |
DK (1) | DK2846827T3 (ja) |
ES (1) | ES2729123T3 (ja) |
HK (2) | HK1208366A1 (ja) |
IL (2) | IL235526B2 (ja) |
IN (1) | IN2014MN02438A (ja) |
MX (2) | MX369056B (ja) |
RU (3) | RU2646102C2 (ja) |
WO (1) | WO2013170022A1 (ja) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
DE112008001301T5 (de) | 2007-05-14 | 2010-04-29 | Reserach Foundation Of State University Of New York | Induktion einer physiologischen Dispersions-Antwort in Bakterien-Zellen in einem Biofilm |
CN104736172A (zh) * | 2012-05-09 | 2015-06-24 | 康特拉费克特公司 | 针对革兰氏阳性细菌的噬菌体溶素和抗生素组合 |
BR112016030580B1 (pt) * | 2014-06-26 | 2023-12-19 | The Rockefeller University | Polipeptídeo de lisina e fragmento de polipeptídeo com atividade para matar bactérias gram-negativas |
CN104805066B (zh) * | 2015-05-18 | 2018-04-24 | 武汉菲吉乐科生物科技有限公司 | 一种葡萄球菌裂解酶及其应用 |
EP3120866A1 (en) * | 2015-07-24 | 2017-01-25 | Zymetech ehf. | Use of marine serine proteases for removal, prevention and inhibition of formation and growth of biofilms |
US11103547B2 (en) | 2016-02-04 | 2021-08-31 | Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. | Methods for disrupting biofilms |
WO2017140770A1 (en) * | 2016-02-19 | 2017-08-24 | Forschungszentrum Borstel Leibniz-Zentrum Für Medizin Und Biowissenschaften | Means and methods for treating bacterial infections |
RU2664708C1 (ru) * | 2017-06-08 | 2018-08-21 | Сергей Иванович Черныш | Способ разрушения и предотвращения образования бактериальных биопленок комплексом антимикробных пептидов насекомых |
MX2020008860A (es) * | 2018-02-26 | 2020-12-10 | Contrafect Corp | Lisinas plyss2 modificadas y sus usos. |
US11541105B2 (en) | 2018-06-01 | 2023-01-03 | The Research Foundation For The State University Of New York | Compositions and methods for disrupting biofilm formation and maintenance |
JP2022525914A (ja) * | 2019-03-22 | 2022-05-20 | コントラフェクト コーポレイション | 感染性心内膜炎を治療する方法 |
CN114025783A (zh) * | 2019-04-11 | 2022-02-08 | 康特拉费克特公司 | 治疗和预防骨和关节感染的方法 |
KR102097128B1 (ko) * | 2019-06-19 | 2020-04-06 | 서울대학교산학협력단 | 황색포도상구균 제어에 효과적인 키메릭 엔도라이신 Lys109 |
CN111019876B (zh) * | 2019-12-30 | 2023-04-28 | 延安大学 | 一种铜绿假单胞菌工程菌的构建方法及应用 |
WO2021236636A1 (en) * | 2020-05-19 | 2021-11-25 | Contrafect Corporation | MODIFIED PlySs2 LYSINS AND ANTIBIOTIC COMBINATIONS FOR USE AGAINST GRAM-POSITIVE BACTERIA |
KR102426421B1 (ko) * | 2021-01-06 | 2022-07-29 | 주식회사 리신바이오 | 신규 재조합 엔도라이신 및 이의 용도 |
WO2024007055A1 (en) * | 2022-07-05 | 2024-01-11 | The University Of Adelaide | Method of production of modified phage and method of treatment using same |
Family Cites Families (37)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU8108587A (en) | 1986-10-08 | 1988-05-06 | David Bernstein | Method for exposing group a streptococcal antigens and an improved diagnostic test for the identification of group a streptococci |
US20060292135A1 (en) | 1997-10-31 | 2006-12-28 | Lawrence Loomis | Use of bacterial phage-associated lysing proteins for preventing and treating bacterial infections in humans, animals and fowl |
US6248324B1 (en) | 1997-10-31 | 2001-06-19 | Vincent Fischetti | Bacterial phage associated lysing enzymes for treating dermatological infections |
US6264945B1 (en) | 1997-10-31 | 2001-07-24 | Vincent A Fischetti | Parenteral use of bacterial phage associated lysing enzymes for the therapeutic treatment of bacterial infections |
US6254866B1 (en) | 1997-10-31 | 2001-07-03 | New Horizons Diagnostics Corporation | Use of phage associated lytic enzymes for treating bacterial infections of the digestive tract |
WO2000050069A1 (en) | 1999-02-25 | 2000-08-31 | New Horizons Diagnostics, Inc. | A means for the prophylactic and therapeutic treatment of streptococcal infections |
US5997862A (en) | 1997-10-31 | 1999-12-07 | New Horizons Diagnostics Corporation | Therapeutic treatment of group A streptococcal infections |
US6056955A (en) | 1999-09-14 | 2000-05-02 | Fischetti; Vincent | Topical treatment of streptococcal infections |
US20040213765A1 (en) | 2001-07-13 | 2004-10-28 | Vincent Fischetti | Use of bacterial phage associated lytic enzymes to prevent food poisoning |
AU2003291614A1 (en) | 2002-05-17 | 2004-04-08 | New Horizons Diagnostics Corporation | Identification of a phage associated lytic enzyme to rapidly and specifically detect and kill bacillus anthracis |
US7569223B2 (en) | 2004-03-22 | 2009-08-04 | The Rockefeller University | Phage-associated lytic enzymes for treatment of Streptococcus pneumoniae and related conditions |
EP1744779A2 (en) | 2004-03-24 | 2007-01-24 | The Rockfeller University | Lytic enzymes and spore surface antigen for detection and treatment of "bacillus anthracis" bacteria and spores |
EP1621205A1 (en) * | 2004-07-28 | 2006-02-01 | OctoPlus Technologies B.V. | Antimicrobial peptides derived from CAP18 |
CN102657855B (zh) * | 2004-09-22 | 2015-12-09 | 葛兰素史密丝克莱恩生物有限公司 | 用于进行抗葡萄球菌接种的免疫原性组合物 |
US8389469B2 (en) | 2005-06-06 | 2013-03-05 | The Rockefeller University | Bacteriophage lysins for Bacillus anthracis |
US7582291B2 (en) | 2005-06-30 | 2009-09-01 | The Rockefeller University | Bacteriophage lysins for Enterococcus faecalis, Enterococcus faecium and other bacteria |
US8105585B2 (en) | 2005-08-24 | 2012-01-31 | The Rockefeller Universtiy | Ply-GBS mutant lysins |
US20080019956A1 (en) | 2006-07-24 | 2008-01-24 | Manoj Kumar | Enzymatic prevention and control of biofilm |
US8058225B2 (en) | 2007-08-22 | 2011-11-15 | Hyglos Invest Gmbh | Proteins for use in human and animal Staphylococcus infections |
EP2238157A2 (en) | 2008-01-10 | 2010-10-13 | Trustees of Boston University | Engineered bacteriophages as adjuvants for antimicrobial agents and compositions and methods of use thereof |
AU2009266982B2 (en) * | 2008-07-03 | 2015-06-25 | The Rockefeller University | A chimeric bacteriophage lysin with activity against staphylococci bacteria |
SG189733A1 (en) * | 2008-10-10 | 2013-05-31 | Lusomedicamenta S A | Antibacterial phage peptides and methods of use thereof |
KR101016918B1 (ko) | 2009-01-08 | 2011-02-25 | 주식회사 인트론바이오테크놀로지 | 박테리아 특이적 넓은 항균 활성을 갖는 신규한 리신 단백질 |
JP5779092B2 (ja) | 2009-05-01 | 2015-09-16 | 株式会社きもと | 離型性組成物および表面保護フィルム |
EP2338916A1 (en) * | 2009-12-23 | 2011-06-29 | Hyglos Invest GmbH | Chimeric polypeptides and their use in bacterial decoloniation |
US8951532B2 (en) | 2010-01-25 | 2015-02-10 | Alere Scarborough, Inc. | A25 bacteriophage lysin |
AU2011247584B2 (en) * | 2010-04-27 | 2016-01-14 | Lysando Ag | Method of reducing biofilms |
EP2397548A1 (en) * | 2010-06-18 | 2011-12-21 | Hyglos Invest GmbH | Methods of generating and screening for lytic chimeric polypeptides |
US9034322B2 (en) * | 2011-04-21 | 2015-05-19 | The Rockefeller University | Streptococcus bacteriophage lysins for detection and treatment of gram positive bacteria |
WO2012145573A2 (en) * | 2011-04-21 | 2012-10-26 | Universiteit Utrecht Holding Bv | Streptococcus bacteriophage lysins for treatment of gram positive bacteria in companion animals and livestock |
US20140120074A1 (en) | 2011-04-27 | 2014-05-01 | Lysando Ag | Antimicrobial agents |
CN104736172A (zh) | 2012-05-09 | 2015-06-24 | 康特拉费克特公司 | 针对革兰氏阳性细菌的噬菌体溶素和抗生素组合 |
EP2835193A1 (en) | 2013-08-05 | 2015-02-11 | Refractory Intellectual Property GmbH & Co. KG | Refractory ceramic nozzle |
CN104073478A (zh) * | 2014-06-13 | 2014-10-01 | 上海交通大学 | 杀灭革兰氏阳性菌的酶抗生素及其制备、用途 |
CN104726439B (zh) * | 2015-04-13 | 2017-11-14 | 武汉菲吉乐科生物科技有限公司 | 一种广谱的链球菌裂解酶及其应用 |
CN104805066B (zh) * | 2015-05-18 | 2018-04-24 | 武汉菲吉乐科生物科技有限公司 | 一种葡萄球菌裂解酶及其应用 |
BR112018005316A2 (pt) * | 2015-09-17 | 2018-12-11 | Contrafect Corporation | ?uso de lisina para restabelecer/aumentar a atividade antibacteriana na presença de surfactante pulmonar de antibióticos inibidos desse modo? |
-
2013
- 2013-05-09 US US14/399,588 patent/US9499594B2/en active Active
- 2013-05-09 AU AU2013259427A patent/AU2013259427B2/en active Active
- 2013-05-09 IN IN2438MUN2014 patent/IN2014MN02438A/en unknown
- 2013-05-09 JP JP2015511701A patent/JP6348901B2/ja active Active
- 2013-05-09 KR KR1020217030507A patent/KR20210118980A/ko not_active IP Right Cessation
- 2013-05-09 KR KR1020147034615A patent/KR102084388B1/ko active Application Filing
- 2013-05-09 CA CA3187222A patent/CA3187222A1/en active Pending
- 2013-05-09 WO PCT/US2013/040340 patent/WO2013170022A1/en active Application Filing
- 2013-05-09 RU RU2014149348A patent/RU2646102C2/ru active
- 2013-05-09 BR BR112014027818-0A patent/BR112014027818B1/pt active IP Right Grant
- 2013-05-09 CA CA2872911A patent/CA2872911C/en active Active
- 2013-05-09 EP EP13787555.5A patent/EP2846827B1/en active Active
- 2013-05-09 MX MX2014013587A patent/MX369056B/es active IP Right Grant
- 2013-05-09 DK DK13787555.5T patent/DK2846827T3/da active
- 2013-05-09 RU RU2018102796A patent/RU2735103C2/ru active
- 2013-05-09 KR KR1020207005447A patent/KR20200023521A/ko active Application Filing
- 2013-05-09 ES ES13787555T patent/ES2729123T3/es active Active
- 2013-05-09 KR KR1020237030790A patent/KR20230135161A/ko active Application Filing
- 2013-05-09 CN CN202010800525.9A patent/CN111803620A/zh active Pending
- 2013-05-09 EP EP19156777.5A patent/EP3513807A1/en not_active Withdrawn
- 2013-05-09 CN CN201380036474.5A patent/CN104780933B/zh active Active
-
2014
- 2014-11-06 IL IL235526A patent/IL235526B2/en unknown
- 2014-11-07 MX MX2019012877A patent/MX2019012877A/es unknown
-
2015
- 2015-09-17 HK HK15109108.3A patent/HK1208366A1/xx unknown
-
2016
- 2016-01-05 HK HK16100031.3A patent/HK1212208A1/xx unknown
- 2016-10-14 US US15/293,586 patent/US20170127683A1/en not_active Abandoned
-
2018
- 2018-02-23 JP JP2018031017A patent/JP6873939B2/ja active Active
- 2018-03-09 AU AU2018201736A patent/AU2018201736B2/en active Active
-
2019
- 2019-04-22 US US16/391,272 patent/US11524046B2/en active Active
- 2019-09-18 IL IL26942619A patent/IL269426A/en unknown
-
2020
- 2020-06-16 AU AU2020204014A patent/AU2020204014A1/en not_active Abandoned
- 2020-08-07 JP JP2020134278A patent/JP2020189860A/ja active Pending
- 2020-10-12 RU RU2020133461A patent/RU2020133461A/ru unknown
-
2022
- 2022-08-18 JP JP2022130371A patent/JP7368018B2/ja active Active
- 2022-11-11 US US18/054,587 patent/US20230277617A1/en active Pending
Also Published As
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP6873939B2 (ja) | バクテリオファージ溶解素によるバイオフィルムの防止、破壊および処置 | |
JP2022058682A (ja) | グラム陽性菌に対するバクテリオファージ溶解素と抗生物質との組み合わせ |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20180223 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20181204 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190301 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20190426 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20190604 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20191105 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200205 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20200317 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20200324 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20200407 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20200807 |
|
C60 | Trial request (containing other claim documents, opposition documents) |
Free format text: JAPANESE INTERMEDIATE CODE: C60 Effective date: 20200807 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20200811 |
|
C876 | Explanation why request for accelerated appeal examination is justified |
Free format text: JAPANESE INTERMEDIATE CODE: C876 Effective date: 20200904 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20200910 |
|
C21 | Notice of transfer of a case for reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C21 Effective date: 20200915 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20201002 |
|
C211 | Notice of termination of reconsideration by examiners before appeal proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C211 Effective date: 20201006 |
|
C305 | Report on accelerated appeal examination |
Free format text: JAPANESE INTERMEDIATE CODE: C305 Effective date: 20201009 |
|
C22 | Notice of designation (change) of administrative judge |
Free format text: JAPANESE INTERMEDIATE CODE: C22 Effective date: 20201013 |
|
C13 | Notice of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: C13 Effective date: 20201027 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20210126 |
|
C23 | Notice of termination of proceedings |
Free format text: JAPANESE INTERMEDIATE CODE: C23 Effective date: 20210316 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20210126 |
|
C03 | Trial/appeal decision taken |
Free format text: JAPANESE INTERMEDIATE CODE: C03 Effective date: 20210413 |
|
C30A | Notification sent |
Free format text: JAPANESE INTERMEDIATE CODE: C3012 Effective date: 20210413 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20210421 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6873939 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |