CN115397836A - 新型抗菌肽及其用途 - Google Patents
新型抗菌肽及其用途 Download PDFInfo
- Publication number
- CN115397836A CN115397836A CN202180028141.2A CN202180028141A CN115397836A CN 115397836 A CN115397836 A CN 115397836A CN 202180028141 A CN202180028141 A CN 202180028141A CN 115397836 A CN115397836 A CN 115397836A
- Authority
- CN
- China
- Prior art keywords
- trp
- arg
- val
- leu
- lys
- 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.)
- Pending
Links
- 239000003910 polypeptide antibiotic agent Substances 0.000 title claims abstract description 217
- 230000000844 anti-bacterial effect Effects 0.000 claims abstract description 40
- 239000000203 mixture Substances 0.000 claims abstract description 36
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 35
- 239000004480 active ingredient Substances 0.000 claims abstract description 23
- 230000003115 biocidal effect Effects 0.000 claims abstract description 19
- 239000002537 cosmetic Substances 0.000 claims abstract description 12
- 235000013373 food additive Nutrition 0.000 claims abstract description 6
- 239000002778 food additive Substances 0.000 claims abstract description 6
- 239000003674 animal food additive Substances 0.000 claims abstract description 5
- 108700042778 Antimicrobial Peptides Proteins 0.000 claims description 72
- 102000044503 Antimicrobial Peptides Human genes 0.000 claims description 72
- 150000001413 amino acids Chemical class 0.000 claims description 46
- 150000003839 salts Chemical class 0.000 claims description 34
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 22
- 239000000194 fatty acid Substances 0.000 claims description 22
- 229930195729 fatty acid Natural products 0.000 claims description 22
- 150000004665 fatty acids Chemical class 0.000 claims description 19
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 18
- GHVNFZFCNZKVNT-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 claims description 13
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- 125000003545 alkoxy group Chemical group 0.000 claims description 10
- 229910052736 halogen Chemical group 0.000 claims description 9
- 125000003277 amino group Chemical group 0.000 claims description 8
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 8
- 150000002367 halogens Chemical class 0.000 claims description 7
- 239000005632 Capric acid (CAS 334-48-5) Substances 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 6
- 239000000126 substance Substances 0.000 claims description 6
- 238000006467 substitution reaction Methods 0.000 claims description 6
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 claims description 5
- 125000001041 indolyl group Chemical group 0.000 claims description 5
- 229910052717 sulfur Inorganic materials 0.000 claims description 5
- 239000011593 sulfur Substances 0.000 claims description 5
- JTKLCCFLSLCCST-SZMVWBNQSA-N Arg-Arg-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N)C(O)=O)=CNC2=C1 JTKLCCFLSLCCST-SZMVWBNQSA-N 0.000 claims description 4
- 230000013595 glycosylation Effects 0.000 claims description 4
- 238000006206 glycosylation reaction Methods 0.000 claims description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 4
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 claims description 3
- 125000001429 N-terminal alpha-amino-acid group Chemical group 0.000 claims description 3
- QTXGUIMEHKCPBH-FHWLQOOXSA-N Val-Trp-Lys Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](CCCCN)C(O)=O)=CNC2=C1 QTXGUIMEHKCPBH-FHWLQOOXSA-N 0.000 claims description 3
- RTJPAGFXOWEBAI-SRVKXCTJSA-N Val-Val-Arg Chemical compound CC(C)[C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N RTJPAGFXOWEBAI-SRVKXCTJSA-N 0.000 claims description 3
- 125000003368 amide group Chemical group 0.000 claims description 3
- 210000004899 c-terminal region Anatomy 0.000 claims description 2
- 125000003275 alpha amino acid group Chemical group 0.000 claims 15
- 125000005843 halogen group Chemical group 0.000 claims 2
- ZHZLQVLQBDBQCQ-WDSOQIARSA-N Trp-Lys-Arg Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N ZHZLQVLQBDBQCQ-WDSOQIARSA-N 0.000 claims 1
- 241000894006 Bacteria Species 0.000 abstract description 45
- 229940088710 antibiotic agent Drugs 0.000 abstract description 28
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 9
- 229940126534 drug product Drugs 0.000 abstract description 7
- 231100000135 cytotoxicity Toxicity 0.000 abstract description 4
- 230000003013 cytotoxicity Effects 0.000 abstract description 4
- 230000000853 biopesticidal effect Effects 0.000 abstract description 3
- KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 description 50
- LZDNBBYBDGBADK-UHFFFAOYSA-N L-valyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C(C)C)C(O)=O)=CNC2=C1 LZDNBBYBDGBADK-UHFFFAOYSA-N 0.000 description 29
- 108010066427 N-valyltryptophan Proteins 0.000 description 29
- XPSGESXVBSQZPL-SRVKXCTJSA-N Arg-Arg-Arg Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O XPSGESXVBSQZPL-SRVKXCTJSA-N 0.000 description 26
- 108090000765 processed proteins & peptides Proteins 0.000 description 26
- RIOVOFZXVOWCCX-SBCJRHGPSA-N Trp-Ile-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=3C4=CC=CC=C4NC=3)[C@@H](C)CC)C(O)=O)=CNC2=C1 RIOVOFZXVOWCCX-SBCJRHGPSA-N 0.000 description 23
- 235000001014 amino acid Nutrition 0.000 description 23
- 229940024606 amino acid Drugs 0.000 description 23
- 239000003814 drug Substances 0.000 description 23
- 229940079593 drug Drugs 0.000 description 22
- YOZCKMXHBYKOMQ-IHRRRGAJSA-N Leu-Arg-Lys Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N YOZCKMXHBYKOMQ-IHRRRGAJSA-N 0.000 description 19
- 238000011282 treatment Methods 0.000 description 18
- 241000588626 Acinetobacter baumannii Species 0.000 description 17
- MXKUGFHWYYKVDV-SZMVWBNQSA-N Trp-Val-Val Chemical compound CC(C)[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(C)C)C(O)=O MXKUGFHWYYKVDV-SZMVWBNQSA-N 0.000 description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 15
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 15
- BQVUABVGYYSDCJ-UHFFFAOYSA-N Nalpha-L-Leucyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)CC(C)C)C(O)=O)=CNC2=C1 BQVUABVGYYSDCJ-UHFFFAOYSA-N 0.000 description 15
- -1 etc.) Natural products 0.000 description 15
- 239000000243 solution Substances 0.000 description 15
- 241000191967 Staphylococcus aureus Species 0.000 description 13
- 230000001580 bacterial effect Effects 0.000 description 13
- 239000012528 membrane Substances 0.000 description 13
- KIMOCKLJBXHFIN-YLVFBTJISA-N Trp-Ile-Gly Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)NCC(O)=O)=CNC2=C1 KIMOCKLJBXHFIN-YLVFBTJISA-N 0.000 description 12
- CCZXBOFIBYQLEV-IHPCNDPISA-N Trp-Leu-Leu Chemical compound CC(C)C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(O)=O CCZXBOFIBYQLEV-IHPCNDPISA-N 0.000 description 12
- 108010050848 glycylleucine Proteins 0.000 description 12
- 102000004196 processed proteins & peptides Human genes 0.000 description 12
- 241000194032 Enterococcus faecalis Species 0.000 description 11
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 description 11
- WMBFONUKQXGLMU-WDSOQIARSA-N Trp-Leu-Val Chemical compound CC(C)C[C@@H](C(=O)N[C@@H](C(C)C)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N WMBFONUKQXGLMU-WDSOQIARSA-N 0.000 description 11
- FFWCYWZIVFIUDM-OYDLWJJNSA-N Trp-Val-Trp Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(O)=O FFWCYWZIVFIUDM-OYDLWJJNSA-N 0.000 description 11
- 229940032049 enterococcus faecalis Drugs 0.000 description 11
- 238000009472 formulation Methods 0.000 description 11
- UQDJGEHQDNVPGU-UHFFFAOYSA-N serine phosphoethanolamine Chemical compound [NH3+]CCOP([O-])(=O)OCC([NH3+])C([O-])=O UQDJGEHQDNVPGU-UHFFFAOYSA-N 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- RFKJNTRMXGCKFE-FHWLQOOXSA-N Val-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)CC(C)C)C(O)=O)=CNC2=C1 RFKJNTRMXGCKFE-FHWLQOOXSA-N 0.000 description 9
- 239000000872 buffer Substances 0.000 description 9
- 239000002502 liposome Substances 0.000 description 9
- 241000699670 Mus sp. Species 0.000 description 8
- 241000589517 Pseudomonas aeruginosa Species 0.000 description 8
- QNMIVTOQXUSGLN-SZMVWBNQSA-N Trp-Arg-Arg Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O)=CNC2=C1 QNMIVTOQXUSGLN-SZMVWBNQSA-N 0.000 description 8
- 230000002401 inhibitory effect Effects 0.000 description 8
- KUWPCJHYPSUOFW-YBXAARCKSA-N 2-nitrophenyl beta-D-galactoside Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1OC1=CC=CC=C1[N+]([O-])=O KUWPCJHYPSUOFW-YBXAARCKSA-N 0.000 description 7
- 108010078777 Colistin Proteins 0.000 description 7
- 241000192125 Firmicutes Species 0.000 description 7
- 238000004458 analytical method Methods 0.000 description 7
- 229960003346 colistin Drugs 0.000 description 7
- 239000004615 ingredient Substances 0.000 description 7
- 108010054155 lysyllysine Proteins 0.000 description 7
- JORAUNFTUVJTNG-BSTBCYLQSA-N n-[(2s)-4-amino-1-[[(2s,3r)-1-[[(2s)-4-amino-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-3-[(1r)-1-hydroxyethyl]-12,15-bis(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]butan-2-yl]amino]-3-h Chemical compound CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O.CCC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@H]([C@@H](C)O)CN[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(C)C)NC(=O)[C@H](CCN)NC1=O JORAUNFTUVJTNG-BSTBCYLQSA-N 0.000 description 7
- XDJYMJULXQKGMM-UHFFFAOYSA-N polymyxin E1 Natural products CCC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O XDJYMJULXQKGMM-UHFFFAOYSA-N 0.000 description 7
- KNIWPHSUTGNZST-UHFFFAOYSA-N polymyxin E2 Natural products CC(C)CCCCC(=O)NC(CCN)C(=O)NC(C(C)O)C(=O)NC(CCN)C(=O)NC1CCNC(=O)C(C(C)O)NC(=O)C(CCN)NC(=O)C(CCN)NC(=O)C(CC(C)C)NC(=O)C(CC(C)C)NC(=O)C(CCN)NC1=O KNIWPHSUTGNZST-UHFFFAOYSA-N 0.000 description 7
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- 241000588724 Escherichia coli Species 0.000 description 6
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000006071 cream Substances 0.000 description 6
- 229920001184 polypeptide Polymers 0.000 description 6
- 230000004083 survival effect Effects 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- BAXJVFSJQOWTCF-NSHDSACASA-N (2s)-3-(1h-indol-3-yl)-2-(methoxyamino)propanoic acid Chemical compound C1=CC=C2C(C[C@H](NOC)C(O)=O)=CNC2=C1 BAXJVFSJQOWTCF-NSHDSACASA-N 0.000 description 5
- LHNIIDJCEODSHA-OQRUQETBSA-N (6r,7r)-3-[(e)-2-(2,4-dinitrophenyl)ethenyl]-8-oxo-7-[(2-thiophen-2-ylacetyl)amino]-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound N([C@H]1[C@H]2SCC(=C(N2C1=O)C(=O)O)\C=C\C=1C(=CC(=CC=1)[N+]([O-])=O)[N+]([O-])=O)C(=O)CC1=CC=CS1 LHNIIDJCEODSHA-OQRUQETBSA-N 0.000 description 5
- BTJVOUQWFXABOI-IHRRRGAJSA-N Arg-Lys-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@@H](N)CCCNC(N)=N BTJVOUQWFXABOI-IHRRRGAJSA-N 0.000 description 5
- 241000588747 Klebsiella pneumoniae Species 0.000 description 5
- 239000004472 Lysine Substances 0.000 description 5
- WUGMRIBZSVSJNP-UHFFFAOYSA-N N-L-alanyl-L-tryptophan Natural products C1=CC=C2C(CC(NC(=O)C(N)C)C(O)=O)=CNC2=C1 WUGMRIBZSVSJNP-UHFFFAOYSA-N 0.000 description 5
- BRBCKMMXKONBAA-KWBADKCTSA-N Trp-Ala-Ala Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(O)=O)=CNC2=C1 BRBCKMMXKONBAA-KWBADKCTSA-N 0.000 description 5
- YYXIWHBHTARPOG-HJXMPXNTSA-N Trp-Ile-Ala Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N YYXIWHBHTARPOG-HJXMPXNTSA-N 0.000 description 5
- YTZYHKOSHOXTHA-TUSQITKMSA-N Trp-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=3C4=CC=CC=C4NC=3)CC(C)C)C(O)=O)=CNC2=C1 YTZYHKOSHOXTHA-TUSQITKMSA-N 0.000 description 5
- WHNSHJJNWNSTSU-BZSNNMDCSA-N Val-Val-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@@H](N)C(C)C)C(O)=O)=CNC2=C1 WHNSHJJNWNSTSU-BZSNNMDCSA-N 0.000 description 5
- 238000002835 absorbance Methods 0.000 description 5
- 108010062796 arginyllysine Proteins 0.000 description 5
- 210000000170 cell membrane Anatomy 0.000 description 5
- 210000002421 cell wall Anatomy 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000000839 emulsion Substances 0.000 description 5
- 235000013305 food Nutrition 0.000 description 5
- 244000005700 microbiome Species 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000003755 preservative agent Substances 0.000 description 5
- 239000000725 suspension Substances 0.000 description 5
- YYGJQPKPUWCRIM-JTQLQIEISA-N (2s)-2-(fluoroamino)-3-(1h-indol-3-yl)propanoic acid Chemical compound C1=CC=C2C(C[C@@H](C(=O)O)NF)=CNC2=C1 YYGJQPKPUWCRIM-JTQLQIEISA-N 0.000 description 4
- JKMHFZQWWAIEOD-UHFFFAOYSA-N 2-[4-(2-hydroxyethyl)piperazin-1-yl]ethanesulfonic acid Chemical compound OCC[NH+]1CCN(CCS([O-])(=O)=O)CC1 JKMHFZQWWAIEOD-UHFFFAOYSA-N 0.000 description 4
- HJVGMOYJDDXLMI-AVGNSLFASA-N Arg-Arg-Lys Chemical compound NCCCC[C@@H](C(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@@H](N)CCCNC(N)=N HJVGMOYJDDXLMI-AVGNSLFASA-N 0.000 description 4
- WWZKQHOCKIZLMA-UHFFFAOYSA-N Caprylic acid Natural products CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 4
- 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 4
- NSTUFLGQJCOCDL-UWVGGRQHSA-N Gly-Leu-Arg Chemical compound NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@H](C(O)=O)CCCN=C(N)N NSTUFLGQJCOCDL-UWVGGRQHSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- YLMIDMSLKLRNHX-HSCHXYMDSA-N Leu-Trp-Ile Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(O)=O YLMIDMSLKLRNHX-HSCHXYMDSA-N 0.000 description 4
- ZJWIXBZTAAJERF-IHRRRGAJSA-N Lys-Lys-Arg Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@H](C(O)=O)CCCN=C(N)N ZJWIXBZTAAJERF-IHRRRGAJSA-N 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 239000004098 Tetracycline Substances 0.000 description 4
- KJFBXCFOPAKPTM-BZSNNMDCSA-N Val-Trp-Val Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@@H](N)C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O)=CNC2=C1 KJFBXCFOPAKPTM-BZSNNMDCSA-N 0.000 description 4
- GONOPSZTUGRENK-UHFFFAOYSA-N benzyl(trichloro)silane Chemical compound Cl[Si](Cl)(Cl)CC1=CC=CC=C1 GONOPSZTUGRENK-UHFFFAOYSA-N 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 210000003743 erythrocyte Anatomy 0.000 description 4
- 239000008103 glucose Substances 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- 230000002335 preservative effect Effects 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 229960002180 tetracycline Drugs 0.000 description 4
- 229930101283 tetracycline Natural products 0.000 description 4
- 235000019364 tetracycline Nutrition 0.000 description 4
- 150000003522 tetracyclines Chemical class 0.000 description 4
- 230000001988 toxicity Effects 0.000 description 4
- 231100000419 toxicity Toxicity 0.000 description 4
- ZENNTZUZBRESKJ-ZETCQYMHSA-N (2s)-2-(1-benzothiophen-2-ylamino)propanoic acid Chemical compound C1=CC=C2SC(N[C@@H](C)C(O)=O)=CC2=C1 ZENNTZUZBRESKJ-ZETCQYMHSA-N 0.000 description 3
- UQTZMGFTRHFAAM-ZETCQYMHSA-N 3-iodo-L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C(I)=C1 UQTZMGFTRHFAAM-ZETCQYMHSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 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 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 241000588914 Enterobacter Species 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- RVKIPWVMZANZLI-UHFFFAOYSA-N H-Lys-Trp-OH Natural products C1=CC=C2C(CC(NC(=O)C(N)CCCCN)C(O)=O)=CNC2=C1 RVKIPWVMZANZLI-UHFFFAOYSA-N 0.000 description 3
- 239000007995 HEPES buffer Substances 0.000 description 3
- 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 3
- FOBUGKUBUJOWAD-IHPCNDPISA-N Leu-Leu-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CC(C)C)C(O)=O)=CNC2=C1 FOBUGKUBUJOWAD-IHPCNDPISA-N 0.000 description 3
- WBSCNDJQPKSPII-KKUMJFAQSA-N Lys-Lys-Lys Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O WBSCNDJQPKSPII-KKUMJFAQSA-N 0.000 description 3
- KXYLFJIQDIMURW-IHPCNDPISA-N Lys-Trp-Leu Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@@H](N)CCCCN)=CNC2=C1 KXYLFJIQDIMURW-IHPCNDPISA-N 0.000 description 3
- MSFSPUZXLOGKHJ-UHFFFAOYSA-N Muraminsaeure Natural products OC(=O)C(C)OC1C(N)C(O)OC(CO)C1O MSFSPUZXLOGKHJ-UHFFFAOYSA-N 0.000 description 3
- 108010087066 N2-tryptophyllysine Proteins 0.000 description 3
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 3
- 229930182555 Penicillin Natural products 0.000 description 3
- 108010013639 Peptidoglycan Proteins 0.000 description 3
- 108010059712 Pronase Proteins 0.000 description 3
- OFOBLEOULBTSOW-UHFFFAOYSA-N Propanedioic acid Natural products OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 description 3
- NMOIRIIIUVELLY-WDSOQIARSA-N Trp-Val-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@H](C(=O)N[C@@H](CC(C)C)C(O)=O)C(C)C)=CNC2=C1 NMOIRIIIUVELLY-WDSOQIARSA-N 0.000 description 3
- QIVBCDIJIAJPQS-UHFFFAOYSA-N Tryptophan Natural products C1=CC=C2C(CC(N)C(O)=O)=CNC2=C1 QIVBCDIJIAJPQS-UHFFFAOYSA-N 0.000 description 3
- 108010059993 Vancomycin Proteins 0.000 description 3
- 125000000217 alkyl group Chemical group 0.000 description 3
- 239000003963 antioxidant agent Substances 0.000 description 3
- 235000006708 antioxidants Nutrition 0.000 description 3
- 239000002585 base Substances 0.000 description 3
- 125000004432 carbon atom Chemical group C* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007796 conventional method Methods 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 238000002845 discoloration Methods 0.000 description 3
- 238000002296 dynamic light scattering Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 125000003588 lysine group Chemical group [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 239000008188 pellet Substances 0.000 description 3
- 230000035699 permeability Effects 0.000 description 3
- 239000004460 silage Substances 0.000 description 3
- 239000000600 sorbitol Substances 0.000 description 3
- 241000894007 species Species 0.000 description 3
- 239000004094 surface-active agent Substances 0.000 description 3
- 108010045269 tryptophyltryptophan Proteins 0.000 description 3
- 229960003165 vancomycin Drugs 0.000 description 3
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 3
- MYPYJXKWCTUITO-UHFFFAOYSA-N vancomycin Natural products O1C(C(=C2)Cl)=CC=C2C(O)C(C(NC(C2=CC(O)=CC(O)=C2C=2C(O)=CC=C3C=2)C(O)=O)=O)NC(=O)C3NC(=O)C2NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(CC(C)C)NC)C(O)C(C=C3Cl)=CC=C3OC3=CC2=CC1=C3OC1OC(CO)C(O)C(O)C1OC1CC(C)(N)C(O)C(C)O1 MYPYJXKWCTUITO-UHFFFAOYSA-N 0.000 description 3
- 235000015112 vegetable and seed oil Nutrition 0.000 description 3
- 239000008158 vegetable oil Substances 0.000 description 3
- PUPZLCDOIYMWBV-UHFFFAOYSA-N (+/-)-1,3-Butanediol Chemical compound CC(O)CCO PUPZLCDOIYMWBV-UHFFFAOYSA-N 0.000 description 2
- JBFNEVNUGGFPBQ-DDMCRLCFSA-N (2s,3r)-2-acetamido-3-hydroxy-n-[(2r)-3-hydroxy-1-oxo-1-[[(3s,6s,9s,12s,15r,18s,21s)-6,9,18-tris(2-aminoethyl)-15-benzyl-3-[(1r)-1-hydroxyethyl]-12-(2-methylpropyl)-2,5,8,11,14,17,20-heptaoxo-1,4,7,10,13,16,19-heptazacyclotricos-21-yl]amino]propan-2-yl]bu Chemical compound N1C(=O)[C@H](CCN)NC(=O)[C@@H](NC(=O)[C@@H](CO)NC(=O)[C@@H](NC(C)=O)[C@@H](C)O)CCNC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1CC1=CC=CC=C1 JBFNEVNUGGFPBQ-DDMCRLCFSA-N 0.000 description 2
- SOVUOXKZCCAWOJ-HJYUBDRYSA-N (4s,4as,5ar,12ar)-9-[[2-(tert-butylamino)acetyl]amino]-4,7-bis(dimethylamino)-1,10,11,12a-tetrahydroxy-3,12-dioxo-4a,5,5a,6-tetrahydro-4h-tetracene-2-carboxamide Chemical compound C1C2=C(N(C)C)C=C(NC(=O)CNC(C)(C)C)C(O)=C2C(O)=C2[C@@H]1C[C@H]1[C@H](N(C)C)C(=O)C(C(N)=O)=C(O)[C@@]1(O)C2=O SOVUOXKZCCAWOJ-HJYUBDRYSA-N 0.000 description 2
- NHBKXEKEPDILRR-UHFFFAOYSA-N 2,3-bis(butanoylsulfanyl)propyl butanoate Chemical compound CCCC(=O)OCC(SC(=O)CCC)CSC(=O)CCC NHBKXEKEPDILRR-UHFFFAOYSA-N 0.000 description 2
- 229920001817 Agar Polymers 0.000 description 2
- 239000000592 Artificial Cell Substances 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 208000035143 Bacterial infection Diseases 0.000 description 2
- RGHNJXZEOKUKBD-SQOUGZDYSA-N D-gluconic acid Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C(O)=O RGHNJXZEOKUKBD-SQOUGZDYSA-N 0.000 description 2
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 2
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229930182566 Gentamicin Natural products 0.000 description 2
- CEAZRRDELHUEMR-URQXQFDESA-N Gentamicin Chemical compound O1[C@H](C(C)NC)CC[C@@H](N)[C@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](NC)[C@@](C)(O)CO2)O)[C@H](N)C[C@@H]1N CEAZRRDELHUEMR-URQXQFDESA-N 0.000 description 2
- 241000606768 Haemophilus influenzae Species 0.000 description 2
- DRKZDEFADVYTLU-AVGNSLFASA-N His-Val-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](C(C)C)C(O)=O DRKZDEFADVYTLU-AVGNSLFASA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- VAXBXNPRXPHGHG-BJDJZHNGSA-N Ile-Ala-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)O)N VAXBXNPRXPHGHG-BJDJZHNGSA-N 0.000 description 2
- MGUTVMBNOMJLKC-VKOGCVSHSA-N Ile-Trp-Val Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](C(C)C)C(=O)O)N MGUTVMBNOMJLKC-VKOGCVSHSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- IDGRADDMTTWOQC-WDSOQIARSA-N Leu-Trp-Arg Chemical compound [H]N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](CCCNC(N)=N)C(O)=O IDGRADDMTTWOQC-WDSOQIARSA-N 0.000 description 2
- 102000004895 Lipoproteins Human genes 0.000 description 2
- 108090001030 Lipoproteins Proteins 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 206010029155 Nephropathy toxic Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 2
- 108091006899 SPR741 Proteins 0.000 description 2
- 241000607142 Salmonella Species 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 244000299461 Theobroma cacao Species 0.000 description 2
- 229920004890 Triton X-100 Polymers 0.000 description 2
- WKCFCVBOFKEVKY-HSCHXYMDSA-N Trp-Leu-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N WKCFCVBOFKEVKY-HSCHXYMDSA-N 0.000 description 2
- MEZCXKYMMQJRDE-PMVMPFDFSA-N Trp-Leu-Tyr Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)CC(C)C)C(O)=O)C1=CC=C(O)C=C1 MEZCXKYMMQJRDE-PMVMPFDFSA-N 0.000 description 2
- WGBFZZYIWFSYER-BVSLBCMMSA-N Trp-Val-Tyr Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CC1=CC=C(C=C1)O)C(=O)O)NC(=O)[C@H](CC2=CNC3=CC=CC=C32)N WGBFZZYIWFSYER-BVSLBCMMSA-N 0.000 description 2
- PAPWZOJOLKZEFR-AVGNSLFASA-N Val-Arg-Lys Chemical compound CC(C)[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N PAPWZOJOLKZEFR-AVGNSLFASA-N 0.000 description 2
- WFTKOJGOOUJLJV-VKOGCVSHSA-N Val-Trp-Ile Chemical compound C1=CC=C2C(C[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C([O-])=O)NC(=O)[C@@H]([NH3+])C(C)C)=CNC2=C1 WFTKOJGOOUJLJV-VKOGCVSHSA-N 0.000 description 2
- 241000607479 Yersinia pestis Species 0.000 description 2
- XLOMVQKBTHCTTD-UHFFFAOYSA-N Zinc monoxide Chemical compound [Zn]=O XLOMVQKBTHCTTD-UHFFFAOYSA-N 0.000 description 2
- 239000000654 additive Substances 0.000 description 2
- 239000008272 agar Substances 0.000 description 2
- 229910052783 alkali metal Inorganic materials 0.000 description 2
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 2
- 229940126575 aminoglycoside Drugs 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 239000000427 antigen Substances 0.000 description 2
- 102000036639 antigens Human genes 0.000 description 2
- 108091007433 antigens Proteins 0.000 description 2
- 108010068380 arginylarginine Proteins 0.000 description 2
- 150000001507 asparagine derivatives Chemical class 0.000 description 2
- 208000022362 bacterial infectious disease Diseases 0.000 description 2
- 239000000981 basic dye Substances 0.000 description 2
- 239000000440 bentonite Substances 0.000 description 2
- 229910000278 bentonite Inorganic materials 0.000 description 2
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- SESFRYSPDFLNCH-UHFFFAOYSA-N benzyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCC1=CC=CC=C1 SESFRYSPDFLNCH-UHFFFAOYSA-N 0.000 description 2
- 108010034752 beta-lactamase NDM-1 Proteins 0.000 description 2
- 235000013361 beverage Nutrition 0.000 description 2
- 235000014121 butter Nutrition 0.000 description 2
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 2
- MYSWGUAQZAJSOK-UHFFFAOYSA-N ciprofloxacin Chemical compound C12=CC(N3CCNCC3)=C(F)C=C2C(=O)C(C(=O)O)=CN1C1CC1 MYSWGUAQZAJSOK-UHFFFAOYSA-N 0.000 description 2
- 235000009508 confectionery Nutrition 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000011156 evaluation Methods 0.000 description 2
- 230000005284 excitation Effects 0.000 description 2
- 150000002191 fatty alcohols Chemical class 0.000 description 2
- 239000006260 foam Substances 0.000 description 2
- 239000000499 gel Substances 0.000 description 2
- 229960002518 gentamicin Drugs 0.000 description 2
- RWSXRVCMGQZWBV-WDSKDSINSA-N glutathione Chemical compound OC(=O)[C@@H](N)CCC(=O)N[C@@H](CS)C(=O)NCC(O)=O RWSXRVCMGQZWBV-WDSKDSINSA-N 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229940047650 haemophilus influenzae Drugs 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 150000002632 lipids Chemical class 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000013372 meat Nutrition 0.000 description 2
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 2
- 235000013336 milk Nutrition 0.000 description 2
- 239000008267 milk Substances 0.000 description 2
- 210000004080 milk Anatomy 0.000 description 2
- 150000007522 mineralic acids Chemical class 0.000 description 2
- 230000007694 nephrotoxicity Effects 0.000 description 2
- 231100000417 nephrotoxicity Toxicity 0.000 description 2
- 239000012457 nonaqueous media Substances 0.000 description 2
- 235000012149 noodles Nutrition 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000007911 parenteral administration Methods 0.000 description 2
- 244000052769 pathogen Species 0.000 description 2
- 150000002960 penicillins Chemical class 0.000 description 2
- VLTRZXGMWDSKGL-UHFFFAOYSA-N perchloric acid Chemical compound OCl(=O)(=O)=O VLTRZXGMWDSKGL-UHFFFAOYSA-N 0.000 description 2
- 239000008020 pharmaceutical preservative Substances 0.000 description 2
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 2
- 235000018102 proteins Nutrition 0.000 description 2
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical compound OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 239000000344 soap Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 230000001954 sterilising effect Effects 0.000 description 2
- 238000004659 sterilization and disinfection Methods 0.000 description 2
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- 229960004089 tigecycline Drugs 0.000 description 2
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 239000001993 wax Substances 0.000 description 2
- 150000003952 β-lactams Chemical class 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
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 description 1
- RRBGTUQJDFBWNN-MUGJNUQGSA-N (2s)-6-amino-2-[[(2s)-6-amino-2-[[(2s)-6-amino-2-[[(2s)-2,6-diaminohexanoyl]amino]hexanoyl]amino]hexanoyl]amino]hexanoic acid Chemical compound NCCCC[C@H](N)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(O)=O RRBGTUQJDFBWNN-MUGJNUQGSA-N 0.000 description 1
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 description 1
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 description 1
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 description 1
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 1
- WNWHHMBRJJOGFJ-UHFFFAOYSA-N 16-methylheptadecan-1-ol Chemical class CC(C)CCCCCCCCCCCCCCCO WNWHHMBRJJOGFJ-UHFFFAOYSA-N 0.000 description 1
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- KQFRUSHJPKXBMB-BHDSKKPTSA-N Ala-Ala-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H](C)NC(=O)[C@@H](N)C)C(O)=O)=CNC2=C1 KQFRUSHJPKXBMB-BHDSKKPTSA-N 0.000 description 1
- MUXONAMCEUBVGA-DCAQKATOSA-N Arg-Arg-Gln Chemical compound NC(N)=NCCC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCC(N)=O)C(O)=O MUXONAMCEUBVGA-DCAQKATOSA-N 0.000 description 1
- JGDGLDNAQJJGJI-AVGNSLFASA-N Arg-Arg-His Chemical compound C1=C(NC=N1)C[C@@H](C(=O)O)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CCCN=C(N)N)N JGDGLDNAQJJGJI-AVGNSLFASA-N 0.000 description 1
- POZKLUIXMHIULG-FDARSICLSA-N Arg-Trp-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CCCN=C(N)N)N POZKLUIXMHIULG-FDARSICLSA-N 0.000 description 1
- GMRGSBAMMMVDGG-GUBZILKMSA-N Asn-Arg-Arg Chemical compound C(C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)NC(=O)[C@H](CC(=O)N)N)CN=C(N)N GMRGSBAMMMVDGG-GUBZILKMSA-N 0.000 description 1
- YUELDQUPTAYEGM-XIRDDKMYSA-N Asp-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CC(=O)O)N YUELDQUPTAYEGM-XIRDDKMYSA-N 0.000 description 1
- DCXYFEDJOCDNAF-UHFFFAOYSA-N Asparagine Natural products OC(=O)C(N)CC(N)=O DCXYFEDJOCDNAF-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 241001465180 Botrytis Species 0.000 description 1
- 241000186146 Brevibacterium Species 0.000 description 1
- 241000251522 Cephalochordata Species 0.000 description 1
- 229940123150 Chelating agent Drugs 0.000 description 1
- 241000193163 Clostridioides difficile Species 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-UHFFFAOYSA-N D-gluconic acid Natural products OCC(O)C(O)C(O)C(O)C(O)=O RGHNJXZEOKUKBD-UHFFFAOYSA-N 0.000 description 1
- 108010013198 Daptomycin Proteins 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- GZDFHIJNHHMENY-UHFFFAOYSA-N Dimethyl dicarbonate Chemical compound COC(=O)OC(=O)OC GZDFHIJNHHMENY-UHFFFAOYSA-N 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 241000255896 Galleria mellonella Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- KWUSGAIFNHQCBY-DCAQKATOSA-N Gln-Arg-Arg Chemical compound NC(=O)CC[C@H](N)C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCN=C(N)N)C(O)=O KWUSGAIFNHQCBY-DCAQKATOSA-N 0.000 description 1
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 description 1
- 108010024636 Glutathione Proteins 0.000 description 1
- MREVELMMFOLESM-HOCLYGCPSA-N Gly-Trp-Val Chemical compound [H]NCC(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C(C)C)C(O)=O MREVELMMFOLESM-HOCLYGCPSA-N 0.000 description 1
- 238000003794 Gram staining Methods 0.000 description 1
- 206010018910 Haemolysis Diseases 0.000 description 1
- 241000238631 Hexapoda Species 0.000 description 1
- ZNTSGDNUITWTRA-WDSOQIARSA-N His-Trp-Val Chemical compound [H]N[C@@H](CC1=CNC=N1)C(=O)N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C(C)C)C(O)=O ZNTSGDNUITWTRA-WDSOQIARSA-N 0.000 description 1
- CKONPJHGMIDMJP-IHRRRGAJSA-N His-Val-His Chemical compound C([C@H](N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1NC=NC=1)C(O)=O)C1=CN=CN1 CKONPJHGMIDMJP-IHRRRGAJSA-N 0.000 description 1
- 108090000604 Hydrolases Proteins 0.000 description 1
- 102000004157 Hydrolases Human genes 0.000 description 1
- NYEYYMLUABXDMC-NHCYSSNCSA-N Ile-Gly-Leu Chemical compound CC[C@H](C)[C@@H](C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)O)N NYEYYMLUABXDMC-NHCYSSNCSA-N 0.000 description 1
- GLLAUPMJCGKPFY-BLMTYFJBSA-N Ile-Ile-Trp Chemical compound C1=CC=C2C(C[C@H](NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H](N)[C@@H](C)CC)C(O)=O)=CNC2=C1 GLLAUPMJCGKPFY-BLMTYFJBSA-N 0.000 description 1
- RQQCJTLBSJMVCR-DSYPUSFNSA-N Ile-Leu-Trp Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)O)N RQQCJTLBSJMVCR-DSYPUSFNSA-N 0.000 description 1
- BLFXHAFTNYZEQE-VKOGCVSHSA-N Ile-Trp-Arg Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H](CC1=CNC2=CC=CC=C21)C(=O)N[C@@H](CCCN=C(N)N)C(=O)O)N BLFXHAFTNYZEQE-VKOGCVSHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- SENJXOPIZNYLHU-UHFFFAOYSA-N L-leucyl-L-arginine Natural products CC(C)CC(N)C(=O)NC(C(O)=O)CCCN=C(N)N SENJXOPIZNYLHU-UHFFFAOYSA-N 0.000 description 1
- 241000186660 Lactobacillus 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
- OJMMVQQUTAEWLP-UHFFFAOYSA-N Lincomycin Natural products CN1CC(CCC)CC1C(=O)NC(C(C)O)C1C(O)C(O)C(O)C(SC)O1 OJMMVQQUTAEWLP-UHFFFAOYSA-N 0.000 description 1
- 241000693467 Macroporus Species 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- RJQXTJLFIWVMTO-TYNCELHUSA-N Methicillin Chemical compound COC1=CC=CC(OC)=C1C(=O)N[C@@H]1C(=O)N2[C@@H](C(O)=O)C(C)(C)S[C@@H]21 RJQXTJLFIWVMTO-TYNCELHUSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 108010062010 N-Acetylmuramoyl-L-alanine Amidase Proteins 0.000 description 1
- 229930193140 Neomycin Natural products 0.000 description 1
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 239000004952 Polyamide Substances 0.000 description 1
- 101710088675 Proline-rich peptide Proteins 0.000 description 1
- 208000035415 Reinfection Diseases 0.000 description 1
- 240000004808 Saccharomyces cerevisiae Species 0.000 description 1
- 229920005654 Sephadex Polymers 0.000 description 1
- 239000012507 Sephadex™ Substances 0.000 description 1
- FVFUOQIYDPAIJR-XIRDDKMYSA-N Ser-Trp-Leu Chemical compound CC(C)C[C@@H](C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)NC(=O)[C@H](CO)N FVFUOQIYDPAIJR-XIRDDKMYSA-N 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000193998 Streptococcus pneumoniae Species 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- ULUAUXLGCMPNKK-UHFFFAOYSA-N Sulfobutanedioic acid Chemical compound OC(=O)CC(C(O)=O)S(O)(=O)=O ULUAUXLGCMPNKK-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- 235000005764 Theobroma cacao ssp. cacao Nutrition 0.000 description 1
- 235000005767 Theobroma cacao ssp. sphaerocarpum Nutrition 0.000 description 1
- WKDDRNSBRWANNC-UHFFFAOYSA-N Thienamycin Natural products C1C(SCCN)=C(C(O)=O)N2C(=O)C(C(O)C)C21 WKDDRNSBRWANNC-UHFFFAOYSA-N 0.000 description 1
- 229920001615 Tragacanth Polymers 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
- 239000007983 Tris buffer Substances 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- BIJDDZBDSJLWJY-PJODQICGSA-N Trp-Ala-Val Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H](C)C(=O)N[C@@H](C(C)C)C(O)=O BIJDDZBDSJLWJY-PJODQICGSA-N 0.000 description 1
- MVHHTXAUJCIOMZ-WDSOQIARSA-N Trp-Arg-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCN=C(N)N)C(=O)N[C@@H](CCCCN)C(=O)O)N MVHHTXAUJCIOMZ-WDSOQIARSA-N 0.000 description 1
- LDMUNXDDIDAPJH-VMBFOHBNSA-N Trp-Ile-Ile Chemical compound CC[C@H](C)[C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)O)NC(=O)[C@H](CC1=CNC2=CC=CC=C21)N LDMUNXDDIDAPJH-VMBFOHBNSA-N 0.000 description 1
- KULBQAVOXHQLIY-HSCHXYMDSA-N Trp-Ile-Leu Chemical compound C1=CC=C2C(C[C@H](N)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(O)=O)=CNC2=C1 KULBQAVOXHQLIY-HSCHXYMDSA-N 0.000 description 1
- WNZRNOGHEONFMS-PXDAIIFMSA-N Trp-Ile-Tyr Chemical compound [H]N[C@@H](CC1=CNC2=C1C=CC=C2)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC1=CC=C(O)C=C1)C(O)=O WNZRNOGHEONFMS-PXDAIIFMSA-N 0.000 description 1
- WLQRIHCMPFHGKP-PMVMPFDFSA-N Trp-Leu-Phe Chemical compound C([C@H](NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C2=CC=CC=C2NC=1)CC(C)C)C(O)=O)C1=CC=CC=C1 WLQRIHCMPFHGKP-PMVMPFDFSA-N 0.000 description 1
- UUIYFDAWNBSWPG-IHPCNDPISA-N Trp-Lys-Lys Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CCCCN)C(=O)O)N UUIYFDAWNBSWPG-IHPCNDPISA-N 0.000 description 1
- LFGHEUIUSIRJAE-TUSQITKMSA-N Trp-Lys-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O)N LFGHEUIUSIRJAE-TUSQITKMSA-N 0.000 description 1
- HWCBFXAWVTXXHZ-NYVOZVTQSA-N Trp-Ser-Trp Chemical compound C1=CC=C2C(=C1)C(=CN2)C[C@@H](C(=O)N[C@@H](CO)C(=O)N[C@@H](CC3=CNC4=CC=CC=C43)C(=O)O)N HWCBFXAWVTXXHZ-NYVOZVTQSA-N 0.000 description 1
- UGFOSENEZHEQKX-PJODQICGSA-N Trp-Val-Ala Chemical compound CC(C)[C@H](NC(=O)[C@@H](N)Cc1c[nH]c2ccccc12)C(=O)N[C@@H](C)C(O)=O UGFOSENEZHEQKX-PJODQICGSA-N 0.000 description 1
- BXJQKVDPRMLGKN-PMVMPFDFSA-N Tyr-Trp-Leu Chemical compound C([C@H](N)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 BXJQKVDPRMLGKN-PMVMPFDFSA-N 0.000 description 1
- ATBOMIWRCZXYSZ-XZBBILGWSA-N [1-[2,3-dihydroxypropoxy(hydroxy)phosphoryl]oxy-3-hexadecanoyloxypropan-2-yl] (9e,12e)-octadeca-9,12-dienoate Chemical compound CCCCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCC\C=C\C\C=C\CCCCC ATBOMIWRCZXYSZ-XZBBILGWSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- 108010078114 alanyl-tryptophyl-alanine Proteins 0.000 description 1
- 235000013334 alcoholic beverage Nutrition 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 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
- AWUCVROLDVIAJX-UHFFFAOYSA-N alpha-glycerophosphate Natural products OCC(O)COP(O)(O)=O AWUCVROLDVIAJX-UHFFFAOYSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 239000010775 animal oil Substances 0.000 description 1
- 238000011482 antibacterial activity assay Methods 0.000 description 1
- 239000011260 aqueous acid Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 235000009582 asparagine Nutrition 0.000 description 1
- 229960001230 asparagine Drugs 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 230000002358 autolytic effect Effects 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229960002903 benzyl benzoate Drugs 0.000 description 1
- 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 1
- 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 1
- 229950008086 bezlotoxumab Drugs 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- SXDBWCPKPHAZSM-UHFFFAOYSA-N bromic acid Chemical compound OBr(=O)=O SXDBWCPKPHAZSM-UHFFFAOYSA-N 0.000 description 1
- 239000001273 butane 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
- 125000004106 butoxy group Chemical group [*]OC([H])([H])C([H])([H])C(C([H])([H])[H])([H])[H] 0.000 description 1
- 235000001046 cacaotero Nutrition 0.000 description 1
- DEGAKNSWVGKMLS-UHFFFAOYSA-N calcein Chemical compound O1C(=O)C2=CC=CC=C2C21C1=CC(CN(CC(O)=O)CC(O)=O)=C(O)C=C1OC1=C2C=C(CN(CC(O)=O)CC(=O)O)C(O)=C1 DEGAKNSWVGKMLS-UHFFFAOYSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000000378 calcium silicate Substances 0.000 description 1
- 229910052918 calcium silicate Inorganic materials 0.000 description 1
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 108010068385 carbapenemase Proteins 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 150000001768 cations Chemical class 0.000 description 1
- 229960004261 cefotaxime Drugs 0.000 description 1
- AZZMGZXNTDTSME-JUZDKLSSSA-M cefotaxime sodium Chemical compound [Na+].N([C@@H]1C(N2C(=C(COC(C)=O)CS[C@@H]21)C([O-])=O)=O)C(=O)\C(=N/OC)C1=CSC(N)=N1 AZZMGZXNTDTSME-JUZDKLSSSA-M 0.000 description 1
- 229960000484 ceftazidime Drugs 0.000 description 1
- ORFOPKXBNMVMKC-DWVKKRMSSA-N ceftazidime Chemical compound S([C@@H]1[C@@H](C(N1C=1C([O-])=O)=O)NC(=O)\C(=N/OC(C)(C)C(O)=O)C=2N=C(N)SC=2)CC=1C[N+]1=CC=CC=C1 ORFOPKXBNMVMKC-DWVKKRMSSA-N 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960005091 chloramphenicol Drugs 0.000 description 1
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 description 1
- KYKAJFCTULSVSH-UHFFFAOYSA-N chloro(fluoro)methane Chemical compound F[C]Cl KYKAJFCTULSVSH-UHFFFAOYSA-N 0.000 description 1
- 235000019219 chocolate Nutrition 0.000 description 1
- 229960003405 ciprofloxacin Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 230000001143 conditioned effect Effects 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 235000018417 cysteine Nutrition 0.000 description 1
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 1
- 125000000151 cysteine group Chemical group N[C@@H](CS)C(=O)* 0.000 description 1
- 235000013365 dairy product Nutrition 0.000 description 1
- 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 description 1
- 229960005484 daptomycin Drugs 0.000 description 1
- 230000007123 defense Effects 0.000 description 1
- 239000000645 desinfectant Substances 0.000 description 1
- 239000003599 detergent Substances 0.000 description 1
- 230000006866 deterioration Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- OGQYPPBGSLZBEG-UHFFFAOYSA-N dimethyl(dioctadecyl)azanium Chemical compound CCCCCCCCCCCCCCCCCC[N+](C)(C)CCCCCCCCCCCCCCCCCC OGQYPPBGSLZBEG-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N dimethylformamide Substances CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- BPHQZTVXXXJVHI-UHFFFAOYSA-N dimyristoyl phosphatidylglycerol Chemical compound CCCCCCCCCCCCCC(=O)OCC(COP(O)(=O)OCC(O)CO)OC(=O)CCCCCCCCCCCCC BPHQZTVXXXJVHI-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 125000003438 dodecyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 229960000895 doripenem Drugs 0.000 description 1
- AVAACINZEOAHHE-VFZPANTDSA-N doripenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](CNS(N)(=O)=O)C1 AVAACINZEOAHHE-VFZPANTDSA-N 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 238000004043 dyeing Methods 0.000 description 1
- 230000003073 embolic effect Effects 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 239000002158 endotoxin Substances 0.000 description 1
- 229960003276 erythromycin Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- CCIVGXIOQKPBKL-UHFFFAOYSA-M ethanesulfonate Chemical compound CCS([O-])(=O)=O CCIVGXIOQKPBKL-UHFFFAOYSA-M 0.000 description 1
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000855 fermentation Methods 0.000 description 1
- 230000004151 fermentation Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 229960003760 florfenicol Drugs 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 239000005417 food ingredient Substances 0.000 description 1
- 239000005452 food preservative Substances 0.000 description 1
- 235000019249 food preservative Nutrition 0.000 description 1
- 239000010794 food waste Substances 0.000 description 1
- 229960000308 fosfomycin Drugs 0.000 description 1
- YMDXZJFXQJVXBF-STHAYSLISA-N fosfomycin Chemical compound C[C@@H]1O[C@@H]1P(O)(O)=O YMDXZJFXQJVXBF-STHAYSLISA-N 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 230000002068 genetic effect Effects 0.000 description 1
- 239000000174 gluconic acid Substances 0.000 description 1
- 235000012208 gluconic acid Nutrition 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 229960003180 glutathione Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000008588 hemolysis Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 108010028295 histidylhistidine Proteins 0.000 description 1
- 210000005260 human cell Anatomy 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 230000002209 hydrophobic effect Effects 0.000 description 1
- 229940089468 hydroxyethylpiperazine ethane sulfonic acid Drugs 0.000 description 1
- 235000015243 ice cream Nutrition 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- ZSKVGTPCRGIANV-ZXFLCMHBSA-N imipenem Chemical compound C1C(SCC\N=C\N)=C(C(O)=O)N2C(=O)[C@H]([C@H](O)C)[C@H]21 ZSKVGTPCRGIANV-ZXFLCMHBSA-N 0.000 description 1
- 229960002182 imipenem Drugs 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 210000005007 innate immune system Anatomy 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- FZWBNHMXJMCXLU-BLAUPYHCSA-N isomaltotriose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1OC[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@@H](OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O)O1 FZWBNHMXJMCXLU-BLAUPYHCSA-N 0.000 description 1
- 229960000318 kanamycin Drugs 0.000 description 1
- 229930027917 kanamycin Natural products 0.000 description 1
- SBUJHOSQTJFQJX-NOAMYHISSA-N kanamycin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N SBUJHOSQTJFQJX-NOAMYHISSA-N 0.000 description 1
- 229930182823 kanamycin A Natural products 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 108010053037 kyotorphin Proteins 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229940039696 lactobacillus Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 235000019388 lanolin Nutrition 0.000 description 1
- 229940039717 lanolin Drugs 0.000 description 1
- 108010034529 leucyl-lysine Proteins 0.000 description 1
- 108010000761 leucylarginine Proteins 0.000 description 1
- OJMMVQQUTAEWLP-KIDUDLJLSA-N lincomycin Chemical compound CN1C[C@H](CCC)C[C@H]1C(=O)N[C@H]([C@@H](C)O)[C@@H]1[C@H](O)[C@H](O)[C@@H](O)[C@@H](SC)O1 OJMMVQQUTAEWLP-KIDUDLJLSA-N 0.000 description 1
- 229960005287 lincomycin Drugs 0.000 description 1
- 229920006008 lipopolysaccharide Polymers 0.000 description 1
- 244000144972 livestock Species 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229960003511 macrogol Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960002260 meropenem Drugs 0.000 description 1
- DMJNNHOOLUXYBV-PQTSNVLCSA-N meropenem Chemical compound C=1([C@H](C)[C@@H]2[C@H](C(N2C=1C(O)=O)=O)[C@H](O)C)S[C@@H]1CN[C@H](C(=O)N(C)C)C1 DMJNNHOOLUXYBV-PQTSNVLCSA-N 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- CQDGTJPVBWZJAZ-UHFFFAOYSA-N monoethyl carbonate Chemical compound CCOC(O)=O CQDGTJPVBWZJAZ-UHFFFAOYSA-N 0.000 description 1
- IJDNQMDRQITEOD-UHFFFAOYSA-N n-butane Chemical compound CCCC IJDNQMDRQITEOD-UHFFFAOYSA-N 0.000 description 1
- OFBQJSOFQDEBGM-UHFFFAOYSA-N n-pentane Natural products CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 description 1
- 229960004927 neomycin Drugs 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960002378 oftasceine Drugs 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 239000005416 organic matter Substances 0.000 description 1
- 239000012285 osmium tetroxide Substances 0.000 description 1
- 229910000489 osmium tetroxide Inorganic materials 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000004430 oxygen atom Chemical group O* 0.000 description 1
- FJKROLUGYXJWQN-UHFFFAOYSA-N papa-hydroxy-benzoic acid Natural products OC(=O)C1=CC=C(O)C=C1 FJKROLUGYXJWQN-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 239000006072 paste Substances 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000002304 perfume Substances 0.000 description 1
- 210000001322 periplasm Anatomy 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 108010083476 phenylalanyltryptophan Proteins 0.000 description 1
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 description 1
- 239000002504 physiological saline solution Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 235000013550 pizza Nutrition 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 229920000515 polycarbonate Polymers 0.000 description 1
- 239000004417 polycarbonate Substances 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- XAEFZNCEHLXOMS-UHFFFAOYSA-M potassium benzoate Chemical compound [K+].[O-]C(=O)C1=CC=CC=C1 XAEFZNCEHLXOMS-UHFFFAOYSA-M 0.000 description 1
- DWHGNUUWCJZQHO-ZVDZYBSKSA-M potassium;(2s,5r,6r)-6-[[(2r)-2-amino-2-(4-hydroxyphenyl)acetyl]amino]-3,3-dimethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid;(2r,3z,5r)-3-(2-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3.2.0]heptane-2-carboxylate Chemical compound [K+].[O-]C(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21.C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 DWHGNUUWCJZQHO-ZVDZYBSKSA-M 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 210000001236 prokaryotic cell Anatomy 0.000 description 1
- 230000035755 proliferation Effects 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- LISFMEBWQUVKPJ-UHFFFAOYSA-N quinolin-2-ol Chemical compound C1=CC=C2NC(=O)C=CC2=C1 LISFMEBWQUVKPJ-UHFFFAOYSA-N 0.000 description 1
- 239000001044 red dye Substances 0.000 description 1
- 239000011347 resin Substances 0.000 description 1
- 229920005989 resin Polymers 0.000 description 1
- OARRHUQTFTUEOS-UHFFFAOYSA-N safranin Chemical compound [Cl-].C=12C=C(N)C(C)=CC2=NC2=CC(C)=C(N)C=C2[N+]=1C1=CC=CC=C1 OARRHUQTFTUEOS-UHFFFAOYSA-N 0.000 description 1
- 229960004889 salicylic acid Drugs 0.000 description 1
- 229940071089 sarcosinate Drugs 0.000 description 1
- 235000013580 sausages Nutrition 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 235000011888 snacks Nutrition 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- ZUFONQSOSYEWCN-UHFFFAOYSA-M sodium;2-(methylamino)acetate Chemical compound [Na+].CNCC([O-])=O ZUFONQSOSYEWCN-UHFFFAOYSA-M 0.000 description 1
- 235000014347 soups Nutrition 0.000 description 1
- 238000009987 spinning Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 238000010186 staining Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 229940031000 streptococcus pneumoniae Drugs 0.000 description 1
- 229960005322 streptomycin Drugs 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229940124530 sulfonamide Drugs 0.000 description 1
- 150000003456 sulfonamides Chemical class 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- HNKJADCVZUBCPG-UHFFFAOYSA-N thioanisole Chemical compound CSC1=CC=CC=C1 HNKJADCVZUBCPG-UHFFFAOYSA-N 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 229960000707 tobramycin Drugs 0.000 description 1
- NLVFBUXFDBBNBW-PBSUHMDJSA-N tobramycin Chemical compound N[C@@H]1C[C@H](O)[C@@H](CN)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O[C@@H]2[C@@H]([C@@H](N)[C@H](O)[C@@H](CO)O2)O)[C@H](N)C[C@@H]1N NLVFBUXFDBBNBW-PBSUHMDJSA-N 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000011269 treatment regimen Methods 0.000 description 1
- IEDVJHCEMCRBQM-UHFFFAOYSA-N trimethoprim Chemical compound COC1=C(OC)C(OC)=CC(CC=2C(=NC(N)=NC=2)N)=C1 IEDVJHCEMCRBQM-UHFFFAOYSA-N 0.000 description 1
- 229960001082 trimethoprim Drugs 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 125000000430 tryptophan group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C2=C([H])C([H])=C([H])C([H])=C12 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 238000003260 vortexing Methods 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Images
Classifications
-
- 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
- A01N37/00—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids
- A01N37/44—Biocides, pest repellants or attractants, or plant growth regulators containing organic compounds containing a carbon atom having three bonds to hetero atoms with at the most two bonds to halogen, e.g. carboxylic acids containing at least one carboxylic group or a thio analogue, or a derivative thereof, and a nitrogen atom attached to the same carbon skeleton by a single or double bond, this nitrogen atom not being a member of a derivative or of a thio analogue of a carboxylic group, e.g. amino-carboxylic acids
- A01N37/46—N-acyl derivatives
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
- A01P1/00—Disinfectants; Antimicrobial compounds or mixtures thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/142—Amino acids; Derivatives thereof
- A23K20/147—Polymeric derivatives, e.g. peptides or proteins
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23K—FODDER
- A23K20/00—Accessory food factors for animal feeding-stuffs
- A23K20/10—Organic substances
- A23K20/195—Antibiotics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/127—Antibiotics
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/17—Amino acids, peptides or proteins
- A23L33/18—Peptides; Protein hydrolysates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/64—Proteins; Peptides; Derivatives or degradation products thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
- A61Q17/005—Antimicrobial preparations
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q19/00—Preparations for care of the skin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
- C07K7/04—Linear peptides containing only normal peptide links
- C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2200/00—Function of food ingredients
- A23V2200/30—Foods, ingredients or supplements having a functional effect on health
- A23V2200/324—Foods, ingredients or supplements having a functional effect on health having an effect on the immune system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
- A61K2800/10—General cosmetic use
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
-
- 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
- Life Sciences & Earth Sciences (AREA)
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Polymers & Plastics (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Organic Chemistry (AREA)
- Zoology (AREA)
- Food Science & Technology (AREA)
- Medicinal Chemistry (AREA)
- Molecular Biology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pest Control & Pesticides (AREA)
- Plant Pathology (AREA)
- Wood Science & Technology (AREA)
- Environmental Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Epidemiology (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Husbandry (AREA)
- Nutrition Science (AREA)
- Mycology (AREA)
- Dentistry (AREA)
- Genetics & Genomics (AREA)
- Communicable Diseases (AREA)
- Agronomy & Crop Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Oncology (AREA)
- Birds (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- Dermatology (AREA)
- Gastroenterology & Hepatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Immunology (AREA)
- Peptides Or Proteins (AREA)
Abstract
本发明涉及一种新型抗菌肽和包含该抗菌肽作为活性成分的组合物。本发明的新型抗菌肽对耐抗生素细菌以及革兰氏阳性菌和革兰氏阴性菌具有优异的抗菌活性,并且细胞毒性低,因此可以有利地用作抗生素、化妆品组合物、食品添加剂、饲料添加剂、生物农药、准药物产品等中的活性成分。
Description
技术领域
本发明涉及一种新型抗菌肽和包含所述抗菌肽作为活性成分的组合物。
背景技术
细菌感染是人类疾病最常见和最致命的原因之一。然而不幸的是,由于抗生素的滥用,出现了对抗生素产生抗药性的细菌。事实上,细菌对新抗生素产生耐药性的速度远快于新抗生素的开发速度。例如,威胁生命的细菌物种,如粪肠球菌(Enterococcusfaecalis)、铜绿假单胞菌(Pseudomonas aeruginosa)和肺炎克雷伯菌(Klebsiellapneumoniae),对迄今为止所有已知的抗生素都有抗药性。
另一方面,抗生素耐受性最早是在1970年代在肺炎球菌中发现的,提供了有关青霉素作用机制的重要线索。对抗生素有抗药性的物种在正常浓度的抗生素存在下会停止生长,但不会因此而死亡。产生耐受性是因为当抗生素抑制细胞壁合成酶时,细菌自溶酶如自溶素的活性不会发生。事实上,青霉素通过激活内源性水解酶杀死细菌,即使用抗生素治疗,细菌也能通过抑制其活性而存活(KR 10-2039400 B1)。
细菌对各种抗生素具有耐受性在临床上非常重要,因为如果无法消除对抗生素具有耐受性的细菌,那么在细菌感染的情况下抗生素治疗的有效性就会降低。此外,耐受性的发展被认为是对抗生素产生抗性的先决条件,因为这会导致产生虽有抗生素治疗仍能存活的菌株。这些菌株获得了对抗生素有抗药性的新遗传元素,并在抗生素存在的情况下继续生长。事实上,众所周知,所有对抗生素产生耐药性的细菌都具有耐受性,因此有必要开发能够杀死这些耐药细菌的新型抗生素。
另一方面,细菌可以通过合成肽或有机小分子来杀死邻近的细菌。包括昆虫在内的动物会产生天然存在的肽抗生素,其在结构上分为三组。第一个是富含半胱氨酸的β-折叠肽,第二个是α-螺旋两亲分子,第三个是富含脯氨酸的肽。这些抗菌肽在宿主防御和先天免疫系统中发挥重要作用。这些抗菌肽根据氨基酸序列具有不同的结构。在这些结构中,在文昌鱼中发现的抗菌肽mBjAMP1形成两亲性α螺旋结构。
现有技术文件
专利文件
(专利文件1)KR 10-2039400 B1
发明内容
技术问题
本发明人通过确认由特定氨基酸序列构成的肽显示出抗菌活性,特别是对抗生素耐药性的细菌显示出抗菌活性,从而完成了本发明。具体而言,本发明的目的在于提供一种含有三种色氨酸(Trp)的抗菌肽。
问题的解决方案
为了实现上述目的,本发明的一个方面,提供了一种含有三种色氨酸(Trp)或其盐的抗菌肽。在本发明的另一个方面,提供了由以下结构式I或结构式II表示的抗菌肽或其盐:
[结构式I]
N'-A-B-C-C'
[结构式II]
N'-C-B-A-C'
其中,
N’是抗菌肽的N端,C’是抗菌肽的C端,C端是羧基或羧基的羟基(-OH)被胺基(-NH2)取代的一端,
A由(X1)a-(X2)b-(X3)c-(X4)d的氨基酸序列组成,
其中a、b、c和d各自独立地是0或1,并且
X1至X4各自独立地是选自Arg、Lys、Asn、Gln、Asp、Val、Leu、Ser、His、Gly和Tyr组成的组的任何一个氨基酸,并且
B由Trp-(Z1)e-(Z2)f-Trp-(Z3)g-(Z4)h-Trp的氨基酸序列组成,
其中e、f、g和h各自独立地是0或1,并且
Z1至Z4各自独立地是选自Val、Leu、Ile、Gly、Ala、Ser、Phe、Tyr、Trp、Lys和His组成的组的任何一个氨基酸,并且
C由(X5)i-(X6)j-(X7)k-(X8)l的氨基酸序列组成,
其中,i、j、k和l各自独立地是0或1,并且
X5至X8各自独立地是选自Arg、Lys、Asn、Gln、Asp、Val、Leu、Ser、His、Gly和Tyr组成的组中的任何一个氨基酸,并且
其中Trp可以被C1-6烷氧基或卤素取代,或者Trp的吲哚环中的氮(N)可以被硫(S)修饰,以及
当N端氨基酸为Lys时,C3至C10脂肪酸可进一步与胺基结合,
Tyr可以被卤素取代,以及
Asn可以被糖基化。
本发明的另一个方面,提供了一种抗菌肽或其盐,由以下组成的组中的任一氨基酸序列组成:Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys,Lys-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Ile-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Phe-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Tyr-Trp-Ile-Leu-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Tyr-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Val-Tyr-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Tyr-Val-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Tyr-Arg-Lys-Lys-Arg,Trp-Leu-Ile-Trp-Val-Tyr-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Tyr-Arg-Arg-Arg,Trp-Val-Val-Val-Val-Trp-Arg-Arg-Arg,Trp-Val-Val-His-Val-Val-Trp-Arg-Arg-Arg,Arg-Arg-Arg-His-Val-His-Val-Val-Trp-Lys,Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg-Tyr,Trp-Leu-Val-Tyr-Val-Trp-Leu-Arg-Lys-Lys-Arg,Ser-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Val-Val-His-Val-Val-Trp-Arg-Arg-Arg-Asn(糖基化),Arg-Arg-Arg-Trp-Val-Val-Val-Val-Val-Trp,Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys,Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg,Leu-Leu-Trp-Ile-Ala-Leu-Lys-Lys-Lys-Lys,Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Tyr-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Val-Tyr-Val-Arg-Lys-Lys-Arg,Trp-Leu-Trp-Val-Trp-Val-Arg-Lys-Lys-Arg,Val-Trp-Val-Trp-Val-Trp-Val-Arg-Lys-Lys-Arg,Trp-Val-Val-Trp-Val-Tyr-Val-Arg-Lys-Lys-Arg,Trp-Val-Val-Trp-Val-Val-Tyr-Arg-Lys-Lys-Arg,Trp-Leu-Ala-Trp-Leu-Tyr-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Leu-Tyr-Ala-Arg-Lys-Lys-Arg,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg-Arg,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Lys,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg-Lys-Lys,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Arg-Lys,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg,Arg-Arg-Arg-Trp-Val-Trp-Val-Val-Val-Trp和Arg-Arg-Arg-Trp-Val-Val-Val-Val-Trp-Trp。
本发明的另一个方面,提供了一种抗生素,其包含所述抗菌肽或其盐作为活性成分。
本发明的另一个方面,提供了一种化妆品组合物,其包含所述抗菌肽或其盐作为活性成分。
本发明的另一个方面,提供了一种食品添加剂,其包含所述抗菌肽或其盐作为活性成分。
本发明的另一个方面,提供了一种饲料添加剂,其包含所述抗菌肽或其盐作为活性成分。
本发明的另一个方面,提供了一种非人的抗菌方法,包括将药学有效量的抗菌肽或其盐施用于人以外的对象。
发明的效果
本发明的新型抗菌肽对耐抗生素细菌以及革兰氏阳性菌和革兰氏阴性菌表现出优异的抗菌活性,并且细胞毒性低,因此,可以有利地用作抗生素、化妆品组合物、食品添加剂、饲料添加剂、生物农药、准药物产品等中的活性成分。
附图说明
图1说明了本发明的抗菌肽的获取方法。
图2显示了通过分析本发明的一些抗菌肽(KSH42和KSH43)对链霉蛋白酶(链霉蛋白酶混合物)的稳定性获得的结果。
图3显示了通过比较根据用KSH29、KSH42和KSH43处理的人工细胞膜渗漏程度而获得的结果。
图4为多重耐药菌株(鲍曼不动杆菌(Acinetobacter baumannii)和金黄色葡萄球菌(Staphylococcus aureus))经KSH29处理后在电子显微镜下的形态照片。
图5显示了通过分析根据用KSH29、KSH42和KSH43处理的脂质体渗漏程度而获得的结果。
图6显示了通过分析根据用KSH29、KSH42和KSH43处理的动态光散射程度而获得的结果。
图7显示了通过分析根据用KSH29、KSH42和KSH43处理的多重耐药金黄色葡萄球菌(MRSA)的诱导膜电位差干扰程度获得的结果。
图8显示了通过分析根据用KSH29、KSH42和KSH43处理的多重耐药粪肠球菌(MREF)的诱导膜电位差干扰程度获得的结果。
图9显示了通过分析根据用KSH29、KSH42和KSH43处理的多重耐药鲍曼不动杆菌(MRAB)的诱导膜电位差干扰程度获得的结果。
图10显示了通过分析根据用KSH29、KSH42和KSH43以及头孢硝噻吩(Nitrocefin)或ONPG(O-硝基苯基-β-D-吡喃半乳糖苷)处理的大肠杆菌的细胞膜渗透性而获得的结果。
图11显示了通过分析KSH29在每个治疗时间对多重耐药铜绿假单胞菌(MRPA)、多重耐药粪肠球菌(MREF)、多重耐药鲍曼不动杆菌(MRAB)和多重耐药金黄色葡萄球菌(MRSA)的抗菌作用获得的结果。
图12显示了通过分析KSH42和KSH43在每个处理时间对多重耐药鲍曼不动杆菌(MRAB)和多重耐药金黄色葡萄球菌(MRSA)的抗菌效果获得的结果。
图13显示了通过分析根据用KSH29、KSH42和KSH43处理的微生物的抗性获得诱导程度获得的结果。
图14显示了通过分析根据用KSH37(阴性对照)、KSH42和KSH43处理的对细菌(鲍曼不动杆菌、金黄色葡萄球菌和粪肠球菌)的抗菌活性而获得的大孔菌(Galleriamellonella)存活率的结果。
图15-23显示了本发明的抗菌肽的毒性评价分析获得的结果。
图24和25分别显示了通过测量本发明的抗菌肽KSH 1的纯度和分子量获得的结果。
图26和27分别显示了通过测量本发明的抗菌肽KSH 3的纯度和分子量获得的结果。
图28和29分别显示了通过测量本发明的抗菌肽KSH 4的纯度和分子量获得的结果。
图30和31分别显示了通过测量本发明的抗菌肽KSH 5的纯度和分子量获得的结果。
图32和33分别显示了通过测量本发明的抗菌肽KSH 6的纯度和分子量获得的结果。
图34和35分别显示了通过测量本发明的抗菌肽KSH 7的纯度和分子量获得的结果。
图36和37分别显示了通过测量本发明的抗菌肽KSH 8的纯度和分子量获得的结果。
图38和39分别显示了通过测量本发明的抗菌肽KSH 9的纯度和分子量获得的结果。
图40和41分别显示了通过测量本发明的抗菌肽KSH 10的纯度和分子量获得的结果。
图42和43分别显示了通过测量本发明的抗菌肽KSH 11的纯度和分子量获得的结果。
图44和45分别显示了通过测量本发明的抗菌肽KSH 12的纯度和分子量获得的结果。
图46和47分别显示了通过测量本发明的抗菌肽KSH 13的纯度和分子量获得的结果。
图48和49分别显示了通过测量本发明的抗菌肽KSH 15的纯度和分子量获得的结果。
图50和51分别显示了通过测量本发明的抗菌肽KSH 16的纯度和分子量获得的结果。
图52和53分别显示了通过测量本发明的抗菌肽KSH 18的纯度和分子量获得的结果。
图54和55分别显示了通过测量本发明的抗菌肽KSH 20的纯度和分子量获得的结果。
图56和57分别显示了通过测量本发明的抗菌肽IKSH 5-1的纯度和分子量获得的结果。
图58和59分别显示了通过测量本发明的抗菌肽IKSH 5-2的纯度和分子量获得的结果。
图60和61分别显示了通过测量本发明的抗菌肽KSH YL的纯度和分子量获得的结果。
图62和63分别显示了通过测量本发明的抗菌肽KSH VY的纯度和分子量获得的结果。
图64和65分别显示了通过测量本发明的抗菌肽KSH VY2的纯度和分子量获得的结果。
图66和67分别显示了通过测量本发明的抗菌肽KSH VY3的纯度和分子量获得的结果。
图68和69分别显示了通过测量本发明的抗菌肽KSH VY4的纯度和分子量获得的结果。
图70和71分别显示了通过测量本发明的抗菌肽XSH 2的纯度和分子量获得的结果。
图72和73分别显示了通过测量本发明的抗菌肽LSH 6的纯度和分子量获得的结果。
图74和75分别显示了通过测量本发明的抗菌肽LSH 7的纯度和分子量获得的结果。
图76和77分别显示了通过测量本发明的抗菌肽LSH 8的纯度和分子量获得的结果。
图78和79分别显示了通过测量本发明的抗菌肽LSH 9的纯度和分子量获得的结果。
图80和81分别显示了通过测量本发明的抗菌肽KSH 29的纯度和分子量获得的结果。
图82和83分别显示了通过测量本发明的抗菌肽KSH 30的纯度和分子量获得的结果。
图84和85分别显示了通过测量本发明的抗菌肽KSH 31的纯度和分子量获得的结果。
图86和87分别显示了通过测量本发明的抗菌肽KSH 32的纯度和分子量获得的结果。
图88和89分别显示了通过测量本发明的抗菌肽KSH 33的纯度和分子量获得的结果。
图90和91分别显示了通过测量本发明的抗菌肽KSH 35的纯度和分子量获得的结果。
图92和93分别显示了通过测量本发明的抗菌肽KSH 36的纯度和分子量获得的结果。
图94和95分别显示了通过测量本发明的抗菌肽KSH 37的纯度和分子量获得的结果。
图96和97分别显示了通过测量本发明的抗菌肽KSH 39的纯度和分子量获得的结果。
图98和99分别显示了通过测量本发明的抗菌肽KSH 40的纯度和分子量获得的结果。
图100和101分别显示了通过测量本发明的抗菌肽KSH 41的纯度和分子量获得的结果。
图102和103分别显示了通过测量本发明的抗菌肽KSH 32的纯度和分子量获得的结果。
图104和105分别显示了通过测量本发明的抗菌肽KSH 43的纯度和分子量获得的结果。
图106和107分别显示了通过测量本发明的抗菌肽KSH 44的纯度和分子量获得的结果。
图108和109分别显示了通过测量本发明的抗菌肽KSH 45的纯度和分子量获得的结果。
图110和111分别显示了通过测量本发明的抗菌肽KSH 46的纯度和分子量获得的结果。
图112和113分别显示了通过测量本发明的抗菌肽KSH 47的纯度和分子量获得的结果。
图114和115分别显示了通过测量本发明的抗菌肽KSH 48的纯度和分子量获得的结果。
图116和117分别显示了通过测量本发明的抗菌肽KSH 49的纯度和分子量获得的结果。
图118和119分别显示了通过测量本发明的抗菌肽KSH 50的纯度和分子量获得的结果。
图120和121分别显示了通过测量本发明的抗菌肽KSH 51的纯度和分子量获得的结果。
图122和123分别显示了通过测量本发明的抗菌肽KSH 52的纯度和分子量获得的结果。
图124和125分别显示了通过测量本发明的抗菌肽KSH 54的纯度和分子量获得的结果。
图126和127分别显示了通过测量本发明的抗菌肽KSH 55的纯度和分子量获得的结果。
图128和129分别显示了通过测量本发明的抗菌肽KSH 56的纯度和分子量获得的结果。
图130和131分别显示了通过测量本发明的抗菌肽KSH 57的纯度和分子量获得的结果。
图132和133分别显示了通过测量本发明的抗菌肽KSH 58的纯度和分子量获得的结果。
图134和135分别显示了通过测量本发明的抗菌肽KSH 59的纯度和分子量获得的结果。
图136和137分别显示了通过测量本发明的抗菌肽KSH 60的纯度和分子量获得的结果。
图138和139分别显示了通过测量本发明的抗菌肽KSH 61的纯度和分子量获得的结果。
图140和141分别显示了通过测量本发明的抗菌肽KSH 62的纯度和分子量获得的结果。
图142和143分别显示了通过测量本发明的抗菌肽KSH 63的纯度和分子量获得的结果。
图144和145分别显示了通过测量本发明的抗菌肽KSH 64的纯度和分子量获得的结果。
图146和147分别显示了通过测量本发明的抗菌肽KSH 19的纯度和分子量获得的结果。
图148和149分别显示了通过测量本发明的抗菌肽LSH 28的纯度和分子量获得的结果。
图150和151分别显示了通过测量本发明的抗菌肽LSH 1的纯度和分子量获得的结果。
图152和153分别显示了通过测量本发明的抗菌肽LSH 2的纯度和分子量获得的结果。
图154和155分别显示了通过测量本发明的抗菌肽LSH 3的纯度和分子量获得的结果。
图156和157分别显示了通过测量本发明的抗菌肽LSH 5的纯度和分子量获得的结果。
图158和159分别显示了通过测量本发明的抗菌肽LSH 99的纯度和分子量获得的结果。
图160和161分别显示了通过测量本发明的抗菌肽KSH 66的纯度和分子量获得的结果。
图162和163分别显示了通过测量本发明的抗菌肽KSH 67的纯度和分子量获得的结果。
图164和165分别显示了通过测量本发明的抗菌肽KSH 68的纯度和分子量获得的结果。
图166和167分别显示了通过测量本发明的抗菌肽KSH 69的纯度和分子量获得的结果。
图168和169分别显示了通过测量本发明的抗菌肽KSH 70的纯度和分子量获得的结果。
图170和171分别显示了通过测量本发明的抗菌肽KSH 71的纯度和分子量获得的结果。
图172和173分别显示了通过测量本发明的抗菌肽KSH 72的纯度和分子量获得的结果。
图174和175分别显示了通过测量本发明的抗菌肽KSH 73的纯度和分子量获得的结果。
图176和177分别显示了通过测量本发明的抗菌肽KSH 74的纯度和分子量获得的结果。
图178和179分别显示了通过测量本发明的抗菌肽KSH 75的纯度和分子量获得的结果。
图180和181分别显示了通过测量本发明的抗菌肽KSH 76的纯度和分子量获得的结果。
图182和183分别显示了通过测量本发明的抗菌肽KSH 77的纯度和分子量获得的结果。
图184和185分别显示了通过测量本发明的抗菌肽KSH 78的纯度和分子量获得的结果。
图186和187分别显示了通过测量本发明的抗菌肽KSH 79的纯度和分子量获得的结果。
图188和189分别显示了通过测量本发明的抗菌肽KSH 80的纯度和分子量获得的结果。
图190和191分别显示了通过测量本发明的抗菌肽KSH 81的纯度和分子量获得的结果。
图192和193分别显示了通过测量本发明的抗菌肽KSH 82的纯度和分子量获得的结果。
图194和195分别显示了通过测量本发明的抗菌肽KSH 83的纯度和分子量获得的结果。
图196和197分别显示了通过测量本发明的抗菌肽KSH 84的纯度和分子量获得的结果。
图198和199分别显示了通过测量本发明的抗菌肽KSH 85的纯度和分子量获得的结果。
图200和201分别显示了通过测量本发明的抗菌肽KSH 86的纯度和分子量获得的结果。
图202和203分别显示了通过测量本发明的抗菌肽KSH 90的纯度和分子量获得的结果。
图204和205分别显示了通过测量本发明的抗菌肽KSH 91的纯度和分子量获得的结果。
图206和207分别显示了通过测量本发明的抗菌肽KSH 27的纯度和分子量获得的结果。
图208和209分别显示了通过测量本发明的抗菌肽KSH 28的纯度和分子量获得的结果。
图210和211分别显示了通过测量本发明的抗菌肽KSH V的纯度和分子量获得的结果。
图212和213分别显示了通过测量本发明的抗菌肽KSH I的纯度和分子量获得的结果。
图214和215分别显示了通过测量本发明的抗菌肽KSH F的纯度和分子量获得的结果。
图216显示了根据用KSH43处理小鼠(BALB/c,雌性,7周)的存活率来分析对细菌(大肠杆菌)的抗菌活性所得到的结果。
具体实施方式
下面将对本发明进行更详细的描述。
本发明的一个方面,提供了一种含有三个Trps的抗菌肽或其盐。在这种情况下,三个Trps可以由一个或两个氨基酸分开。在这种情况下,存在于Trps之间的氨基酸可以是选自Val、Leu、Ile、Gly、Ala、Ser、Phe、Tyr、Trp、Lys和His组的任何一种氨基酸。此外,抗菌肽可进一步包括N端和/或C端至少一个或多个氨基酸。在这种情况下,与N-端和/或C-端结合的氨基酸可以是选自Arg、Lys、Asn、Gln、Asp、Val、Leu、Ser、His、Gly和Tyr组成的组的任何一种氨基酸。该抗菌肽可由6至12个氨基酸组成。在这种情况下,它可以是在抗菌肽的C端用-CONH2修饰-COOH的形式。此外,一个脂肪酸可以与构成该肽的氨基酸结合。
本发明的一个方面,提供了一种由以下结构式I或结构式II表示的抗菌肽或其盐:
[结构式I]
N'-A-B-C-C'
[结构式II]
N'-C-B-A-C'
其中,
N’是抗菌肽的N端,C’是抗菌肽的C端,C端是羧基或羧基的羟基(-OH)被胺基(-NH2)取代的一端,
A由(X1)a-(X2)b-(X3)c-(X4)d的氨基酸序列组成,
其中a、b、c和d各自独立地是0或1,并且
X1至X4各自独立地是选自Arg、Lys、Asn、Gln、Asp、Val、Leu、Ser、His、Gly和Tyr组成的组的任何一个氨基酸,并且
B由Trp-(Z1)e-(Z2)f-Trp-(Z3)g-(Z4)h-Trp的氨基酸序列组成,
其中e、f、g和h各自独立地是0或1,并且
Z1至Z4各自独立地是选自Val、Leu、Ile、Gly、Ala、Ser、Phe、Tyr、Trp、Lys和His组成的组的任何一个氨基酸,并且
C由(X5)i-(X6)j-(X7)k-(X8)l的氨基酸序列组成,
其中,i、j、k和l各自独立地是0或1,并且
X5至X8各自独立地是选自Arg、Lys、Asn、Gln、Asp、Val、Leu、Ser、His、Gly和Tyr组成的组中的任何一个氨基酸,并且
其中Trp可以被C1-6烷氧基或卤素取代,或者Trp的吲哚环中的氮(N)可以被硫(S)修饰,以及
当N端氨基酸为Lys时,C3至C10脂肪酸可进一步与胺基结合,
Tyr可以被卤素取代,以及
Asn可以被糖基化。
除非另有说明,上述“烷氧基”是指具有公式-O-烷基的基团,其中如上定义的烷基通过一个氧原子连接到母体化合物。烷氧基的烷基部分可以有1至20个碳原子(即C1-C20烷氧基),1至12个碳原子(即C1-C12烷氧基),或1至6个碳原子(即C1-C6烷氧基)。合适的烷氧基的例子包括甲氧基(-O-CH3或-OMe)、乙氧基(-OCH2CH3或-OEt)、丁氧基(-O-C(CH3)3或-O-tBu),等等。
如本文所用,除非另有说明,术语“卤素”是指F、Cl、Br或I。
本发明中,e、f、g和h中的任一个可以是0,其余的可以是1。
此外,X1至X8、Z1至Z4和Trp可以各自独立地是L型或D型氨基酸。
本发明中,所述抗菌肽的C'可以是其中羧基的羟基(-OH)被胺基(-NH2)取代的一种。
根据本发明的抗菌肽可以对革兰氏阳性细菌具有优良的抗菌活性。此外,该抗菌肽可对革兰氏阴性细菌具有优异的抗菌活性。
本发明中,“革兰氏阳性菌”是原核生物的一种类型,是指其细胞壁被革兰氏染色法染成紫色的细菌。由于革兰氏阳性菌的细胞壁是由几层肽聚糖组成的,所以即使在用水晶紫等碱性染料染色后用乙醇处理,也会呈现紫色而不变色。在本发明中,革兰氏阳性菌可以是金黄色葡萄球菌、肺炎链球菌、粪肠球菌或乳酸杆菌,但不限于此。在本发明中,革兰氏阳性菌可以是对抗生素有抵抗力的细菌,也可以是对两种或更多抗生素有抵抗力的革兰氏阳性多药耐药菌。
在本发明中,“革兰氏阴性菌”是原核细胞的一种类型,具有由脂多糖、脂蛋白和其他复杂的高分子物质组成的外膜,而不是与革兰氏阳性菌相比,细胞壁中具有相对较少的肽聚糖。用水晶紫等碱性染料染色后,用乙醇处理会导致变色,而用红色染料(如番红)进行复染色则会出现红色。与革兰氏阳性细菌相比,革兰氏阴性细菌的细胞壁由非常薄的肽聚糖和外膜组成。肽聚糖与连接到外膜的脂蛋白结合,不含磷壁酸。周质是一个厚度约为15纳米的空间,存在于革兰氏阴性菌的外膜和内膜之间,含有高浓度的蛋白质并保持类似细胞质的状态。
在本发明中,革兰氏阴性菌可以是鲍曼不动杆菌、大肠杆菌、肺炎克雷伯氏菌(Klebsiella penumoniae)、沙门氏菌属(Salmonella spp.)、铜绿假单胞菌(Pseudomonasaeruginosa)、流感嗜血杆菌(Haemophilus influenzae)、肠杆菌属(Enterobacter spp.)或耶尔森氏菌(Yersinia pestis),但不限于此。在本发明中,革兰氏阴性菌可以是对抗生素有抗性的细菌,也可以是对两种或更多抗生素有抗性的革兰氏阴性多药耐药菌。
抗生素的细菌可以是鲍曼不动杆菌、铜绿假单胞菌、粪肠球菌或金黄色葡萄球菌,但不限于此。抗生素可包括如氨基糖苷类(氨基糖苷、庆大霉素、新霉素等)、青霉素类(氨苄青霉素等)、磺胺类、β-内酰胺类(β-内酰胺、阿莫西林/克拉维酸等)等抗生素。氯霉素类、红霉素类、氟苯尼考类、磷霉素类、卡那霉素类、林可霉素类、甲氧西林类、喹诺酮类、链霉素类、四环素类、三甲氧嘧啶类和万古霉素类,但不限于此。
在本发明的抗菌肽的一个实施方案中,B可以由Trp-Leu-Val-Trp-Ile-Trp(SEQID NO:1)的氨基酸序列组成。在这种情况下,抗菌肽可以是选自由以下的任一氨基酸序列组成的组中Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Lys-Arg(SEQ ID NO:2),Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Arg(SEQ ID NO:3),Trp-Leu-Val-Trp-Ile-Trp-Gln-Arg-Arg-Arg(SEQ ID NO:4),Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Gln-Arg(SEQ ID NO:5),Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg(SEQ ID NO:6),Lys-Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Arg(SEQ ID NO:7)and Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Lys-Arg(SEQ ID NO:75)。
在本发明的抗菌肽的一个实施方案中,抗菌肽由以下氨基酸序列组成Trp-Val-Val-Trp-Val-Val-Trp-Arg-Arg-Arg(SEQ ID NO:8)。
在本发明的抗菌肽的一个实施方案中,B可以由Trp-Ile-Trp-Val-Leu-Trp(SEQIDNO:9)的氨基酸序列组成。在这种情况下,抗菌肽可以是选自由以下组成的组中任一氨基酸序列组成Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys(SEQ ID NO:10),Lys-Lys-Lys-Trp-Ile-Trp-Val-Leu-Trp-Lys(SEQ ID NO:11),Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Arg(D型)(SEQ ID NO:12),Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Arg(L型)(SEQ ID NO:13),Asn(糖基化)-Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys(SEQ ID NO:57),Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys-Asn(SEQ ID NO:79)和Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp(SEQ ID NO:84)。
在本发明的一个实施方案中,抗菌肽由以下组成的组中的任一氨基酸序列组成Trp-Leu-Val-Trp-Lys-Trp-Arg-Arg-Arg(SEQ ID NO:14),Trp-Leu-Val-Trp-Ser-Trp-Arg-Arg-Arg(SEQ ID NO:15),Trp-Val-Val-Trp-Val-Trp-Arg-Arg-Arg(SEQ ID NO:16),Trp-Leu-Trp-Ile-Trp-Arg-Arg-Arg(SEQ ID NO:17),Arg-Arg-Trp-Val-Trp-Val-Val-Trp-Lys(SEQ ID NO:18),Arg-Arg-Arg-Trp-Val-Trp-Val-Val-Trp-Lys(SEQ ID NO:19),Arg-Arg-Arg-Trp-Ile-Trp-Ile-Leu-Trp(SEQ ID NO:20),Arg-Arg-Arg-Trp-Ile-Trp-Ile-Ile-Trp(SEQ ID NO:21),以及Trp-Ile-Ile-Trp-Ile-Trp-Arg-Arg-Arg(SEQ ID NO:22),Trp-Val-Leu-Trp-Val-Trp-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:67),Asp-Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Arg(SEQ ID NO:56),Trp-Val-Val-Trp-Val-Trp-Lys-Lys-Lys(SEQ ID NO:77),Trp-Val-Val-Trp-Val-Val-Trp-Lys-Lys-Lys(SEQ ID NO:78),Trp-Ala-Ala-Trp-Val-Val-Trp-Arg-Arg-Arg(SEQ ID NO:81),Trp-Val-Val-Trp-Ala-Ala-Trp-Arg-Arg-Arg(SEQ ID NO:83),Arg-Arg-Arg-Gly-Trp-Val-Trp-Val-Val-Trp-Lys(SEQ IDNO:98),以及Arg-Arg-Arg-Trp-Ile-Trp-Trp-Leu-Trp-Lys(SEQ ID NO:40),Arg-Arg-Lys-Trp-Ile-Trp-Trp-Leu-Trp-Lys(SEQ ID NO:41),Arg-Arg-Lys-Trp-Ile-Trp-Trp-Leu-Trp-Lys-Lys-Lys(SEQ ID NO:42),Trp-Leu-Leu-Trp-Val-Leu-Trp-Arg-Lys-Lys-Arg(SEQID NO:69),Trp-Val-Ala-Trp-Ala-Val-Trp-Arg-Arg-Arg(SEQ ID NO:82),Arg-Arg-Arg-Trp-Ile-Trp-Ala-Ala-Trp-Lys(SEQ ID NO:85),Arg-Arg-Arg-Trp-Val-Trp-Trp-Val-Trp-Trp(SEQ ID NO:90),Arg-Arg-Arg-Trp-Val-Trp-Trp-Val-Val-Trp(SEQ IDNO:91),Arg-Arg-Arg-Trp-Val-Trp-Val-Val-Trp-Trp(SEQ ID NO:92),Arg-Arg-Arg-Trp-Val-Val-Trp-Val-Trp-Trp(SEQ ID NO:94),Arg-Arg-Arg-Trp-Val-Val-Trp-Val-Val-Trp(SEQID NO:95),以及Arg-Arg-His-His-Trp-Val-Val-Trp-Val-Val-Trp-Lys(SEQ ID NO:99)。
在本发明的另一个实施方案中,提供的抗菌肽由以下组成的组中的任一氨基酸序列组成Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:24),Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys(SEQ ID NO:25),Lys-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:48),Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQID NO:27),Trp-Leu-Val-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:28),Trp-Leu-Ile-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:29),Trp-Leu-Phe-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:30),Trp-Leu-Tyr-Trp-Ile-Leu-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:31),Trp-Leu-Val-Trp-Ile-Tyr-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:32),Trp-Leu-Val-Trp-Val-Tyr-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:33),Trp-Leu-Val-Trp-Ile-Tyr-Val-Arg-Lys-Lys-Arg(SEQ ID NO:34),Trp-Leu-Val-Trp-Ile-Tyr-Arg-Lys-Lys-Arg(SEQ ID NO:35),Trp-Leu-Ile-Trp-Val-Tyr-Arg-Lys-Lys-Arg(SEQ ID NO:36),Trp-Leu-Val-Trp-Ile-Tyr-Arg-Arg-Arg(SEQ ID NO:37),Trp-Val-Val-Val-Val-Trp-Arg-Arg-Arg(SEQ ID NO:38),Trp-Val-Val-His-Val-Val-Trp-Arg-Arg-Arg(SEQ ID NO:39),Arg-Arg-Arg-His-Val-His-Val-Val-Trp-Lys(SEQ ID NO:43),Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg-Tyr(SEQ ID NO:65),Trp-Leu-Val-Tyr-Val-Trp-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:68),Ser-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:55),Trp-Val-Val-His-Val-Val-Trp-Arg-Arg-Arg-Asn(糖基化)(SEQ ID NO:59),Arg-Arg-Arg-Trp-Val-Val-Val-Val-Val-Trp(SEQ ID NO:97),Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:23),Lys(连接己酸(C6))-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:26),Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys(SEQ IDNO:47),Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:49),Leu-Leu-Trp-Ile-Ala-Leu-Lys-Lys-Lys-Lys(SEQ ID NO:50),Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:51),Tyr-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:64),Trp Leu Leu Trp Val Tyr Val Arg Lys Lys Arg(SEQ ID NO:66),Trp-Leu-Trp-Val-Trp-Val-Arg-Lys-Lys-Arg(SEQ ID NO:70),Val-Trp-Val-Trp-Val-Trp-Val-Arg-Lys-Lys-Arg(SEQ ID NO:76),Trp-Val-Val-Trp-Val-Tyr-Val-Arg-Lys-Lys-Arg(SEQ ID NO:71),Trp-Val-Val-Trp-Val-Val-Tyr-Arg-Lys-Lys-Arg(SEQ ID NO:72),Trp-Leu-Ala-Trp-Leu-Tyr-Leu-Arg-Lys-Lys-Arg(SEQ ID NO:73),Trp-Leu-Leu-Trp-Leu-Tyr-Ala-Arg-Lys-Lys-Arg(SEQ ID NO:74),Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg-Arg(SEQ IDNO:80),Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Lys(SEQ ID NO:86),Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg-Lys-Lys(SEQ ID NO:87),Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Arg-Lys(SEQ ID NO:88),Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg(SEQ ID NO:89),Arg-Arg-Arg-Trp-Val-Trp-Val-Val-Val-Trp(SEQ ID NO:93)和Arg-Arg-Arg-Trp-Val-Val-Val-Val-Trp-Trp(SEQ ID NO:96)。
在本发明的一个实施方案中,抗菌肽的氨基酸可以是L-型或D-型。具体来说,抗菌肽中可能具有L-型的氨基酸由L-型表示,但由L-型表示的氨基酸的形式可能包括D-型,这取决于加工环境。因此,氨基酸的形式不受指示的限制。
在本发明的一个实施方案中,抗菌肽的每个氨基酸都可以是改性衍生物。具体来说,色氨酸(Trp)可以是由以下公式1表示的甲氧基色氨酸(Wm),可以是由以下公式2表示的苯并噻吩基丙氨酸(Ws),可以是由以下公式3表示的氟色氨酸(Wf)。
[式1]
[式2]
[式3]
此外,在本发明的一个实施方案中,酪氨酸(Tyr)可以是由下式4表示的单碘酪氨酸。
[式4]
此外,在本发明的一个实施方案中,氢、C1-10烷基或C1-C20脂肪酸可以结合到赖氨酸(Lys)的NH3+末端,在一个实施方案中,它可以是己酸(C6脂肪酸)或癸酸(C10脂肪酸),但不限于此。另一方面,在本发明的一个实施方案中,抗菌肽的赖氨酸可以形成多抗原肽结合(MAP结合)。多抗原肽(MAP)是一种人工分支的肽,赖氨酸部分可用作支架核心,以支持形成8个或更少的具有可变或相同肽序列的分支。在本发明的一个实施方案中,抗菌肽的赖氨酸与含有色氨酸的肽形成分支。
此外,在本发明的一个实施方案中,天冬酰胺(Asn)可以是糖基化的天冬酰胺。
在本发明的一个实施方案中,由氨基酸序列Lys-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg组成的抗菌肽可以是其中C1至C20脂肪酸进一步在N端与Lys的胺基结合。具体而言,可以进一步结合C3~C10的脂肪酸。脂肪酸可以是己酸或癸酸。具体地,它可以是己酸,但不限于此。
由氨基酸序列Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg、Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-组成的抗菌肽Lys可以是其中C3至C10脂肪酸进一步在N端结合到Lys的胺基的一种。具体而言,可以进一步结合C3~C10的脂肪酸。脂肪酸可以是己酸或癸酸。具体地,它可以是己酸,但不限于此。
由Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg的氨基酸序列组成的抗菌肽C末端的Arg可以是L型或D型。
由Trp-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg的氨基酸序列组成的抗菌肽的Trp可以被C1-6烷氧基或卤素取代,或者Trp的吲哚环中的氮(N)可以被硫(S)修饰。
该盐对人类的毒性应该很低,对母体化合物的生物活性和理化性质不应该有任何负面作用。例如,该盐可以是由药学上可接受的游离酸形成的酸加成盐。
游离酸可以是无机酸或有机酸,其中无机酸可以是盐酸、硫酸、硝酸、磷酸、高氯酸、溴酸等,而有机酸可以是乙酸、甲磺酸、乙磺酸、对甲苯磺酸、富马酸、马来酸、丙二酸、邻苯二甲酸、琥珀酸、乳酸、柠檬酸、葡萄糖酸、酒石酸、水杨酸、苹果酸、草酸、苯甲酸、栓塞酸、天冬氨酸、谷氨酸等。
酸加成盐可以通过常规方法制备,例如,将多肽溶解在过量的酸水溶液中,并使用水溶性有机溶剂如甲醇、乙醇、丙酮或乙腈沉淀该盐。
此外,该盐可以是碱金属盐(钠盐等)或碱土金属盐(钾盐等)。碱金属盐或碱土金属盐可以通过例如将多肽溶解在过量的碱金属氢氧化物或碱土金属氢氧化物溶液中,过滤未溶解的复合盐,然后蒸发和干燥滤液来获得。
与市面上的抗生素相比,本发明的抗菌肽表现出优异的抗菌活性。具体地说,在本发明的一个实施方案中,当用碳青霉烯(一种已知的作为是否确定多药耐药菌的指标的抗生素)处理时,具有耐药酶KPC(肺炎克雷伯菌碳青霉烯酶)和NDM(新德里金属β-内酰胺酶)的菌株数量增加。但证实本发明的抗菌肽对耐碳青霉烯的鲍曼不动杆菌和铜绿假单胞菌表现出优异的抗菌活性。此外,在本发明的一个实施方案中,抗生素四环素的杀菌能力不足,靶蛋白有变异的趋势,但经证实,本发明的抗菌肽对耐四环素的鲍曼不动杆菌表现出抗菌活性,并具有优良的杀菌能力,靶蛋白变异的趋势降低。此外,在本发明的一个实施方案中,万古霉素是一种针对革兰氏阳性菌的抗生素,其存在产生耐药菌株的问题,但经证实,本发明的抗菌肽对耐万古霉素的粪肠球菌具有抗菌活性。在本发明的一个实施方案中,被称为新型抗体型抗生素的bezlotoxumab专门用于预防艰难梭菌(C.Difficile)的再感染,但本发明的抗菌肽的优点是,本发明的抗菌肽对病原体表现出广谱的抗菌活性。
在本发明的一个实施方案中,证实了本发明的抗菌肽对革兰氏阳性菌和革兰氏阴性菌都表现出抗菌活性,但达托霉素和格拉米星是市售的抗生素,只对革兰氏阳性菌表现出抗菌活性。此外,部分满足对革兰氏阳性菌和革兰氏阴性菌的最小生长抑制浓度的多肽protegrin具有有高细胞毒性的问题。
另一方面,黏菌素是一种多重耐药的革兰氏阴性菌抗生素,会造成致命的肾脏损害,它很难与其他药物联合使用,而且存在耐药菌发生的问题。因此,人们开发了SPR206和SPR741等抗生素。具体而言,SPR206将黏菌素的抗菌活性提高了3至4倍,并将肾脏毒性降低了1/3。然而,存在一个问题,即耐药菌是由黏菌素共享的。SPR741消除了黏菌素的肾脏毒性,但本身没有抗菌活性,所以存在一个问题,即必须与革兰氏阳性细菌的抗生素联合使用。另一方面,本发明的抗菌肽不仅对革兰氏阳性菌和革兰氏阴性菌有抗菌活性,而且对耐黏菌素的细菌也有抗菌活性,还能抑制耐药菌株的产生。
本发明的抗菌肽对人源细胞的细胞毒性可能很低。
在本发明的另一个方面,提供了一种包括抗菌肽作为活性成分的抗生素。
本发明的抗菌肽在临床用药过程中可以口服或肠外给药,并可以以一般药物制剂的形式使用。口服给药的制剂可采取各种形式,如糖浆、片剂、胶囊、膏剂和润喉糖。肠外给药可指通过口服以外的途径给药,如直肠、静脉、腹膜、肌肉、动脉、经皮、鼻腔、吸入、眼底和皮下给药。当本发明的抗菌肽作为药品使用时,它可以进一步包括一种或多种表现出相同或类似功能的活性成分。
也就是说,本发明的抗菌肽可以用各种配方进行肠外给药。在配制时,使用常用的稀释剂或赋形剂,如填充剂、扩展剂、粘合剂、湿润剂、崩解剂、表面活性剂等。肠外给药的制剂包括无菌水溶液、非水溶液、悬浮液、乳剂、冻干制剂和栓剂。作为非水溶液和悬浮剂,可使用丙二醇、聚乙二醇、植物油(如橄榄油)和注射用酯类(如油酸乙酯)。作为栓剂的基质,可以使用Witepsol、聚乙二醇(Macrogol)、吐温61、可可脂、月桂脂、甘油,明胶等。
此外,本发明的抗菌肽可通过与各种药学上可接受的载体如生理盐水或有机溶剂混合使用。此外,用于增加稳定性或吸收性的碳水化合物如葡萄糖、蔗糖或葡聚糖,抗氧化剂如抗坏血酸或谷胱甘肽、螯合剂、低分子量蛋白质或其他稳定剂也可作为药物使用。
本发明的抗菌肽的有效剂量为0.01μg/kg至2mg/kg,具体为0.5mg/kg至1mg/kg,可每天给药1至3次。
在本发明的抗生素中,本发明的新型肽的总有效量可以在相对较短的时间内以单剂量的形式或以输液的形式给予病人,而多剂量可以通过分次治疗方案给予,在较长的时间内给予。病人的有效剂量是通过考虑各种因素,如病人的年龄和健康状况,以及给药途径和治疗频率来确定的。考虑到这一点,本领域的普通技术人员将能够根据本发明的新型多肽作为抗生素的具体用途确定适当的有效剂量。
在本发明的另一个方面,提供了一种抗菌化妆品组合物,包括作为活性成分的抗菌肽。
本发明的化妆品组合物除了抗菌肽外,还包括化妆品组合物中常用的成分,例如,常规佐剂,如抗氧化剂、稳定剂、增溶剂、维生素、颜料和香料以及载体。
在本发明的化妆品组合物中,本发明的抗菌肽在通常含有的化妆品组合物中的添加量可以是0.1至50%(重量),最好是1至10%(重量)。
本发明的化妆品组合物可以用本领域常规的任何配方来制备。例如,它可以配制成溶液、悬浮液、乳剂、糊状物、凝胶、乳霜、乳液、粉末、肥皂、含表面活性剂的清洁剂、油、粉底、乳液底、蜡质底和喷雾等,但不限于此。更具体地说,它可以以护肤品(爽肤水)、滋养乳液(牛奶乳液)、滋养霜、按摩霜、精华、眼霜、清洁霜、清洁泡沫、清洁水、包装、喷雾或粉末的形式制备。
当本发明的配方为膏状物、霜状物或凝胶时,可使用动物油、植物油、蜡、石蜡、淀粉、黄蓍、纤维素衍生物、聚乙二醇、硅酮、膨润土、硅石、滑石、氧化锌等作为载体成分。当本发明的配方为粉末或喷雾时,可使用乳糖、滑石、硅石、氢氧化铝、硅酸钙或聚酰胺粉末作为载体成分,特别是在喷雾的情况下,可进一步包括推进剂,如氯氟烃、丙烷/丁烷或二甲醚。当本发明的制剂为溶液或乳剂时,使用溶剂、增溶剂或乳化剂作为载体成分,例如水、乙醇、异丙醇、碳酸乙酯、乙酸乙酯、苯甲醇、苯甲酸苄酯、丙二醇、1,3-丁二醇油、甘油脂肪酯、聚乙二醇的脂肪酸酯或山梨醇。当本发明的制剂为悬浮液时,可使用液体稀释剂如水、乙醇或丙二醇,悬浮剂如乙氧基化异硬脂醇、聚氧乙烯山梨醇酯和聚氧乙烯山梨醇酯,以及微晶纤维素、偏氢氧化铝、膨润土、琼脂或三角糖作为载体成分。当本发明的配方是含有表面活性剂的清洁剂时,脂肪醇硫酸盐、脂肪醇醚硫酸盐、磺基琥珀酸单酯、异硫酸盐、咪唑啉衍生物、甲基牛磺酸酯、肌氨酸酯。脂肪酸酰胺醚硫酸盐、烷基胺基甜菜碱、脂肪族醇、脂肪酸甘油酯、脂肪酸二乙醇酰胺、植物油、羊毛脂衍生物或乙氧基化甘油脂肪酸酯等可作为载体成分使用。
在本发明的另一个方面,提供了一种抗菌食品添加剂,包括抗菌肽作为活性成分。
当本发明的抗菌肽作为食品添加剂使用时,抗菌肽可按原样添加或与其他食品成分一起使用,并可按照常规方法适当使用。活性成分的混合量可根据其使用目的适当确定。一般来说,本发明的多肽以原料为基础,添加量为15份(重量)或更少,最好为10份(重量)或更少。然而,在长期给药的情况下,用量可以低于上述范围,由于在稳定性方面没有问题,活性成分的使用量可以高于上述范围。
食品的类型没有特别限制。可以添加上述物质的食品的例子包括肉、香肠、面包、巧克力、糖果、零食、糖果、比萨、拉面、其他面条、胶质、乳制品包括冰淇淋、各种汤、饮料、茶、饮料、酒精饮料和复合维生素等,并包括传统意义上的所有食品。
在本发明的另一个方面,提供了一种抗菌饲料添加剂,包括作为活性成分的抗菌肽。
本发明的饲料组合物可替代现有的抗生素,抑制有害食品病原体的生长,从而改善动物机体的健康状况,提高牲畜的增重和肉质,增加牛奶产量和免疫力。本发明的饲料组合物可以以发酵饲料、配合饲料、颗粒状、青贮饲料等形式制备。
发酵饲料可以通过添加本发明的肽以外的各种微生物种群或酶使有机物发酵来制备,复合饲料可以通过将几种普通饲料与本发明的肽混合来制备。颗粒形式的饲料可通过在颗粒机中对复合饲料等进行加热和加压来制备,而青贮饲料可通过用微生物发酵青饲料来制备。湿式发酵饲料可通过收集和运输食物残渣等有机物,按一定比例混合用于灭菌过程和水分控制的辅料,然后在适合发酵的温度下发酵24小时以上,使水分含量达到70%左右来制备。干式发酵饲料可通过对湿式发酵饲料施加额外的干燥过程来制备,使其水分含量约为30%至40%。
在本发明的另一个方面,提供了一种包括抗菌肽作为活性成分的抗菌生物农药。
在本发明的另一方面,提供了一种包含抗菌肽作为活性成分的防腐剂组合物。
该防腐剂组合物包括化妆品防腐剂或药物防腐剂。食品防腐剂、化妆品防腐剂和药物防腐剂是用于防止药品变质、腐烂、变色和化学变化的添加剂,包括杀菌剂和抗氧化剂,还包括抑制细菌、霉菌、酵母等微生物增殖的功能性抗生素,从而抑制食品和药品中腐败微生物的生长或杀菌。在这种防腐剂组合物的理想条件下,它应该是无毒的,即使是少量的也应该是有效的。
在本发明的另一个方面,提供了一种包含抗菌肽作为活性成分的抗菌准药产品组合物。
当抗菌肽作为准药物产品添加剂使用时,抗菌肽可按原样加入,或与其他准药物产品或准药物产品成分一起使用,并可按照常规方法适当使用。活性成分的混合量可根据其使用目的适当确定。本发明的准药物产品成分可以是消毒清洁剂、淋浴泡沫、加格列宁、湿纸巾、洗涤皂、洗手液、加湿器填料、口罩、软膏、贴片或过滤器填料,但不限于此。
在本发明的另一方面,提供了一种抗菌方法,包括向受试者施用药学上有效量的抗菌肽。该受试者可以是除人类以外的哺乳动物,但不限于此。
本发明的实施方式
下面,将通过实施例对本发明进行详细描述。然而,下面的实施例只是为了说明本发明,本发明并不限于以下的实施例。
实施例1抗菌肽的制备
本发明的抗菌肽是通过图1所示的制备方法制备的。
具体来说,Rink-amid-MBHA树脂用二氯甲烷溶胀,然后用哌啶去保护。用D,D-二甲基甲酰胺、二异丙基碳二亚胺和1-羟基苯并三唑溶液连接Fmoc保护的氨基酸,同时进行变化,然后用硫代苯甲醚和TFA裂解,制备本发明的抗菌肽。
所制备的抗菌肽用乙腈纯化,使用HPLC C18柱。
实验例1.抗菌肽的分析
实验例1.1.抗菌肽的溶解度分析
对本发明的抗菌肽的溶解度进行了测定,结果见下表1。
[表1]
肽浓度为25~200μM,室温下观察12小时。
另外,本发明的抗菌肽的KSH42和KSH43对链霉蛋白酶的稳定性分析结果如图2所示。
此外,通过比较根据用KSH29、KSH42和KSH43处理的人工细胞膜渗漏程度获得的结果如图3所示。
实验例1.2.抗菌肽的分子量和纯度测量
分别测定了本发明的抗菌肽的纯度和分子量,结果见下表2和图24至215。
[表2]
在上表2的氨基酸序列中,大写字母是L型氨基酸,小写字母是D型氨基酸。k是与癸酸(C10脂肪酸)结合的赖氨酸,k是与己酸(C6脂肪酸)结合的赖氨酸。另外,Wm为下式1所示的甲氧基色氨酸(Wm),Ws为下式2所示的苯并噻吩基丙氨酸,Wf为下式3所示的氟代色氨酸。
[式1]
[式2]
[式3]
其中Y是由下式4表示的单碘酪氨酸。
[式4]
其中N是糖基化天冬酰胺。
实验例2.最小生长抑制浓度(MIC)分析
测定本发明抗菌肽的最低生长抑制浓度,结果见下表3。
具体而言,将菌株在CAMHB中生长至对数中期,然后用PBS缓冲液稀释至1×106cfu/ml制备菌液,将上述实施例1制备的抗菌肽用CAMHB稀释至80μM,40μM、20μM、10μM、5μM、2.5μM、1.25μM和0.63μM,然后用等体积处理菌液。37℃培养18小时,测定MIC。
[表3]
使用阳离子调节的Mueller Hinton肉汤(含有10mg/L Mg2+和50mg/L Ca2+)测定MIC值。结果是三个独立实验的平均值。
实验例3.体外抗菌活性分析
在电子显微镜下对经KSH29处理的多重耐药菌株(鲍曼不动杆菌和金黄色葡萄球菌)的形态进行拍照,结果见图4。
具体而言,将MRAB和MRSA分别用与MIC相同浓度的实施例1制备的抗菌肽处理0、15、30、60分钟,分别用4%多聚甲醛和1%四氧化锇溶液处理1小时并固定。之后,用液氮快速冷冻后冷冻干燥。使用Pt涂层场发射扫描电子显微镜(S-4700,EMAX系统)在10,000放大倍率下观察。
此外,通过分析根据用KSH29、KSH42和KSH43处理的脂质体渗漏程度获得的结果如图5所示。
脂质体按以下方式制备。
具体而言,将7μM DMPC(磷脂酰胆碱)和3μM DMPG(磷脂酰甘油)溶解在甲醇中,然后蒸发至干。之后,加入含有70mM calcein的Tris缓冲液,重复涡旋和冻融。使用Avestin50x聚碳酸酯膜(直径=0.75nm。孔径=100nm)过滤器形成大小为100μM的脂质体。使用Sephadex G50柱对形成的脂质体进行孔分离,并稀释至200μM用以制备。
另外,脂质体渗漏的程度以下列方式进行分析。
具体而言,将制备的脂质体用上述实施例1中制备的抗菌肽稀释为20μM、2μM和0.2μM(脂质:肽的比例分别为10:1、100:1和1000:1)。在Flex条件下拍摄,激发波长490nm,发射波长520nm,总共1200秒,拍摄开始后30秒加入抗菌肽。
此外,根据用KSH29、KSH42和KSH43处理得到的动态光散射的分析结果如图6所示。
动态光散射以下列方式进行分析。
具体来说,将制备的脂质体与上述实施例1中制备的20μM的抗菌肽进行稀释(脂质:肽的比例为10:1)。将5μl的稀释液装入AvidNano黑池,在设置如下后测量疏水直径:溶质:脂质体,溶剂:水,运行:10,采集:10。
此外,根据KSH29、KSH42和KSH43的处理,分析诱导耐多药金黄色葡萄球菌(MRSA)的膜电位差干扰程度,得到的结果如图7所示。
诱导膜电位差干扰的程度以下列方式进行分析。
具体来说,将25μM短杆菌肽、25μM粘菌素以及MIC40倍、MIC20倍、MIC10倍和MIC5倍的样品肽在5mM HEPES(羟乙基哌嗪乙烷磺酸)、20mM葡萄糖和100mM KCl缓冲液中稀释以制备试剂。将在CAMHB中培养至中期的菌株用5mM HEPES和20mM葡萄糖缓冲液洗三次,并用5mMHEPES、20mM葡萄糖和100mM KCl缓冲液稀释至OD值为0.1,制备细菌溶液。将diSC35染料加入稀释后的细菌溶液至2μM,孵育30分钟,然后按90μl分装,制备。在Flex条件下拍照,激发波长620纳米,发射波长670纳米,共600秒,在开始拍照120秒后向细菌溶液中加入10微升试剂。
此外,根据用KSH29、KSH42和KSH43处理,分析诱导耐多药的粪肠球菌(MREF)的膜电位差干扰程度,得到的结果如图8所示。
此外,通过分析根据用KSH29、KSH42和KSH43处理诱导多药耐药鲍曼不动杆菌(MRAB)的膜电位差干扰程度而得到的结果如图9所示。
此外,根据用KSH29、KSH42和KSH43以及头孢硝噻吩或ONPG(O-硝基苯基-β-D-吡喃半乳糖苷)处理,分析大肠杆菌的细胞膜渗透性所得到的结果如图10所示。
大肠杆菌的细胞膜渗透性以下列方式进行分析。
具体来说,将在CAMHB中培养至中对数期的菌株清洗三次,然后用PBS缓冲液稀释至OD值为0.4,制备菌液。装入10mM ONPG(O-硝基苯基-β-D-吡喃半乳糖苷)和120μM头孢硝噻吩,然后将上述实施例1中制备的抗菌肽分别加入到4倍的所需浓度中,制备试剂。用该试剂处理细菌溶液,然后在37℃下以1分钟为间隔在420nm处测量ONPG的吸光度,在490nm处测量头孢硝噻吩的吸光度,持续1小时。
此外,通过分析KSH29在每个处理时间内对耐多药的铜绿假单胞菌(MRPA)、耐多药的粪肠球菌(MREF)、耐多药的鲍曼不动杆菌(MRAB)和耐多药的金黄色葡萄球菌(MRSA)的抗菌效果得到的结果如图11所示。
每个处理时间的抗菌效果按以下方式进行分析。
具体来说,将菌株在CAMHB中生长至中对数期,然后用PBS缓冲液稀释至1×106cfu/ml,制备菌液,并将上述实施例1中制备的抗菌肽稀释至各菌株MIC的8倍、4倍和2倍,然后用相同体积的菌液处理,在37℃培养。每隔5分钟、15分钟、30分钟、1小时、2小时、4小时、8小时、16小时和18小时回收混合物,然后将其稀释为1/10,000或1/100,000,分装在CAMHB琼脂中,在37℃下培养,然后测量菌落的数量。
此外,通过分析KSH42和KSH43在每个处理时间内对耐多药鲍曼不动杆菌(MRAB)和耐多药金黄色葡萄球菌(MRSA)的抗菌效果,得到的结果如图12所示。
此外,通过测量KSH29、KSH42和KSH43对30种鲍曼不动杆菌(A.baumannii)的最小抑制浓度得到的结果如下表4所示。
对30种鲍曼不动杆菌的最小抑制浓度(MIC)是以下列方式测定的。
具体地说,将菌株在CAMHB中生长到中期,然后用PBS缓冲液稀释到1×106cfu/ml,以制备细菌溶液,将上述实施例1中制备的抗菌肽用CAMHB稀释到80μM、40μM、20μM、10μM、5μM、2.5μM、1.25μM和0.63μM,然后用相同体积的细菌溶液处理,在37℃下培养18小时,然后确认MIC。
[表4]
菌株1至152、10087和19606是从国立庆福大学医学院纯化和获得的并。这些菌株对抗生素亚胺培南、美罗培南、多里培南、头孢噻肟、妥布霉素、环丙沙星(22号菌株除外)、庆大霉素(22号菌株除外)、头孢他啶(22号菌株除外)和四环素(22号菌株除外)都有抗性。
菌株1605购自ATCC(美国典型培养物保藏中心,美国)。此外,菌株40203购自韩国微生物培养中心。
COLR是指对粘菌素的耐药性,TGCR是指对替加环素的耐药性,TGCI是指替加环素的中间菌株。
此外,多肽对30种鲍曼不动杆菌的MIC50和MIC90如下表5所示。
[表5]
成分 | MIC50 | MIC90 |
KSH29 | 1.25 | 1.25 |
KSH42 | 1.25 | 1.25 |
KSH43 | 0.63 | 1.25 |
此外,通过分析根据用KSH29、KSH42和KSH43处理的微生物的抗性获得诱导程度得到的结果如图13所示。
实验例4.在幼虫体内的抗菌活性
根据KSH37(阴性对照)、KSH42和KSH43的处理,分析对细菌(鲍曼氏菌、金黄色葡萄球菌和粪肠球菌)的抗菌活性,作为大孔菌的存活率,得到的结果如图14所示。
具体来说,将细菌(鲍曼不动杆菌、金黄色葡萄球菌和粪肠杆菌)在CAMHB中生长到中期,然后用PBS缓冲液洗净,感染到1×106、5×105、5×107cfu/ml,用KSH37(阴性对照)、KSH42和KSH43处理为5μg/幼虫。此后,检查幼虫5天的存活率并进行比较,以测量体内的抗菌活性。
实验例5.毒性分析
通过分析本发明的抗菌肽的毒性评价得到的结果如图15至23所示。
具体来说,用PBS稀释8%的hRBC(人红细胞)。每种抗生素用PBS稀释到200μM、100μM、50μM、25μM、12.5μM、6.25μM、3.13μM和1.07μM,用稀释液处理8%的hRBC,用上述实施例1中制备的抗菌肽处理8%的hRBC,用量相同,并在37℃反应1小时。阳性对照用1% TritonX100代替本发明的抗菌肽处理。对于红细胞的溶血,通过在1,000×g下旋转回收汤汁,并在540nm下测量吸光度。hRBC与0.2%Triton X-100反应的红细胞的吸光度视为100%,hRBC与PBS反应的红细胞的吸光度视为0%,并进行比较。
实验例6.小鼠体内的抗菌活性
根据用KSH43处理小鼠(BALB/c,雌性,7周)的存活率,分析对细菌(大肠杆菌)的抗菌活性,得到的结果如图216所示。
具体来说,菌株在CAMHB中生长至对数期,然后用PBS缓冲液洗涤,通过皮下注射感染小鼠至1×106cfu/小鼠。1小时、24小时和48小时后,以100mg/kg的剂量给予KSH43和PBS(阴性对照)。此后,每12小时检查一次小鼠的存活率,持续7天,并进行比较以测量体内的抗菌活性。
结果,所有用KSH43给药的小鼠都存活了7天,而在用PBS给药的小鼠中,只有约10%的小鼠在第3天存活(图216)。
SEQUENCE LISTING
<110> 安尼根有限公司
<120> 新型抗菌肽及其用途
<130> P22116622WP
<150> KR 10-2020-0038642
<151> 2020-03-30
<160> 99
<170> PatentIn version 3.5
<210> 1
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> B 结构域
<400> 1
Trp Leu Val Trp Ile Trp
1 5
<210> 2
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 28
<400> 2
Trp Leu Val Trp Ile Trp Arg Arg Lys Arg
1 5 10
<210> 3
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 29
<400> 3
Trp Leu Val Trp Ile Trp Arg Arg Arg
1 5
<210> 4
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 30
<400> 4
Trp Leu Val Trp Ile Trp Gln Arg Arg Arg
1 5 10
<210> 5
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 31
<400> 5
Trp Leu Val Trp Ile Trp Arg Arg Gln Arg
1 5 10
<210> 6
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 32
<400> 6
Trp Leu Val Trp Ile Trp Arg Arg
1 5
<210> 7
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 35
<400> 7
Lys Trp Leu Val Trp Ile Trp Arg Arg Arg
1 5 10
<210> 8
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 42
<400> 8
Trp Val Val Trp Val Val Trp Arg Arg Arg
1 5 10
<210> 9
<211> 6
<212> PRT
<213> Artificial Sequence
<220>
<223> B 结构域
<400> 9
Trp Ile Trp Val Leu Trp
1 5
<210> 10
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 43
<400> 10
Arg Arg Arg Trp Ile Trp Val Leu Trp Lys
1 5 10
<210> 11
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 46
<400> 11
Lys Lys Lys Trp Ile Trp Val Leu Trp Lys
1 5 10
<210> 12
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 54 - Arg-Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg(D型)
<400> 12
Arg Arg Trp Ile Trp Val Leu Trp Arg
1 5
<210> 13
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 55 - Arg-Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg(L型)
<400> 13
Arg Arg Trp Ile Trp Val Leu Trp Arg
1 5
<210> 14
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 37
<400> 14
Trp Leu Val Trp Lys Trp Arg Arg Arg
1 5
<210> 15
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 39
<400> 15
Trp Leu Val Trp Ser Trp Arg Arg Arg
1 5
<210> 16
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 40
<400> 16
Trp Val Val Trp Val Trp Arg Arg Arg
1 5
<210> 17
<211> 8
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 41
<400> 17
Trp Leu Trp Ile Trp Arg Arg Arg
1 5
<210> 18
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 56
<400> 18
Arg Arg Trp Val Trp Val Val Trp Lys
1 5
<210> 19
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 57
<400> 19
Arg Arg Arg Trp Val Trp Val Val Trp Lys
1 5 10
<210> 20
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 59
<400> 20
Arg Arg Arg Trp Ile Trp Ile Leu Trp
1 5
<210> 21
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 60
<400> 21
Arg Arg Arg Trp Ile Trp Ile Ile Trp
1 5
<210> 22
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 61
<400> 22
Trp Ile Ile Trp Ile Trp Arg Arg Arg
1 5
<210> 23
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 3
<400> 23
Trp Leu Leu Trp Ile Ala Leu Arg Lys Lys Arg
1 5 10
<210> 24
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 5
<400> 24
Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 25
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 6
<400> 25
Trp Leu Leu Trp Ile Ala Leu Arg Lys Lys
1 5 10
<210> 26
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 9 - Lys(连接己酸(C6))-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg
<400> 26
Lys Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 27
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 20
<400> 27
Trp Ala Ala Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 28
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH V
<400> 28
Trp Leu Val Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 29
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH I
<400> 29
Trp Leu Ile Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 30
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH F
<400> 30
Trp Leu Phe Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 31
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH YL
<400> 31
Trp Leu Tyr Trp Ile Leu Leu Arg Lys Lys Arg
1 5 10
<210> 32
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH VY
<400> 32
Trp Leu Val Trp Ile Tyr Leu Arg Lys Lys Arg
1 5 10
<210> 33
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH VY2
<400> 33
Trp Leu Val Trp Val Tyr Leu Arg Lys Lys Arg
1 5 10
<210> 34
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH VY3
<400> 34
Trp Leu Val Trp Ile Tyr Val Arg Lys Lys Arg
1 5 10
<210> 35
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH VY4
<400> 35
Trp Leu Val Trp Ile Tyr Arg Lys Lys Arg
1 5 10
<210> 36
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 27
<400> 36
Trp Leu Ile Trp Val Tyr Arg Lys Lys Arg
1 5 10
<210> 37
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 33
<400> 37
Trp Leu Val Trp Ile Tyr Arg Arg Arg
1 5
<210> 38
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 44
<400> 38
Trp Val Val Val Val Trp Arg Arg Arg
1 5
<210> 39
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 45
<400> 39
Trp Val Val His Val Val Trp Arg Arg Arg
1 5 10
<210> 40
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 50
<400> 40
Arg Arg Arg Trp Ile Trp Trp Leu Trp Lys
1 5 10
<210> 41
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 51
<400> 41
Arg Arg Lys Trp Ile Trp Trp Leu Trp Lys
1 5 10
<210> 42
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 52
<400> 42
Arg Arg Lys Trp Ile Trp Trp Leu Trp Lys Lys Lys
1 5 10
<210> 43
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 58
<400> 43
Arg Arg Arg His Val His Val Val Trp Lys
1 5 10
<210> 44
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 1-
Trp(L型)-Leu(L型)-Leu(L型)-Trp(L型)-Ile(L型)-Ala(L
型)-Leu(L型)-Arg(L型)-Lys(L型)-Lys(L型)-Arg(L型)
<400> 44
Trp Leu Leu Trp Ile Ala Leu Arg Lys Lys Arg
1 5 10
<210> 45
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 4 - Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys(连接己酸(C6) )-Arg
<400> 45
Trp Leu Leu Trp Ile Ala Leu Arg Lys Lys Arg
1 5 10
<210> 46
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 7 - Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys(连接己酸(C6))
<400> 46
Trp Leu Leu Trp Ile Ala Leu Arg Lys Lys
1 5 10
<210> 47
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 8
<400> 47
Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys
1 5 10
<210> 48
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 10 - Lys(连接癸酸(C10))
-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg
<400> 48
Lys Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 49
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 11
<400> 49
Leu Leu Trp Ile Ala Leu Arg Lys Lys Arg
1 5 10
<210> 50
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 12
<400> 50
Leu Leu Trp Ile Ala Leu Lys Lys Lys Lys
1 5 10
<210> 51
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 13
<400> 51
Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 52
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 15 - Trp(连接甲氧基色氨酸)-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg
<400> 52
Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 53
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 16 - Trp(连接苯噻啶-丙氨酸)
-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg
<400> 53
Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 54
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 18 - Trp(连接氟-色氨酸)
-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg
<400> 54
Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 55
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 19
<400> 55
Ser Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 56
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 36
<400> 56
Asp Trp Leu Val Trp Ile Trp Arg Arg Arg
1 5 10
<210> 57
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 47 -
Asn(糖基化)-Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys
<400> 57
Asn Arg Arg Arg Trp Ile Trp Val Leu Trp Lys
1 5 10
<210> 58
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 48 -
Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys-Asn(糖基化)
<400> 58
Arg Arg Arg Trp Ile Trp Val Leu Trp Lys Asn
1 5 10
<210> 59
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 49 -
Trp-Val-Val-His-Val-Val-Trp-Arg-Arg-Arg-Asn(糖基化)
<400> 59
Trp Val Val His Val Val Trp Arg Arg Arg Asn
1 5 10
<210> 60
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 62 - Arg(L型)-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys
<400> 60
Arg Arg Arg Trp Ile Trp Val Leu Trp Lys
1 5 10
<210> 61
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 63 - Arg-Arg(L型)-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys
<400> 61
Arg Arg Arg Trp Ile Trp Val Leu Trp Lys
1 5 10
<210> 62
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 64 - Arg-Arg-Arg(L型)-Trp-Ile-Trp-Val-Leu-Trp-Lys
<400> 62
Arg Arg Arg Trp Ile Trp Val Leu Trp Lys
1 5 10
<210> 63
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH Y
<400> 63
Trp Leu Tyr Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 64
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> IKSH5-1 -
Tyr(单碘酪氨酸)-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg
<400> 64
Tyr Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg
1 5 10
<210> 65
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> IKSH5-2 - Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg-
Tyr(单碘酪氨酸)
<400> 65
Trp Leu Leu Trp Ile Gly Leu Arg Lys Lys Arg Tyr
1 5 10
<210> 66
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> XSH 2
<400> 66
Trp Leu Leu Trp Val Tyr Val Arg Lys Lys Arg
1 5 10
<210> 67
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 1
<400> 67
Trp Val Leu Trp Val Trp Leu Arg Lys Lys Arg
1 5 10
<210> 68
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 2
<400> 68
Trp Leu Val Tyr Val Trp Leu Arg Lys Lys Arg
1 5 10
<210> 69
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 3
<400> 69
Trp Leu Leu Trp Val Leu Trp Arg Lys Lys Arg
1 5 10
<210> 70
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 5
<400> 70
Trp Leu Trp Val Trp Val Arg Lys Lys Arg
1 5 10
<210> 71
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 6
<400> 71
Trp Val Val Trp Val Tyr Val Arg Lys Lys Arg
1 5 10
<210> 72
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 7
<400> 72
Trp Val Val Trp Val Val Tyr Arg Lys Lys Arg
1 5 10
<210> 73
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 8
<400> 73
Trp Leu Ala Trp Leu Tyr Leu Arg Lys Lys Arg
1 5 10
<210> 74
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 9
<400> 74
Trp Leu Leu Trp Leu Tyr Ala Arg Lys Lys Arg
1 5 10
<210> 75
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 28
<400> 75
Trp Leu Val Trp Ile Trp Arg Arg Lys Arg
1 5 10
<210> 76
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> LSH 99
<400> 76
Val Trp Val Trp Val Trp Val Arg Lys Lys Arg
1 5 10
<210> 77
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 66
<400> 77
Trp Val Val Trp Val Trp Lys Lys Lys
1 5
<210> 78
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 67
<400> 78
Trp Val Val Trp Val Val Trp Lys Lys Lys
1 5 10
<210> 79
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 68
<400> 79
Arg Arg Arg Trp Ile Trp Val Leu Trp Lys Asn
1 5 10
<210> 80
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 69
<400> 80
Trp Ala Ala Trp Ile Gly Leu Arg Arg Arg
1 5 10
<210> 81
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 70
<400> 81
Trp Ala Ala Trp Val Val Trp Arg Arg Arg
1 5 10
<210> 82
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 71
<400> 82
Trp Val Ala Trp Ala Val Trp Arg Arg Arg
1 5 10
<210> 83
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 72
<400> 83
Trp Val Val Trp Ala Ala Trp Arg Arg Arg
1 5 10
<210> 84
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 73
<400> 84
Arg Arg Arg Trp Ile Trp Val Leu Trp
1 5
<210> 85
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 74
<400> 85
Arg Arg Arg Trp Ile Trp Ala Ala Trp Lys
1 5 10
<210> 86
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 75
<400> 86
Trp Ala Ala Trp Ile Gly Leu Arg Lys Lys Lys
1 5 10
<210> 87
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 76
<400> 87
Trp Ala Ala Trp Ile Gly Leu Arg Arg Lys Lys
1 5 10
<210> 88
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 77
<400> 88
Trp Ala Ala Trp Ile Gly Leu Arg Lys Arg Lys
1 5 10
<210> 89
<211> 9
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 78
<400> 89
Trp Ala Ala Trp Ile Gly Leu Arg Arg
1 5
<210> 90
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 79
<400> 90
Arg Arg Arg Trp Val Trp Trp Val Trp Trp
1 5 10
<210> 91
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 80
<400> 91
Arg Arg Arg Trp Val Trp Trp Val Val Trp
1 5 10
<210> 92
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 81
<400> 92
Arg Arg Arg Trp Val Trp Val Val Trp Trp
1 5 10
<210> 93
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 82
<400> 93
Arg Arg Arg Trp Val Trp Val Val Val Trp
1 5 10
<210> 94
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 83
<400> 94
Arg Arg Arg Trp Val Val Trp Val Trp Trp
1 5 10
<210> 95
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 84
<400> 95
Arg Arg Arg Trp Val Val Trp Val Val Trp
1 5 10
<210> 96
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 85
<400> 96
Arg Arg Arg Trp Val Val Val Val Trp Trp
1 5 10
<210> 97
<211> 10
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 86
<400> 97
Arg Arg Arg Trp Val Val Val Val Val Trp
1 5 10
<210> 98
<211> 11
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 90
<400> 98
Arg Arg Arg Gly Trp Val Trp Val Val Trp Lys
1 5 10
<210> 99
<211> 12
<212> PRT
<213> Artificial Sequence
<220>
<223> KSH 91
<400> 99
Arg Arg His His Trp Val Val Trp Val Val Trp Lys
1 5 10
Claims (20)
1.一种由以下结构式I或结构式II表示的抗菌肽或其盐:
[结构式I]
N'-A-B-C-C'
[结构式II]
N'-C-B-A-C'
其中,
N’是抗菌肽的N端,C’是抗菌肽的C端,C端是羧基或羧基的羟基(-OH)被胺基(-NH2)取代的一端,
A由(X1)a-(X2)b-(X3)c-(X4)d的氨基酸序列组成,
其中a、b、c和d各自独立地是0或1,并且
X1至X4各自独立地是选自Arg、Lys、Asn、Gln、Asp、Val、Leu、Ser、His、Gly和Tyr组成的组的任何一个氨基酸,并且
B由Trp-(Z1)e-(Z2)f-Trp-(Z3)g-(Z4)h-Trp的氨基酸序列组成,
其中e、f、g和h各自独立地是0或1,并且
Z1至Z4各自独立地是选自Val、Leu、Ile、Gly、Ala、Ser、Phe、Tyr、Trp、Lys和His组成的组的任何一个氨基酸,并且
C由(X5)i-(X6)j-(X7)k-(X8)l的氨基酸序列组成,
其中,i、j、k和l各自独立地是0或1,并且
X5至X8各自独立地是选自Arg、Lys、Asn、Gln、Asp、Val、Leu、Ser、His、Gly和Tyr组成的组中的任何一个氨基酸,并且
其中Trp可以被C1-6烷氧基或卤素取代,或者Trp的吲哚环中的氮(N)可以被硫(S)修饰,以及
当N端氨基酸为Lys时,C3至C10脂肪酸可进一步与胺基结合,
Tyr可以被卤素取代,以及
Asn可以被糖基化。
2.如权利要求1所述的抗菌肽或其盐,其中e、f、g和h中的任何一个为0,其余为1。
3.如权利要求1所述的抗菌肽或其盐,其中B由Trp-Leu-Val-Trp-Ile-Trp的氨基酸序列组成。
4.如权利要求3所述的抗菌肽或其盐,其中所述抗菌肽由以下组成的组中的任一氨基酸序列组成,Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Lys-Arg,Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Arg,Trp-Leu-Val-Trp-Ile-Trp-Gln-Arg-Arg-Arg,Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Gln-Arg,Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg,Lys-Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Arg和Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg-Lys-Arg。
5.如权利要求1所述的抗菌肽或其盐,其中所述抗菌肽由Trp-Val-Val-Trp-Val-Val-Trp-Arg-Arg-Arg所示的氨基酸序列组成。
6.如权利要求1所述的抗菌肽或其盐,其中所述B由Trp-Ile-Trp-Val-Leu-Trp所示的氨基酸序列组成。
7.如权利要求6所述的抗菌肽或其盐,其中所述抗菌肽由以下组成的组中的任一氨基酸序列组成,Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys,Lys-Lys-Lys-Trp-Ile-Trp-Val-Leu-Trp-Lys,Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Arg,Asn(糖基化)-Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys,Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Lys-Asn和Arg-Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp。
8.如权利要求7所述的抗菌肽或其盐,其中所述抗菌肽C端的Arg为L型或D型,由Arg-Arg-Trp-Ile-Trp-Val-Leu-Trp-Arg所示的氨基酸序列组成。
9.如权利要求1所述的抗菌肽或其盐,其中所述抗菌肽由以下组成的组中的任一氨基酸序列组成,Trp-Leu-Val-Trp-Lys-Trp-Arg-Arg-Arg,Trp-Leu-Val-Trp-Ser-Trp-Arg-Arg-Arg,Trp-Val-Val-Trp-Val-Trp-Arg-Arg-Arg,Trp-Leu-Trp-Ile-Trp-Arg-Arg-Arg,Arg-Arg-Trp-Val-Trp-Val-Val-Trp-Lys,Arg-Arg-Arg-Trp-Val-Trp-Val-Val-Trp-Lys,Arg-Arg-Arg-Trp-Ile-Trp-Ile-Leu-Trp,Arg-Arg-Arg-Trp-Ile-Trp-Ile-Ile-Trp,Trp-Ile-Ile-Trp-Ile-Trp-Arg-Arg-Arg,Trp-Val-Leu-Trp-Val-Trp-Leu-Arg-Lys-Lys-Arg,Asp-Trp-Leu-Val-Trp-Ile-Trp-Arg-Arg Arg,Trp-Val-Val-Trp-Val-Trp-Lys-Lys-Lys,Trp-Val-Val-Trp-Val-Val-Trp-Lys-Lys-Lys,Trp-Ala-Ala-Trp-Val-Val-Trp-Arg-Arg-Arg,Trp-Val-Val-Trp-Ala-Ala-Trp-Arg-Arg-Arg,Arg-Arg-Arg-Gly-Trp-Val-Trp-Val-Val-Trp-Lys,Arg-Arg-Arg-Trp-Ile-Trp-Trp-Leu-Trp-Lys,Arg-Arg-Lys-Trp-Ile-Trp-Trp-Leu-Trp-Lys,Arg-Arg-Lys-Trp-Ile-Trp-Trp-Leu-Trp-Lys-Lys-Lys,Trp-Leu-Leu-Trp-Val-Leu-Trp-Arg-Lys-Lys-Arg,Trp-Val-Ala-Trp-Ala-Val-Trp-Arg-Arg-Arg,Arg-Arg-Arg-Trp-Ile-Trp-Ala-Ala-Trp-Lys,Arg-Arg-Arg-Trp-Val-Trp-Trp-Val-Trp-Trp,Arg-Arg-Arg-Trp-Val-Trp-Trp-Val-Val-Trp,Arg-Arg-Arg-Trp-Val-Trp-Val-Val-Trp-Trp,Arg-Arg-Arg-Trp-Val-Val-Trp-Val-Trp-Trp,Arg-Arg-Arg-Trp-Val-Val-Trp-Val-Val-Trp和Arg-Arg-His-His-Trp-Val-Val-Trp-Val-Val-Trp-Lys。
10.一种抗菌肽或其盐,其中所述抗菌肽由以下组成的组中的任一氨基酸序列组成,Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys,Lys-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Ile-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Phe-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Tyr-Trp-Ile-Leu-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Tyr-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Val-Tyr-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Tyr-Val-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Tyr-Arg-Lys-Lys-Arg,Trp-Leu-Ile-Trp-Val-Tyr-Arg-Lys-Lys-Arg,Trp-Leu-Val-Trp-Ile-Tyr-Arg-Arg-Arg,Trp-Val-Val-Val-Val-Trp-Arg-Arg-Arg,Trp-Val-Val-His-Val-Val-Trp-Arg-Arg-Arg,Arg-Arg-Arg-His-Val-His-Val-Val-Trp-Lys,Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg-Tyr,Trp-Leu-Val-Tyr-Val-Trp-Leu-Arg-Lys-Lys-Arg,Ser-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Val-Val-His-Val-Val-Trp-Arg-Arg-Arg-Asn(糖基化),Arg-Arg-Arg-Trp-Val-Val-Val-Val-Val-Trp,Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys,Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg,Leu-Leu-Trp-Ile-Ala-Leu-Lys-Lys-Lys-Lys,Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Tyr-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Val-Tyr-Val-Arg-Lys-Lys-Arg,Trp-Leu-Trp-Val-Trp-Val-Arg-Lys-Lys-Arg,Val-Trp-Val-Trp-Val-Trp-Val-Arg-Lys-Lys-Arg,Trp-Val-Val-Trp-Val-Tyr-Val-Arg-Lys-Lys-Arg,Trp-Val-Val-Trp-Val-Val-Tyr-Arg-Lys-Lys-Arg,Trp-Leu-Ala-Trp-Leu-Tyr-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Leu-Tyr-Ala-Arg-Lys-Lys-Arg,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg-Arg,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Lys,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg-Lys-Lys,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Lys-Arg-Lys,Trp-Ala-Ala-Trp-Ile-Gly-Leu-Arg-Arg,Arg-Arg-Arg-Trp-Val-Trp-Val-Val-Val-Trp和Arg-Arg-Arg-Trp-Val-Val-Val-Val-Trp-Trp。
11.如权利要求10所述的抗菌肽或其盐,其中所述的抗菌肽的N端的Lys的胺基上还结合有C3~C10的脂肪酸,所述抗菌肽由Lys-Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg所示的氨基酸序列组成。
12.如权利要求11所述的抗菌肽或其盐,其中所述的C3~C10的脂肪酸为己酸或癸酸。
13.如权利要求10所述的抗菌肽或其盐,其中所述的抗菌肽的N端的Lys的胺基上还结合有C3~C10的脂肪酸,所述抗菌肽由Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg,Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys所示的氨基酸序列组成。
14.如权利要求13所述的抗菌肽或其盐,其中所述的C3~C10的脂肪酸为癸酸。
15.如权利要求10所述的抗菌肽或其盐,其中所述的抗菌肽的C端的Arg为L型或D型,所述的抗菌肽由Trp-Leu-Leu-Trp-Ile-Ala-Leu-Arg-Lys-Lys-Arg所示的氨基酸序列组成。
16.如权利要求10所述的抗菌肽或其盐,其中所述的抗菌肽的Trp可以被C1-6烷氧基或卤素取代,或者Trp的吲哚环中的氮(N)可以被硫(S)修饰,所述的抗菌肽由Trp-Leu-Leu-Trp-Ile-Gly-Leu-Arg-Lys-Lys-Arg所示的氨基酸序列组成。
17.一种抗生素,包含如权利要求1-16任一项所述的抗菌肽或其盐作为有效成分。
18.一种化妆品组合物,包含如权利要求1-16任一项所述的抗菌肽或其盐作为有效成分。
19.一种食品添加剂,包含如权利要求1-16任一项所述的抗菌肽或其盐作为有效成分。
20.一种抗菌饲料添加剂组合物,包含如权利要求1-16任一项所述的抗菌肽或其盐作为有效成分。
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
KR10-2020-0038642 | 2020-03-30 | ||
KR20200038642 | 2020-03-30 | ||
PCT/KR2021/003939 WO2021201570A1 (ko) | 2020-03-30 | 2021-03-30 | 신규한 항균 펩타이드 및 이의 용도 |
Publications (1)
Publication Number | Publication Date |
---|---|
CN115397836A true CN115397836A (zh) | 2022-11-25 |
Family
ID=77927909
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202180028141.2A Pending CN115397836A (zh) | 2020-03-30 | 2021-03-30 | 新型抗菌肽及其用途 |
Country Status (6)
Country | Link |
---|---|
US (1) | US20230287044A1 (zh) |
EP (1) | EP4129064A4 (zh) |
JP (1) | JP2023519844A (zh) |
KR (1) | KR102509412B1 (zh) |
CN (1) | CN115397836A (zh) |
WO (1) | WO2021201570A1 (zh) |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR20030061718A (ko) * | 2003-05-27 | 2003-07-22 | 애니젠 주식회사 | α-헬릭스 구조의 모델형 항균 펩타이드 |
US9029319B1 (en) | 2014-08-04 | 2015-05-12 | Centaur, Inc. | Water buffalo derived peptide antibiotic therapies |
WO2019226828A2 (en) * | 2018-05-22 | 2019-11-28 | Avidea Technologies, Inc. | Improved methods of manufacturing peptide-based vaccines |
KR102039400B1 (ko) | 2018-08-23 | 2019-11-01 | 조선대학교산학협력단 | mBjAMP1 펩타이드로부터 유래한 신규 항균 펩타이드 및 이의 용도 |
-
2021
- 2021-03-30 KR KR1020210041441A patent/KR102509412B1/ko active IP Right Grant
- 2021-03-30 US US17/995,092 patent/US20230287044A1/en active Pending
- 2021-03-30 EP EP21782374.9A patent/EP4129064A4/en active Pending
- 2021-03-30 CN CN202180028141.2A patent/CN115397836A/zh active Pending
- 2021-03-30 JP JP2022557855A patent/JP2023519844A/ja active Pending
- 2021-03-30 WO PCT/KR2021/003939 patent/WO2021201570A1/ko unknown
Also Published As
Publication number | Publication date |
---|---|
EP4129064A4 (en) | 2023-12-13 |
KR102509412B1 (ko) | 2023-03-14 |
WO2021201570A1 (ko) | 2021-10-07 |
JP2023519844A (ja) | 2023-05-15 |
US20230287044A1 (en) | 2023-09-14 |
KR20210122189A (ko) | 2021-10-08 |
EP4129064A1 (en) | 2023-02-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10301354B2 (en) | Antibacterial and fungicidal peptide in which lysine and tryptophan residues are repeated, and use thereof | |
KR102224929B1 (ko) | 해삼에서 분리한 항균 펩타이드로부터 유래한 신규 항균 펩타이드 및 이의 용도 | |
KR101734064B1 (ko) | 마이시니딘 펩타이드로부터 유래한 신규 항균 펩타이드 및 이의 용도 | |
US9862749B2 (en) | Analogue peptide CMA3 derived from CM-MA peptide and use thereof | |
KR102415725B1 (ko) | 신규한 항균 펩타이드 h123 및 이의 용도 | |
EP3932936A1 (en) | Polypeptide having antibacterial activity, composition for preventing or treating sepsis comprising same, and antibacterial composition | |
KR101493952B1 (ko) | 넙치의 지질다당류결합단백질로부터 유래한 항균 펩타이드 및 이의 용도 | |
KR102415734B1 (ko) | 신규한 항균 펩타이드 및 이의 용도 | |
KR101583025B1 (ko) | 헬리코박터 파일로리균의 리보좀 단백질 l1으로부터 유래된 신규한 항생 펩타이드 및 이의 용도 | |
KR102158036B1 (ko) | Pseudin-2 펩타이드로부터 유래한 신규 항균 펩타이드 및 이의 용도 | |
KR101276643B1 (ko) | 항생 펩타이드 | |
WO2023048411A1 (ko) | 신규한 항균 펩타이드 및 이의 용도 | |
KR102509412B1 (ko) | 신규한 항균 펩타이드 및 이의 용도 | |
US11452758B2 (en) | Antimicrobial peptide derived from LL37 peptide and uses thereof | |
US11117931B2 (en) | Antimicrobial peptide derived from Hp1404 peptide and uses thereof | |
KR102039400B1 (ko) | mBjAMP1 펩타이드로부터 유래한 신규 항균 펩타이드 및 이의 용도 | |
KR102608336B1 (ko) | Pep27 펩타이드로부터 유래한 신규 펩타이드 및 이의 용도 | |
KR102603281B1 (ko) | Hylin a1 펩타이드로부터 유래한 신규 펩타이드 및 이의 용도 | |
JP3661549B2 (ja) | 抗菌及び抗真菌ペプチド | |
KR102451854B1 (ko) | 신규한 항균 펩타이드 h103 및 이의 용도 | |
KR102492395B1 (ko) | 호랑나비 유충으로부터 유래된 펩타이드인 파필리오신-3 및 이의 용도 | |
JP2005532784A (ja) | 新規の抗菌ボリシンペプチド |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PB01 | Publication | ||
PB01 | Publication | ||
SE01 | Entry into force of request for substantive examination | ||
SE01 | Entry into force of request for substantive examination |