CN116942791A - Use of a combination of a DRD2, DRDS or VDCCs antagonist and a polymyxin - Google Patents
Use of a combination of a DRD2, DRDS or VDCCs antagonist and a polymyxin Download PDFInfo
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- CN116942791A CN116942791A CN202210419058.4A CN202210419058A CN116942791A CN 116942791 A CN116942791 A CN 116942791A CN 202210419058 A CN202210419058 A CN 202210419058A CN 116942791 A CN116942791 A CN 116942791A
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- Prior art keywords
- polymyxin
- resistant
- antagonist
- antibiotics
- bacteria
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Links
- 108010040201 Polymyxins Proteins 0.000 title claims abstract description 59
- 239000005557 antagonist Substances 0.000 title claims abstract description 25
- 102000003922 Calcium Channels Human genes 0.000 title claims abstract description 11
- 108090000312 Calcium Channels Proteins 0.000 title claims abstract description 11
- 102100020756 D(2) dopamine receptor Human genes 0.000 title claims abstract description 11
- 101000931901 Homo sapiens D(2) dopamine receptor Proteins 0.000 title claims abstract description 11
- 241000894006 Bacteria Species 0.000 claims abstract description 34
- 239000003242 anti bacterial agent Substances 0.000 claims abstract description 33
- 229940088710 antibiotic agent Drugs 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 27
- 229940079593 drug Drugs 0.000 claims abstract description 23
- 230000003115 biocidal effect Effects 0.000 claims abstract description 15
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 208000015181 infectious disease Diseases 0.000 claims abstract description 5
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 3
- 108010078777 Colistin Proteins 0.000 claims 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 Polymers 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 claims description 6
- 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 claims description 6
- 108010093965 Polymyxin B Proteins 0.000 claims description 4
- 241000607142 Salmonella Species 0.000 claims description 4
- 241000588748 Klebsiella Species 0.000 claims description 3
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims description 3
- 241000607768 Shigella Species 0.000 claims description 3
- 229920000024 polymyxin B Polymers 0.000 claims description 3
- 229960005266 polymyxin b Drugs 0.000 claims description 3
- 239000003937 drug carrier Substances 0.000 claims description 2
- 208000027096 gram-negative bacterial infections Diseases 0.000 claims description 2
- YKQOSKADJPQZHB-YNWHQGOSSA-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-[(1s)-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 Polymers CCC(C)CCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[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 YKQOSKADJPQZHB-YNWHQGOSSA-N 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims description 2
- 239000007972 injectable composition Substances 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
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- 230000002195 synergetic effect Effects 0.000 abstract description 8
- 238000002360 preparation method Methods 0.000 abstract description 2
- 230000003285 pharmacodynamic effect Effects 0.000 abstract 1
- 241000588724 Escherichia coli Species 0.000 description 7
- 230000000844 anti-bacterial effect Effects 0.000 description 6
- 229960000723 ampicillin Drugs 0.000 description 4
- 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 4
- 229960003346 colistin Drugs 0.000 description 4
- 230000034994 death Effects 0.000 description 4
- 231100000517 death Toxicity 0.000 description 4
- 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 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 101150004219 MCR1 gene Proteins 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 229940041153 polymyxins Drugs 0.000 description 3
- 241000588921 Enterobacteriaceae Species 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
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- 238000002835 absorbance Methods 0.000 description 2
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- PYMYPHUHKUWMLA-WDCZJNDASA-N arabinose Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)C=O PYMYPHUHKUWMLA-WDCZJNDASA-N 0.000 description 2
- PYMYPHUHKUWMLA-UHFFFAOYSA-N arabinose Natural products OCC(O)C(O)C(O)C=O PYMYPHUHKUWMLA-UHFFFAOYSA-N 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- SRBFZHDQGSBBOR-UHFFFAOYSA-N beta-D-Pyranose-Lyxose Natural products OC1COC(O)C(O)C1O SRBFZHDQGSBBOR-UHFFFAOYSA-N 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- LNEPOXFFQSENCJ-UHFFFAOYSA-N haloperidol Chemical compound C1CC(O)(C=2C=CC(Cl)=CC=2)CCN1CCCC(=O)C1=CC=C(F)C=C1 LNEPOXFFQSENCJ-UHFFFAOYSA-N 0.000 description 2
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- 238000012216 screening Methods 0.000 description 2
- MDLAAYDRRZXJIF-UHFFFAOYSA-N 1-[4,4-bis(4-fluorophenyl)butyl]-4-[4-chloro-3-(trifluoromethyl)phenyl]-4-piperidinol Chemical compound C1CC(O)(C=2C=C(C(Cl)=CC=2)C(F)(F)F)CCN1CCCC(C=1C=CC(F)=CC=1)C1=CC=C(F)C=C1 MDLAAYDRRZXJIF-UHFFFAOYSA-N 0.000 description 1
- SBKZGLWZGZQVHA-UHFFFAOYSA-N 1-[4-[3-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]propoxy]-3-methoxyphenyl]ethanol Chemical compound COC1=CC(C(C)O)=CC=C1OCCCN1CCC(C=2C3=CC=C(F)C=C3ON=2)CC1 SBKZGLWZGZQVHA-UHFFFAOYSA-N 0.000 description 1
- CFWRDBDJAOHXSH-SECBINFHSA-N 2-azaniumylethyl [(2r)-2,3-diacetyloxypropyl] phosphate Chemical compound CC(=O)OC[C@@H](OC(C)=O)COP(O)(=O)OCCN CFWRDBDJAOHXSH-SECBINFHSA-N 0.000 description 1
- 206010011409 Cross infection Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PLDUPXSUYLZYBN-UHFFFAOYSA-N Fluphenazine Chemical compound C1CN(CCO)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 PLDUPXSUYLZYBN-UHFFFAOYSA-N 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- SBKRTALNRRAOJP-BWSIXKJUSA-N N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,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]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methylheptanamide (6S)-N-[(2S)-4-amino-1-[[(2S,3R)-1-[[(2S)-4-amino-1-oxo-1-[[(3S,6S,9S,12S,15R,18R,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]butan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxobutan-2-yl]-6-methyloctanamide sulfuric acid Polymers OS(O)(=O)=O.CC(C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O.CC[C@H](C)CCCCC(=O)N[C@@H](CCN)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CCN)C(=O)N[C@H]1CCNC(=O)[C@@H](NC(=O)[C@H](CCN)NC(=O)[C@H](CCN)NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc2ccccc2)NC(=O)[C@@H](CCN)NC1=O)[C@@H](C)O SBKRTALNRRAOJP-BWSIXKJUSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
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- 101100206347 Schizosaccharomyces pombe (strain 972 / ATCC 24843) pmh1 gene Proteins 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- WGQKYBSKWIADBV-UHFFFAOYSA-N benzylamine Chemical class NCC1=CC=CC=C1 WGQKYBSKWIADBV-UHFFFAOYSA-N 0.000 description 1
- ZKIAIYBUSXZPLP-UHFFFAOYSA-N brexpiprazole Chemical compound C1=C2NC(=O)C=CC2=CC=C1OCCCCN(CC1)CCN1C1=CC=CC2=C1C=CS2 ZKIAIYBUSXZPLP-UHFFFAOYSA-N 0.000 description 1
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- FGXWKSZFVQUSTL-UHFFFAOYSA-N domperidone Chemical compound C12=CC=CC=C2NC(=O)N1CCCN(CC1)CCC1N1C2=CC=C(Cl)C=C2NC1=O FGXWKSZFVQUSTL-UHFFFAOYSA-N 0.000 description 1
- 229960001253 domperidone Drugs 0.000 description 1
- 229960000394 droperidol Drugs 0.000 description 1
- RMEDXOLNCUSCGS-UHFFFAOYSA-N droperidol Chemical compound C1=CC(F)=CC=C1C(=O)CCCN1CC=C(N2C(NC3=CC=CC=C32)=O)CC1 RMEDXOLNCUSCGS-UHFFFAOYSA-N 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 229960002690 fluphenazine Drugs 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960003878 haloperidol Drugs 0.000 description 1
- 229960003162 iloperidone Drugs 0.000 description 1
- XMXHEBAFVSFQEX-UHFFFAOYSA-N iloperidone Chemical compound COC1=CC(C(C)=O)=CC=C1OCCCN1CCC(C=2C3=CC=C(F)C=C3ON=2)CC1 XMXHEBAFVSFQEX-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- ZESIAEVDVPWEKB-ORCFLVBFSA-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 OS(O)(=O)=O.OS(O)(=O)=O.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 ZESIAEVDVPWEKB-ORCFLVBFSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 229960004505 penfluridol Drugs 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229960003548 polymyxin b sulfate Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000012827 research and development Methods 0.000 description 1
- 239000012313 reversal agent Substances 0.000 description 1
- 229960001534 risperidone Drugs 0.000 description 1
- RAPZEAPATHNIPO-UHFFFAOYSA-N risperidone Chemical compound FC1=CC=C2C(C3CCN(CC3)CCC=3C(=O)N4CCCCC4=NC=3C)=NOC2=C1 RAPZEAPATHNIPO-UHFFFAOYSA-N 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- KQKPFRSPSRPDEB-UHFFFAOYSA-N sumatriptan Chemical compound CNS(=O)(=O)CC1=CC=C2NC=C(CCN(C)C)C2=C1 KQKPFRSPSRPDEB-UHFFFAOYSA-N 0.000 description 1
- 229960003708 sumatriptan Drugs 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 229960000315 trifluoperazine hydrochloride Drugs 0.000 description 1
- BXDAOUXDMHXPDI-UHFFFAOYSA-N trifluoperazine hydrochloride Chemical compound [H+].[H+].[Cl-].[Cl-].C1CN(C)CCN1CCCN1C2=CC(C(F)(F)F)=CC=C2SC2=CC=CC=C21 BXDAOUXDMHXPDI-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- 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
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Immunology (AREA)
- Engineering & Computer Science (AREA)
- Gastroenterology & Hepatology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses an application of DRD2, DRDS or VDCCs antagonist and at least one polymyxin antibiotic in the combined preparation of drugs for treating MCR-carried polymyxin antibiotic sensitive bacteria or drug-resistant bacteria or drugs for resisting gram-negative bacteria infection for human, wherein the antagonist is selected from the following compounds
Description
Technical Field
The invention relates to the technical field of antibiotics, in particular to a novel antibiotic development and application range.
Background
In recent years, multi-drug resistant bacteria have become important pathogenic bacteria for nosocomial infection, cause death of at least 70 ten thousand (not less than 8 ten thousand in China) patients each year worldwide, and are in a continuously rising situation, and the death of 1000 ten thousand patients in 2050 is predicted to be caused, which exceeds the number of tumor deaths and hundreds of millions of infected people. The strains are widely distributed and spread fast, and are easy to generate outbreak epidemic. Infection caused by multiple drug-resistant bacteria presents the characteristics of complexity, intractability and the like, and can lead to prolonged hospitalization time, increased treatment cost and increased fatality rate of patients.
The multi-drug-resistant bacteria (MDRO) mainly refer to bacteria which simultaneously show drug resistance to three or more types of antibacterial drugs used clinically, abuse of broad-spectrum antibiotics is a main reason for forming the multi-drug-resistant bacteria, and the developed Pan-resistant bacteria (Pan-drug resistant bacteria, PDR) are almost totally resistant to common antibacterial drugs. Due to the characteristic of poor permeability of the outer membrane structure of gram-negative bacteria, the research and development of medicines are extremely difficult, and no medicines with new structure types are marketed for nearly 30 years.
Because of the worldwide popularity of multi-resistant bacteria, polymyxin has become the last line of defense against multi-resistant bacteria, particularly gram-negative bacteria, clinically, and is widely used in patients in hospitalization, post-surgery, and particularly in ICU. The antibiotic polypeptide produced by polymyxin and Paenibacillus polymyxa (Paenibacillus polymyxa) is divided into A, B, C, D, E. Clinically, B and E with smaller toxicity are used, and are marketed in 1964. However, the last line of colistin, the gram-negative antibiotic defense, is receiving challenges of the mobilizable colistin resistance factor mobilized colistin resistance determinants (MCR). Since polymyxins have long been widely used in animal husbandry, the detection rate in animals and humans has been rising year by means of plasmid-transmitted MCR in the environment. The detection rate of MCR-1 increased from 5.2% in 2009 to 30% in 2014. The enterobacteriaceae carry MCR in not less than 10 species of bacteria, including the well-known pathogenic bacteria escherichia coli, gram Lei Bo and salmonella. Enterobacteriaceae carrying MCR-1 are distributed among populations in more than 40 countries in 5 continents.
Polymyxin is a potent bactericidal polypeptide that causes bacterial death by binding to LipidA on the outer membrane of bacteria and then forming a pore-like structure that penetrates the cell membrane. The polymyxin resistance factor MCR uses substrate cephalin to change the structure of lipidA, making polymyxin unable to bind, thus losing antibacterial activity against bacteria. The development of an inhibitor of MCR can block the structural change of MCR to lipidA, so as to restore the activity of colistin combined with lipidA and kill bacteria.
Therefore, the screening of a novel synergistic or resistance reversal agent for low-toxicity or non-toxic non-bactericidal non-antibacterial polymyxin antibiotics would be the most effective means to solve the difficulties encountered in practical use of polymyxin antibiotics.
Disclosure of Invention
The invention provides an application of a DRD2, DRDS or VDCCs antagonist and at least one polymyxin antibiotic in the preparation of a medicament for treating MCR-carried polymyxin antibiotic sensitive bacteria or drug-resistant bacteria or a medicament for resisting gram-negative bacteria infection for human, which is characterized in that: the antagonist is selected from the following compounds One of them.
Further, preferably, the polymyxin antibiotic is polymyxin B or polymyxin E.
Further, the drug for resisting the coliform bacteria or the drug-resistant bacteria sensitive to the polymyxin antibiotics is a drug for resisting coliform bacteria sensitive to the polymyxin antibiotics, coliform bacteria resistant to the polymyxin antibiotics, pseudomonas aeruginosa resistant to the polymyxin antibiotics, salmonella resistant to the polymyxin antibiotics, shigella resistant to the polymyxin antibiotics or klebsiella resistant to the polymyxin antibiotics.
Further, the human anti-gram-negative bacterial infection drug is a human anti-colibacillus sensitive to polymyxin antibiotics, colibacillus resistant to polymyxin antibiotics, pseudomonas aeruginosa resistant to polymyxin antibiotics, salmonella resistant to polymyxin antibiotics, shigella resistant to polymyxin antibiotics or klebsiella resistant to polymyxin antibiotics.
Further, as a specific embodiment, the weight ratio of the antagonist to the polymyxin is 1:0.25-4.
Further, as a specific embodiment, the antagonist is administered in the form of an oral, injectable or external formulation.
Further, as a specific embodiment, the antagonist is administered simultaneously, sequentially or separately with the polymyxin.
Further, as a specific embodiment, the antagonist and the polymyxin agent are administered in an effective amount one or more times per day.
The invention also provides a pharmaceutical composition comprising a combination of a DRD2, DRDS or VDCCs antagonist and optionally a pharmaceutically acceptable carrier, and at least one polymyxin antibiotic, said antagonist being selected from the group consisting of the compounds shown below One of them.
In the present invention, the term "combination" means a mode of administration which includes each case where two or more drugs are administered sequentially or sequentially, or simultaneously, and "simultaneously" means that two or more drugs are administered in the same administration cycle with the compound of formula (I) and with any other third component drug, for example, within one day, three days, one week, two weeks, one month. By "sequential or sequential" administration is meant to include the case of separate administration during different administration periods. These modes of administration are all within the scope of the combination administration of the present invention.
An "effective amount" as used herein includes an amount sufficient to ameliorate or prevent a symptom or condition of a medical condition. An effective amount is also meant to be an amount sufficient to permit or facilitate diagnosis. The effective amount for a particular patient or veterinary subject may vary depending on the following factors: such as the condition to be treated, the general health of the patient, the route of administration and the dosage and severity of the side effects. An effective amount may be the maximum dose or regimen that avoids significant side effects or toxic effects.
The invention discloses for the first time that DRD2, DRDS or VDCCs antagonists have remarkable synergistic effect with polymyxin antibiotics. In the invention, the combination of the antagonist of DRD2, DRDS or VDCCs and the polymyxin antibiotics has remarkable drug effect synergistic effect compared with the single drugs thereof, and the application of the antagonist in preparing drugs for treating MCR-carried polymyxin antibiotics sensitive bacteria or drug-resistant bacteria or drugs for treating human gram-negative bacteria infection is suggested.
Detailed Description
For the purpose of describing the present invention, examples are set forth below. It is to be understood that the invention is not limited to these examples but provides a method of practicing the invention.
Example 1
Example 1 the synergistic effect of antagonists and polymyxins on the expression of MCR1, MCR3 in escherichia coli (e.coli) was examined.
Domeridone and polymyxin B were derived from the pharmaceutical company of middle-mezzanine, hangzhou; domperidone, risperidone from sigma aldrich; trifluoperazine hydrochloride, penfluridol, fluphenazine, haloperidol, brexpiprazole, hydroxy Iloperidone Sumatriptan from microphone; droperidol, iloperidone from ala Ding Shiji; ampicillin and arabinose were purchased from Shanghai organisms; LB medium was purchased from BD Difco.
The stock solution of the compound to be examined and polymyxin B sulfate was 10MG/ml, and dissolved in DMSO E.coli MG1655 pBAD-MCR1, E.coli MG1655 pBAD-MCR3, E.coli MG1655 pBAD were cultured in LB medium containing 100. Mu.g/ml ampicillin. The bacteriostasis experiment is carried out by using 96-well culture plates, and the administration concentration of the compound to be examined is respectively 64, 32, 16, 8, 4, 2, 1, 0.5, 0.25, 0.125, 0.06 and 0.03 mug/ml, and the final concentration of each bacterium is controlled between 105 and 106. In experiments investigating the synergistic effect of compounds and polymyxins, LB medium contained 100. Mu.g/ml ampicillin, 2. Mu.g/ml polymyxin sulfate, 2% arabinose; in experiments investigating the bacteriostatic activity of the compounds themselves, LB medium contained 100. Mu.g/ml ampicillin. Incubation was carried out for 24 hours at 37 ℃ after dosing, and a 600nm absorbance test was performed using an enzyme-labeled instrument, with absorbance less than 0.3 being considered no growth. The minimum concentration without growth is the minimum inhibitory concentration MIC. The compound which has no antibacterial activity and has synergistic antibacterial activity with polymyxin is an inhibitor of MCR. And the results are shown in Table 1 with synergistic MIC < 8. Mu.g/ml and MIC of the compounds alone without inhibitory activity against bacteria > 50. Mu.g/ml as screening criteria.
TABLE 1 minimum inhibitory concentration of N-Benzylamide derivatives on colistin sulfate sensitive E.coli in vitro
Claims (9)
1. Use of a DRD2, DRDs or VDCCs antagonist in combination with at least one polymyxin antibiotic for the manufacture of a medicament for the treatment of a MCR-carrying anti-polymyxin antibiotic susceptible or resistant bacteria or a human anti-gram negative bacterial infection, characterized in that: the antagonist is selected from the following compounds One of them.
2. The use according to claim 1, characterized in that: the polymyxin antibiotic is polymyxin B or polymyxin E.
3. The use according to claim 1, characterized in that: the anti-polymyxin antibiotic sensitive bacteria or drug-resistant bacteria are anti-colibacillus sensitive to polymyxin antibiotics, anti-colibacillus resistant to polymyxin antibiotics, anti-pseudomonas aeruginosa resistant to polymyxin antibiotics, anti-salmonella resistant to polymyxin antibiotics, anti-shigella resistant to polymyxin antibiotics or anti-klebsiella resistant to polymyxin antibiotics.
4. The use according to claim 1, characterized in that: the human anti-gram-negative bacteria infection medicine is a human anti-colibacillus sensitive to polymyxin antibiotics, colibacillus resistant to polymyxin antibiotics, pseudomonas aeruginosa resistant to polymyxin antibiotics, salmonella resistant to polymyxin antibiotics, shigella resistant to polymyxin antibiotics or klebsiella resistant to polymyxin antibiotics.
5. The use according to claim 1, characterized in that: the weight ratio of the antagonist to the polymyxin is 1:0.25-4.
6. The use according to claim 1, wherein the antagonist is administered in the form of an oral, injectable or topical formulation.
7. The use according to claim 1, wherein the antagonist is administered simultaneously, sequentially or separately with the polymyxin.
8. The use of claim 1, wherein the antagonist and the polymyxin agent are administered in an effective amount one or more times per day.
9. A pharmaceutical composition comprising a DRD2, DRDs or VDCCs antagonist selected from the group consisting of compounds shown below, and optionally a pharmaceutically acceptable carrier in combination with at least one polymyxin antibiotic One of them.
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