CN117462535A - Application of moracin M in preparation of medicines for inhibiting formation of bacterial biofilm - Google Patents
Application of moracin M in preparation of medicines for inhibiting formation of bacterial biofilm Download PDFInfo
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- CN117462535A CN117462535A CN202311442517.1A CN202311442517A CN117462535A CN 117462535 A CN117462535 A CN 117462535A CN 202311442517 A CN202311442517 A CN 202311442517A CN 117462535 A CN117462535 A CN 117462535A
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- LHPRYOJTASOZGJ-UHFFFAOYSA-N Moracin M Chemical compound O1C2=CC(O)=CC=C2C=C1C1=CC(O)=CC(O)=C1 LHPRYOJTASOZGJ-UHFFFAOYSA-N 0.000 title claims abstract description 46
- 230000001580 bacterial effect Effects 0.000 title claims abstract description 26
- 239000003814 drug Substances 0.000 title claims abstract description 26
- RTDFYRPWAYCBQQ-AZRHEHLBSA-N moracin M Natural products OC[C@H]1O[C@@H](Oc2ccc3C[C@H](Oc3c2)c4cc(O)cc(O)c4)[C@H](O)[C@@H](O)[C@@H]1O RTDFYRPWAYCBQQ-AZRHEHLBSA-N 0.000 title claims abstract description 23
- 230000015572 biosynthetic process Effects 0.000 title claims abstract description 14
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 12
- 238000002360 preparation method Methods 0.000 title claims abstract description 6
- 229940079593 drug Drugs 0.000 title abstract description 8
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 15
- 241000588747 Klebsiella pneumoniae Species 0.000 claims abstract description 14
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 241000191967 Staphylococcus aureus Species 0.000 claims description 11
- 241000894006 Bacteria Species 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 8
- 239000003112 inhibitor Substances 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 5
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 0.000 claims description 2
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims description 2
- 229920002253 Tannate Polymers 0.000 claims description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-M Trifluoroacetate Chemical compound [O-]C(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-M 0.000 claims description 2
- 229940077388 benzenesulfonate Drugs 0.000 claims description 2
- SRSXLGNVWSONIS-UHFFFAOYSA-M benzenesulfonate Chemical compound [O-]S(=O)(=O)C1=CC=CC=C1 SRSXLGNVWSONIS-UHFFFAOYSA-M 0.000 claims description 2
- 239000003937 drug carrier Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 229940049920 malate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 2
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 229940095064 tartrate Drugs 0.000 claims description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 229960003722 doxycycline Drugs 0.000 claims 1
- XQTWDDCIUJNLTR-CVHRZJFOSA-N doxycycline monohydrate Chemical compound O.O=C1C2=C(O)C=CC=C2[C@H](C)[C@@H]2C1=C(O)[C@]1(O)C(=O)C(C(N)=O)=C(O)[C@@H](N(C)C)[C@@H]1[C@H]2O XQTWDDCIUJNLTR-CVHRZJFOSA-N 0.000 claims 1
- 230000032770 biofilm formation Effects 0.000 abstract description 11
- 206010041925 Staphylococcal infections Diseases 0.000 abstract description 6
- MUUDYSFWQUSAOO-UHFFFAOYSA-N cudraflavone C Chemical compound CC(C)=CCC=1C(=O)C2=C(O)C(CC=C(C)C)=C(O)C=C2OC=1C1=CC=C(O)C=C1O MUUDYSFWQUSAOO-UHFFFAOYSA-N 0.000 abstract description 6
- 206010061259 Klebsiella infection Diseases 0.000 abstract description 5
- 208000032536 Pseudomonas Infections Diseases 0.000 abstract description 5
- 208000015339 staphylococcus aureus infection Diseases 0.000 abstract description 5
- UWQYBLOHTQWSQD-UHFFFAOYSA-N Mulberrin Natural products CC(C)=CCC1=C(O)C=C(O)C(C(C=2CC=C(C)C)=O)=C1OC=2C1=CC=C(O)C=C1O UWQYBLOHTQWSQD-UHFFFAOYSA-N 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract 1
- 230000003449 preventive effect Effects 0.000 abstract 1
- 229940126585 therapeutic drug Drugs 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 15
- 238000000338 in vitro Methods 0.000 description 13
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 210000003743 erythrocyte Anatomy 0.000 description 9
- 230000005764 inhibitory process Effects 0.000 description 9
- 239000002504 physiological saline solution Substances 0.000 description 9
- 239000000725 suspension Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 6
- 238000005406 washing Methods 0.000 description 6
- YXOLAZRVSSWPPT-UHFFFAOYSA-N Morin Chemical compound OC1=CC(O)=CC=C1C1=C(O)C(=O)C2=C(O)C=C(O)C=C2O1 YXOLAZRVSSWPPT-UHFFFAOYSA-N 0.000 description 5
- 230000000844 anti-bacterial effect Effects 0.000 description 5
- UXOUKMQIEVGVLY-UHFFFAOYSA-N morin Natural products OC1=CC(O)=CC(C2=C(C(=O)C3=C(O)C=C(O)C=C3O2)O)=C1 UXOUKMQIEVGVLY-UHFFFAOYSA-N 0.000 description 5
- 235000007708 morin Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 230000001988 toxicity Effects 0.000 description 5
- 231100000419 toxicity Toxicity 0.000 description 5
- 208000037581 Persistent Infection Diseases 0.000 description 4
- 238000010790 dilution Methods 0.000 description 4
- 239000012895 dilution Substances 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- XFFOMNJIDRDDLQ-UHFFFAOYSA-N morusin Chemical compound O1C2=C3C=CC(C)(C)OC3=CC(O)=C2C(=O)C(CC=C(C)C)=C1C1=CC=C(O)C=C1O XFFOMNJIDRDDLQ-UHFFFAOYSA-N 0.000 description 4
- 239000013642 negative control Substances 0.000 description 4
- HDHRTQZSBFUBMJ-UHFFFAOYSA-N Artonin E Natural products O1C2=C3C=CC(C)(C)OC3=CC(O)=C2C(=O)C(CC=C(C)C)=C1C1=CC(O)=C(O)C=C1O HDHRTQZSBFUBMJ-UHFFFAOYSA-N 0.000 description 3
- 102400000888 Cholecystokinin-8 Human genes 0.000 description 3
- 101800005151 Cholecystokinin-8 Proteins 0.000 description 3
- 102000004190 Enzymes Human genes 0.000 description 3
- 108090000790 Enzymes Proteins 0.000 description 3
- 239000006137 Luria-Bertani broth Substances 0.000 description 3
- 238000007605 air drying Methods 0.000 description 3
- 239000006161 blood agar Substances 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000012258 culturing Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000004043 dyeing Methods 0.000 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- WUBUWBUVAKMGCO-UHFFFAOYSA-N morusin Natural products CC(=CCC1=C(Cc2c3C=CC(C)(C)Oc3cc(O)c2C1=O)c4ccc(O)cc4O)C WUBUWBUVAKMGCO-UHFFFAOYSA-N 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- IZTQOLKUZKXIRV-YRVFCXMDSA-N sincalide Chemical compound C([C@@H](C(=O)N[C@@H](CCSC)C(=O)NCC(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(N)=O)NC(=O)[C@@H](N)CC(O)=O)C1=CC=C(OS(O)(=O)=O)C=C1 IZTQOLKUZKXIRV-YRVFCXMDSA-N 0.000 description 3
- 238000009631 Broth culture Methods 0.000 description 2
- AOJJSUZBOXZQNB-TZSSRYMLSA-N Doxorubicin Chemical compound O([C@H]1C[C@@](O)(CC=2C(O)=C3C(=O)C=4C=CC=C(C=4C(=O)C3=C(O)C=21)OC)C(=O)CO)[C@H]1C[C@H](N)[C@H](O)[C@H](C)O1 AOJJSUZBOXZQNB-TZSSRYMLSA-N 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- INVGWHRKADIJHF-UHFFFAOYSA-N Sanguinarin Chemical compound C1=C2OCOC2=CC2=C3[N+](C)=CC4=C(OCO5)C5=CC=C4C3=CC=C21 INVGWHRKADIJHF-UHFFFAOYSA-N 0.000 description 2
- 244000052616 bacterial pathogen Species 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000009089 cytolysis Effects 0.000 description 2
- 239000001963 growth medium Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- MSYGAHOHLUJIKV-UHFFFAOYSA-N 3,5-dimethyl-1-(3-nitrophenyl)-1h-pyrazole-4-carboxylic acid ethyl ester Chemical compound CC1=C(C(=O)OCC)C(C)=NN1C1=CC=CC([N+]([O-])=O)=C1 MSYGAHOHLUJIKV-UHFFFAOYSA-N 0.000 description 1
- 208000035143 Bacterial infection Diseases 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- FCEXWTOTHXCQCQ-UHFFFAOYSA-N Ethoxydihydrosanguinarine Natural products C12=CC=C3OCOC3=C2C(OCC)N(C)C(C2=C3)=C1C=CC2=CC1=C3OCO1 FCEXWTOTHXCQCQ-UHFFFAOYSA-N 0.000 description 1
- 241000588748 Klebsiella Species 0.000 description 1
- 206010057249 Phagocytosis Diseases 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 102000011017 Type 4 Cyclic Nucleotide Phosphodiesterases Human genes 0.000 description 1
- 108010037584 Type 4 Cyclic Nucleotide Phosphodiesterases Proteins 0.000 description 1
- 210000005091 airway smooth muscle Anatomy 0.000 description 1
- 230000001088 anti-asthma Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 229940124350 antibacterial drug Drugs 0.000 description 1
- 230000010100 anticoagulation Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 208000022362 bacterial infectious disease Diseases 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 231100000263 cytotoxicity test Toxicity 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000000916 dilatatory effect Effects 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000036737 immune function Effects 0.000 description 1
- 238000011534 incubation Methods 0.000 description 1
- 230000008595 infiltration Effects 0.000 description 1
- 238000001764 infiltration Methods 0.000 description 1
- 210000004969 inflammatory cell Anatomy 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000956 nontoxicity Toxicity 0.000 description 1
- 230000008782 phagocytosis Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 229940084560 sanguinarine Drugs 0.000 description 1
- YZRQUTZNTDAYPJ-UHFFFAOYSA-N sanguinarine pseudobase Natural products C1=C2OCOC2=CC2=C3N(C)C(O)C4=C(OCO5)C5=CC=C4C3=CC=C21 YZRQUTZNTDAYPJ-UHFFFAOYSA-N 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 230000008685 targeting Effects 0.000 description 1
- 230000007838 tissue remodeling Effects 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- 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
Landscapes
- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Epidemiology (AREA)
- Communicable Diseases (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of a moracin M in preparation of a medicament for inhibiting formation of a bacterial biofilm, and belongs to the field of biological medicines. A pharmaceutical preparation for inhibiting bacterial biofilm formation comprises Moracin M or its pharmaceutically acceptable salt, wherein Moracin M has formula C 25 H 24 O 6 The structural formula isProvides effective preventive and/or therapeutic drugs for forming biological films for pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus infection, and the preparation of the drugs for pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus infection related diseases or diseases by the mulberrin M, thereby having important clinical application potential.
Description
Technical Field
The invention belongs to the technical field of biological medicine, and particularly relates to application of a moracin M in preparation of a medicine for inhibiting formation of a bacterial biofilm.
Background
Bacterial biofilms are membrane-like structures formed by the adherence of polymeric substrates secreted by bacteria to the outside of the cell to the surface of the medium for encapsulation of themselves, and more than 70% of chronic refractory infections have been studied to be associated with resistance caused by the formation of biofilms by bacteria. Bacteria form a biological film and then adhere to the surface of an object, and the effective antibacterial concentration of the medicine in the biological film can not be achieved by limiting the medicine permeation, or the antibacterial efficacy of the antibacterial medicine is reduced by mechanisms such as affecting the pH value in the biological film and consequently affecting the dissociation degree of the medicine, so that the medicine resistance of the bacteria is obviously enhanced, and the bacterial chronic infection is caused. In addition, bacterial biofilms can also simultaneously reduce the immune function of the body and phagocytosis of cells. Overall, bacterial biofilm formation presents great difficulties in the clinical treatment of bacterial infections. Pseudomonas aeruginosa, klebsiella pneumoniae and Staphylococcus aureus are all important pathogenic bacteria causing clinical infection, and are common pathogenic bacteria capable of forming biofilm infection. Inhibiting the formation of bacterial biofilm is beneficial to reducing bacterial drug resistance and further improving the antibacterial efficacy of antibacterial drugs, and is expected to relieve the problems of bacterial drug resistance and chronic infection difficult to heal. In pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus infections, especially chronic infections, it is necessary to develop novel inhibitors targeting biofilms.
However, no biofilm inhibitors against pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus infection are successfully applied to clinic, and development of novel biofilm inhibitors is urgently needed. The Moracin M is a phenolic component in cortex Mori, can effectively inhibit phosphodiesterase 4, and has antiinflammatory activity. It was found that the anti-asthmatic effect of the moracin M may be exerted by improving airway epithelial function, dilating airway smooth muscle, improving body antioxidant capacity, inhibiting inflammatory cell infiltration, inhibiting airway tissue remodeling, but the inhibition effect of the moracin M on the formation of biofilms of pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus has not been studied and reported yet.
Disclosure of Invention
The invention aims to provide application of the moracin M in preparing a medicine for inhibiting bacterial biofilm formation, provides an effective medicine for preventing and/or treating bacterial biofilm formation caused by pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus infection, and also provides a medicine for treating diseases or conditions related to the pseudomonas aeruginosa, the klebsiella pneumoniae and the staphylococcus aureus infection.
The above object of the present invention is achieved by the following technical solutions:
the invention provides an application of a Morusin M or a pharmaceutically acceptable salt thereof in preparing medicines for inhibiting bacterial biofilm formation, wherein the Morusin M (Morusin, CAS number 62596-29-6) has a molecular formula of C 25 H 24 O 6 The structural formula is
Preferably, the bacteria are selected from one or more of pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus.
Preferably, the pharmaceutically acceptable salt of the morin M is selected from one or more of hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluenesulfonic acid or benzenesulfonate.
The present invention also provides a pharmaceutical composition comprising a therapeutically effective amount of the sanguinin M and/or a pharmaceutically acceptable salt thereof.
Preferably, the concentration of the doxorubicine M in the pharmaceutical composition is 0.01-100ug/mL.
Preferably, the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient, and can be prepared into injection, emulsion, tablet, powder, granule, ointment, liposome or oral liquid.
The present invention also provides a biofilm inhibitor comprising a therapeutically effective amount of moracin M and/or a pharmaceutically acceptable salt thereof.
Compared with the prior art, the invention has the beneficial effects that:
the invention provides the application of the moracin M in preparing medicines for inhibiting the formation of bacterial biofilms, provides potential inhibitors for the formation of the biofilms of pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus, and improves the treatment effect of antibacterial medicines; meanwhile, the composition can also prevent or treat difficult-to-heal chronic infection caused by the formation of biological films of pseudomonas aeruginosa, klebsiella pneumoniae and staphylococcus aureus, and has important clinical application potential.
Drawings
FIG. 1 shows that the inhibition of P.aeruginosa biofilm formation by the moracin M in vitro is shown in the examples.
FIG. 2 shows that the Mortierein M inhibits Klebsiella pneumoniae biofilm formation in vitro in the examples.
FIG. 3 shows the in vitro inhibition of Staphylococcus aureus biofilm formation by Phellinin M in the examples.
FIG. 4 shows the results of in vitro toxicity test of the sanguinarine on A549 cells in the examples.
FIG. 5 shows the results of in vitro toxicity of the haemagglutinin to erythrocytes in the examples.
Detailed Description
The invention is further illustrated by the following examples:
example 1: inhibition of P.aeruginosa biofilm formation by Phellinin M in vitro
(1) The frozen pseudomonas aeruginosa is recovered, and single colony is divided and purified by a blood agar plate, and cultured overnight in an incubator at 37 ℃.
(2) The single colony with good growth was obtained, and the bacteria solution was adjusted to about 0.5 McO (about 10) 8 CFU/mL), and then diluted 1000 times to give a final concentration of about 10 5 CFU/mL。
(3) Phellinin M was subjected to gradient dilution using LB broth, at concentrations of 7 concentration gradients of 20ug/mL, 10ug/mL, 5ug/mL, 2.5ug/mL, 1.25ug/mL, 0.625ug/mL, 0.3125ug/mL, respectively. Mixing diluted Phellinin M with diluted bacterial suspension in equal volume, adding into cell pore plate, making 3 repeated holes for each concentration, setting the holes without adding medicine and bacterial suspension as negative control, setting the holes without adding medicine and bacterial suspension as blank control, and placing into a 37 deg.C incubator.
(4) After culturing for 24 hours, the liquid in the well plate was poured out and washed 3 times with physiological saline.
(5) Adding methanol, fixing for 10min, washing with physiological saline for 3 times, dyeing with 2% crystal violet for 10min, and washing with physiological saline for 3 times.
(6) After air drying, 30% acetic acid was added to dissolve the biofilm, and the OD570 value was measured with an enzyme-labeled instrument.
The inhibition experimental result is shown in figure 1, which shows that the moracin M can effectively inhibit the formation of a pseudomonas aeruginosa biofilm in vitro and has concentration dependence.
Example 2: inhibition of Klebsiella pneumoniae biofilm formation by Phellinin M in vitro
(1) The frozen Klebsiella inflammatories are recovered, blood agar plates are divided into single colony for purity, and the single colony is cultured overnight in a 37 ℃ incubator.
(2) The single colony with good growth was obtained, and the bacteria solution was adjusted to about 0.5 McO (about 10) 8 CFU/mL), and then diluted 1000 times to give a final concentration of about 10 5 CFU/mL。
(3) Gradient dilution is carried out on the morin M by using LB broth culture medium, the concentrations are 40ug/mL, 20ug/mL and 10ug/mL respectively, the diluted morin M and diluted bacterial suspension are mixed in equal volume, the mixture is added into a cell pore plate, 3 repeated holes are formed in each concentration, a hole without adding medicine and only with bacterial suspension is set as a negative control, a hole without adding medicine and also without adding bacterial suspension is set as a blank control, and the mixture is placed in a 37 ℃ incubator.
(4) After culturing for 24 hours, the liquid in the well plate was poured out and washed 3 times with physiological saline.
(5) Adding methanol, fixing for 10min, washing with physiological saline for 3 times, dyeing with 2% crystal violet for 10min, and washing with physiological saline for 3 times.
(6) After air drying, 30% acetic acid was added to dissolve the biofilm, and the OD570 value was measured with an enzyme-labeled instrument.
The inhibition experimental results are shown in figure 2, which show that the moracin M can effectively inhibit the formation of a pseudomonas aeruginosa biofilm in vitro and has concentration dependence.
Example 3: inhibition of Staphylococcus aureus biofilm formation by Phellinin M in vitro
(1) The frozen staphylococcus aureus is resuscitated, single colony is divided and purified by a blood agar plate, and the frozen staphylococcus aureus is placed in a 37 ℃ incubator for overnight culture.
(2) The single colony with good growth was obtained, and the bacteria solution was adjusted to about 0.5 McO (about 10) 8 CFU/mL), and then diluted 1000 times to give a final concentration of about 10 5 CFU/mL。
(3) Gradient dilution is carried out on the morin M by using LB broth culture medium, the concentrations are 40ug/mL, 20ug/mL and 10ug/mL respectively, the diluted morin M and diluted bacterial suspension are mixed in equal volume, the mixture is added into a cell pore plate, 3 repeated holes are formed in each concentration, a hole without adding medicine and only with bacterial suspension is set as a negative control, a hole without adding medicine and also without adding bacterial suspension is set as a blank control, and the mixture is placed in a 37 ℃ incubator.
(4) After culturing for 24 hours, the liquid in the well plate was poured out and washed 3 times with physiological saline.
(5) Adding methanol, fixing for 10min, washing with physiological saline for 3 times, dyeing with 2% crystal violet for 10min, and washing with physiological saline for 3 times.
(6) After air drying, 30% acetic acid was added to dissolve the biofilm, and the OD570 value was measured with an enzyme-labeled instrument.
The inhibition experimental results are shown in figure 3, which show that the mulberrin M can effectively inhibit the formation of a staphylococcus aureus biofilm in vitro and has concentration dependence.
Example 4: toxicity detection of Phellinin M on A549 cells
(1) A549 cells were plated into 96-well plates to give a cell count of 2×10 per well 4 And (3) placing the mixture in an incubator at 37 ℃ for overnight culture.
(2) The concentration of the mulberrin M was 10 concentration gradients of 80ug/mL, 40ug/mL, 20ug/mL, 10ug/mL, 5ug/mL, 2.5ug/mL, 1.25ug/mL, 0.625ug/mL, 0.3125ug/mL, etc., respectively, by gradient dilution with 2% FBSDMEM.
(3) The same volume of the moracin M with each concentration is added into the A549 cells cultured overnight, 3 repeated holes are arranged on each drug concentration, no cell adding holes are arranged as blank control, and the cells are placed in a 37 ℃ incubator for incubation.
(4) After 1 day, toxicity of the sanguinin M to A549 cells was detected using CCK8, the CCK8 reagent was diluted to 5% detection solution, and then 96-well plates were added, 100 μl per well; the 96-well plate to which CCK8 assay was added was incubated at 37℃for about 1.5 hours, and OD450 per well was measured.
As shown in FIG. 4, the cytotoxicity test result shows that the Phellinin M has almost no toxicity to A549 cells in vitro, and the A549 cells have almost no damage under the action of 40ug/mL of Phellinin M.
Example 5: toxicity detection of Phellinin M on erythrocytes
(1) Blood was collected into EDTA anticoagulation tubes, mixed upside down, centrifuged at 3000rpm for 15min, the supernatant was discarded, and bottom red blood cells were resuspended to 2% concentration with PBS for use.
(2) Phellinin M was gradient diluted with PBS at concentrations of 6 concentration gradients of 80ug/mL, 40ug/mL, 20ug/mL, 10ug/mL, 5ug/mL, 2.5ug/mL, respectively.
(3) The above concentrations of the moracin M were mixed with the same volume of resuspended erythrocytes, triton X-100 treated as positive control, PBS treated as negative control, 3 duplicate wells were all placed and incubated in a 37℃incubator.
(4) After 24 hours, each treatment group of erythrocytes was added to a 96-well plate.
(5) Centrifugation at 4000rpm for 10min, aspiration of the supernatant into a new 96-well plate, measurement of OD560 per well and calculation of erythrocyte activity.
As shown in FIG. 5, the results of the erythrocyte lysis experiment show that the moracin M has almost no in vitro toxicity to erythrocytes, and 40ug/mL of moracin M has almost no lysis effect to erythrocytes.
The foregoing is a preferred embodiment of the present invention, but the present invention should not be limited to the disclosure of this embodiment. So that equivalents and modifications will fall within the scope of the invention, all within the spirit and scope of the invention as disclosed.
Claims (7)
1. Use of a compound of the formula of Phellinin M or a pharmaceutically acceptable salt thereof for the preparation of a medicament for inhibiting the formation of a bacterial biofilm, wherein the molecular formula of Phellinin M is C 25 H 24 O 6 The structural formula is
2. The use according to claim 1, wherein the bacteria are selected from one or more combinations of pseudomonas aeruginosa, klebsiella pneumoniae, staphylococcus aureus.
3. The use according to claim 1, wherein the pharmaceutically acceptable salt of the doxin M is selected from one or more of hydrochloride, hydrobromide, sulfate, acetate, lactate, tartrate, tannate, citrate, trifluoroacetate, malate, maleate, succinate, p-toluene sulfonic acid or benzenesulfonate.
4. A pharmaceutical composition comprising a therapeutically effective amount of a compound of the formula moracin M and/or a pharmaceutically acceptable salt thereof, wherein moracin M has the formula C 25 H 24 O 6 The structural formula is
5. The pharmaceutical composition of claim 4, wherein the concentration of the doxycycline M in the pharmaceutical composition is 0.01-100ug/mL.
6. The pharmaceutical composition of claim 4, further comprising a pharmaceutically acceptable carrier or excipient, and wherein the pharmaceutical composition is formulated as an injection, emulsion, tablet, powder, granule, ointment, liposome, or oral liquid.
7. A biofilm inhibitor comprising a therapeutically effective amount of a moracin M and/or a pharmaceutically acceptable salt thereof, wherein the moracin M has the formula C 25 H 24 O 6 The structural formula is
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| CN202311442517.1A CN117462535A (en) | 2023-11-01 | 2023-11-01 | Application of moracin M in preparation of medicines for inhibiting formation of bacterial biofilm |
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