CN112438989A - Non-antibiotic antibacterial composition and application thereof - Google Patents
Non-antibiotic antibacterial composition and application thereof Download PDFInfo
- Publication number
- CN112438989A CN112438989A CN202011418654.8A CN202011418654A CN112438989A CN 112438989 A CN112438989 A CN 112438989A CN 202011418654 A CN202011418654 A CN 202011418654A CN 112438989 A CN112438989 A CN 112438989A
- Authority
- CN
- China
- Prior art keywords
- auranofin
- pentamidine
- antibacterial
- bacteria
- gram
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 230000000844 anti-bacterial effect Effects 0.000 title claims abstract description 38
- 230000001937 non-anti-biotic effect Effects 0.000 title claims abstract description 17
- 239000000203 mixture Substances 0.000 title claims abstract description 15
- 239000003814 drug Substances 0.000 claims abstract description 60
- AUJRCFUBUPVWSZ-XTZHGVARSA-M auranofin Chemical compound CCP(CC)(CC)=[Au]S[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O AUJRCFUBUPVWSZ-XTZHGVARSA-M 0.000 claims abstract description 59
- 229960005207 auranofin Drugs 0.000 claims abstract description 58
- XDRYMKDFEDOLFX-UHFFFAOYSA-N pentamidine Chemical compound C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 XDRYMKDFEDOLFX-UHFFFAOYSA-N 0.000 claims abstract description 50
- 229960004448 pentamidine Drugs 0.000 claims abstract description 50
- 229940079593 drug Drugs 0.000 claims abstract description 46
- 241000894006 Bacteria Species 0.000 claims abstract description 42
- 241000233866 Fungi Species 0.000 claims abstract description 16
- 241000588724 Escherichia coli Species 0.000 claims description 10
- 241000588626 Acinetobacter baumannii Species 0.000 claims description 8
- 241000588915 Klebsiella aerogenes Species 0.000 claims description 5
- 241000191967 Staphylococcus aureus Species 0.000 claims description 5
- 241000589291 Acinetobacter Species 0.000 claims description 4
- 241000222122 Candida albicans Species 0.000 claims description 4
- 229940092559 enterobacter aerogenes Drugs 0.000 claims description 4
- 241000192125 Firmicutes Species 0.000 claims description 3
- 230000000845 anti-microbial effect Effects 0.000 claims description 3
- 229940095731 candida albicans Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 abstract description 11
- 230000002195 synergetic effect Effects 0.000 abstract description 9
- 230000005764 inhibitory process Effects 0.000 abstract description 5
- 238000012827 research and development Methods 0.000 abstract description 5
- 230000035755 proliferation Effects 0.000 abstract description 3
- 230000002147 killing effect Effects 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 16
- 230000001580 bacterial effect Effects 0.000 description 12
- 229940124350 antibacterial drug Drugs 0.000 description 8
- 230000000694 effects Effects 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 4
- 206010018910 Haemolysis Diseases 0.000 description 4
- 239000003242 anti bacterial agent Substances 0.000 description 4
- 238000012258 culturing Methods 0.000 description 4
- 239000000890 drug combination Substances 0.000 description 4
- 230000001954 sterilising effect Effects 0.000 description 4
- 238000004659 sterilization and disinfection Methods 0.000 description 4
- 230000005540 biological transmission Effects 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000000034 method Methods 0.000 description 3
- 241001232615 Acinetobacter baumannii ATCC 19606 = CIP 70.34 = JCM 6841 Species 0.000 description 2
- 108010077805 Bacterial Proteins Proteins 0.000 description 2
- 206010059866 Drug resistance Diseases 0.000 description 2
- 241000588747 Klebsiella pneumoniae Species 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000000996 additive effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 230000007123 defense Effects 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 210000003743 erythrocyte Anatomy 0.000 description 2
- 230000008588 hemolysis Effects 0.000 description 2
- 230000002949 hemolytic effect Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- YBVNFKZSMZGRAD-UHFFFAOYSA-N pentamidine isethionate Chemical compound OCCS(O)(=O)=O.OCCS(O)(=O)=O.C1=CC(C(=N)N)=CC=C1OCCCCCOC1=CC=C(C(N)=N)C=C1 YBVNFKZSMZGRAD-UHFFFAOYSA-N 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 208000000230 African Trypanosomiasis Diseases 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000006820 Arthralgia Diseases 0.000 description 1
- 241000223836 Babesia Species 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000004554 Leishmaniasis Diseases 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
- 206010034133 Pathogen resistance Diseases 0.000 description 1
- 208000005384 Pneumocystis Pneumonia Diseases 0.000 description 1
- 206010073755 Pneumocystis jirovecii pneumonia Diseases 0.000 description 1
- 108010040201 Polymyxins Proteins 0.000 description 1
- 229920004890 Triton X-100 Polymers 0.000 description 1
- 239000013504 Triton X-100 Substances 0.000 description 1
- 241000223105 Trypanosoma brucei Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000003042 antagnostic effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 230000003356 anti-rheumatic effect Effects 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000003435 antirheumatic agent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 201000008680 babesiosis Diseases 0.000 description 1
- 230000003385 bacteriostatic effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000010611 checkerboard assay Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- PCHJSUWPFVWCPO-UHFFFAOYSA-N gold Chemical compound [Au] PCHJSUWPFVWCPO-UHFFFAOYSA-N 0.000 description 1
- 239000010931 gold Substances 0.000 description 1
- 229910052737 gold Inorganic materials 0.000 description 1
- 208000029080 human African trypanosomiasis Diseases 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960003085 meticillin Drugs 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 244000052769 pathogen Species 0.000 description 1
- 229960001624 pentamidine isethionate Drugs 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 201000000317 pneumocystosis Diseases 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000001243 protein synthesis Methods 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 201000002612 sleeping sickness Diseases 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000007480 spreading Effects 0.000 description 1
- 238000003892 spreading Methods 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000008961 swelling Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 108700012359 toxins Proteins 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7135—Compounds containing heavy metals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Communicable Diseases (AREA)
- Epidemiology (AREA)
- Oncology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
The invention discloses a non-antibiotic antibacterial composition and application thereof. The invention combines two non-antibiotic medicines of auranofin and pentamidine as antibacterial medicines, and provides a brand new thought for the research and development of the antibacterial medicines. The invention discloses that the combination of auranofin and pentamidine can make the antibacterial performance of the medicine play a synergistic effect, which not only reduces the minimum inhibitory concentration of auranofin and pentamidine to bacteria and fungi, but also has very obvious inhibition, proliferation and killing effects to gram-negative bacteria and fungi. In addition, the non-antibiotic antibacterial composition has an inhibiting effect on various clinically common bacteria and fungi, and compared with single application of auranofin and pentamidine, the broad-spectrum antibacterial activity of the composition is improved.
Description
Technical Field
The invention relates to the technical field of antibacterial medicines, in particular to application of a non-antibiotic antibacterial composition.
Background
In recent years, the number of multi-drug resistant bacteria clinically discovered has increased, and the drug resistance of bacteria to various antibiotics has also increased. Bacterial antibiotic resistance has become a very serious global problem today, even with the antibiotic polymyxin, which is the last line of defense for multi-drug resistant gram-negative bacteria, drug resistant strains have been discovered and the plasmid transmission mechanism leads to rapid transmission of resistance, meaning that the last line of defense is about to be breached, also suggesting a true pan-resistant infection. Therefore, there is an urgent need to develop effective novel antibacterial agents, particularly antibacterial agents against gram-negative bacteria. However, the development of new antibiotics is not only expensive but also time consuming and difficult to cope with fast spreading and transmission of bacterial resistance. The 'old medicine new use' is a solution with great potential for solving the drug resistance of bacteria, but the developed 'old medicine new use' antibacterial drugs are generally simple 'reuse' of non-antibacterial drugs which are already on the market, and the antibacterial performance of the antibacterial drugs is generally not ideal or the antibacterial spectrum is narrow.
Auranofin (CAS registry number: 34031-32-8) is a gold-containing oral drug on the market, mainly used for the treatment of rheumatoid arthritis. It can improve symptoms of arthritis, including joint pain, swelling, etc. Recent studies have shown that auranofin has certain effects of inhibiting the synthesis of cell walls, DNA and bacterial proteins at clinically useful concentrations. Thangamani et al found through studies that the ability of auranofin to inhibit bacterial protein synthesis resulted in a significant reduction in the production of methicillin-resistant Staphylococcus aureus (MRSA) toxins. (Thangamani s.et al.antibacterial activity and mechanism of action of aurain against multi-drug resistance bacterium pathogens [ J ]. Scientific Reports,2016,6: 22571.). However, there are few studies on the antibacterial activity of auranofin against gram-negative bacteria or fungi.
Pentamidine (CAS registry number: 140-64-7) is a marketed antiparasitic drug, and is mainly used for treating African trypanosomiasis, Leishmaniasis, babesia, and preventing and treating pneumocystis pneumonia of immunocompromised patients.
The new application of the old medicine is the approval of new treatment application of the medicine, can reduce the medicine cost, effectively shortens the time of research and development and approval of the medicine, and is easier to realize than the research and development of a new medicine. The auranofin and pentamidine are the marketed drugs, can enter a clinical test stage more quickly when developing new application of the auranofin and pentamidine, and have important significance for the research of 'new application of old drugs'.
Disclosure of Invention
The present invention aims to overcome the above-mentioned drawbacks and deficiencies of the prior art and to provide a non-antibiotic antibacterial composition.
The second purpose of the invention is to provide an application of a non-antibiotic antibacterial composition in preparing antibacterial drugs.
The above object of the present invention is achieved by the following technical solutions:
a non-antibiotic antibacterial composition comprises auranofin and pentamidine.
The invention creatively combines the non-antibiotic anti-parasite medicine pentamidine and the non-antibiotic anti-rheumatism medicine auranofin with certain antibacterial ability. The combination of auranofin and pentamidine disclosed by the invention has a synergistic effect on antibacterial action, and the composition has good broad-spectrum antibacterial activity, and also provides a brand new thought for the research and development of antibacterial drugs.
Preferably, the concentration of the auranofin is 0.03-62.5 mug/mL; the concentration of pentamidine is 0.25-62.5 mug/mL.
The invention also provides application of the non-antibiotic antibacterial composition in preparation of antibacterial drugs.
Preferably, the bacteria are bacteria and/or fungi.
Further preferably, the bacteria are gram-negative and/or gram-positive bacteria;
more preferably, the gram-negative bacteria are sensitive gram-negative bacteria and/or drug-resistant gram-negative bacteria.
More preferably, the sensitive gram-negative bacteria is any one or more of sensitive escherichia coli, sensitive acinetobacter baumannii and enterobacter aerogenes.
More preferably, the drug-resistant gram-negative bacterium is any one or more of drug-resistant escherichia coli, drug-resistant acinetobacter baumannii and pneumococcus.
More preferably, the gram positive bacterium is staphylococcus aureus.
More preferably, the fungus is candida albicans.
Compared with the prior art, the invention has the following beneficial effects:
the invention creatively combines the pentamidine and the non-antibiotic antirheumatic medicament auranofin with certain antibacterial capacity, finds that the synergistic effect of the combined use of the auranofin and the pentamidine on the antibacterial action, not only reduces the Minimum Inhibitory Concentration (MIC) of the auranofin and the pentamidine, improves the inhibitory and proliferation effects of the auranofin and the pentamidine on gram-negative bacteria and fungi, but also improves the sterilization effects on the gram-negative bacteria, the gram-positive bacteria and the fungi. Meanwhile, the pharmaceutical composition has an inhibiting effect on various clinically common bacteria and fungi, and compared with auranofin, the broad-spectrum antibacterial property of the pharmaceutical composition is improved. Meanwhile, the invention provides a brand new idea for the research and development of antibacterial drugs by combining two non-antibiotic drugs of auranofin and pentamidine as the antibacterial drugs.
Drawings
FIG. 1 is a schematic of dosing in a 96-well plate.
Fig. 2 is a chessboard test of auranofin in combination with pentamidine against (a) sensitive gram-negative bacteria escherichia coli (e.coli), acinetobacter baumannii 19606(a.baumannii 19606), enterobacter aerogenes (e.aerogens); (b) drug-resistant gram-negative bacteria escherichia coli (e.coli-1), acinetobacter baumannii 1789(a.baumannii-1789), and bacillus pneumoniae (k.pneumoniae-1); (c) gram positive bacteria staphylococcus aureus (s.aureus); (d) synergistic antibacterial action of clinically isolated fungi Candida albicans (Candida albicans-1, Candida albicans-2). MIC: minimum inhibitory concentration; FICI: fractional inhibition concentration index. The darker the color block, the higher the concentration of bacteria, and the poorer the antibacterial effect.
Fig. 3 is a graph showing the inhibition curves of pentamidine, auranofin and combination of the two drugs against multiple drug-resistant a.baumann ni-1789.
Figure 4 is a graph of the bactericidal kinetics of pentamidine, auranofin, and combination dosing against multiple drug resistant acinetobacter baumannii-1789 at different concentrations.
FIG. 5 is a graph of (a) the percentage hemolysis (250. mu.g/mL auranofin) of pentamidine concentration changes when the drugs are combined; (b) percent hemolytic (containing 250. mu.g/mL pentamidine) at varying concentrations of auranofin.
Detailed Description
The invention is further described with reference to the drawings and the following detailed description, which are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated.
Unless otherwise indicated, reagents and materials used in the following examples are commercially available.
Example 1 checkerboard assay for bacterial inhibition by combination of auranofin and pentamidine
1.1 drugs and strains
Medicine preparation: auranofin was purchased from eboantibody shanghai trade ltd and pentamidine isethionate was purchased from Dalian Meiren Biotechnology ltd.
The strain is as follows: sensitive escherichia coli (e.coli), acinetobacter baumannii (a.baumann 19606, a.baumann 1789), enterobacter aerogenes (e.aerogenes), staphylococcus aureus (s.aureus), all of which were purchased from ATCC; drug-resistant Escherichia coli (E.coli-1) and drug-resistant Klebsiella pneumoniae (K.pneumoconiae-1) were awarded by professor of Tian Bao of Chinese college of Zhongshan university, and Candida albicans (Candida albicans-1 and Candida albicans-2) were awarded by professor of Lusha, Sun Yixian Hospital.
The drugs and the strains adopted by the invention are obtained by the methods described above.
1.2 Experimental methods
The bacteria described in 1.1 were inoculated into MHB medium and incubated overnight at 150rpm in a constant temperature shaker at 37 ℃. According to the difference of MIC of each strain of the two drugs, the MIC value of the drug alone is taken as the highest concentration, and the two drugs are sequentially diluted by MHB culture solution containing 10% DI for twice continuously until a series of gradient concentrations are obtained. Each strain was prepared from 3 blank 96-well plates (see figure 1),adding 50 μ L of MHB culture solution containing 10% DI into each well of row H and column 1 as blank control, adding 50 μ L of pentamidine solution from row A to row G, adding 50 μ L of auranofin solution from column 12 to column 2, and adding 100 μ L of 10-concentration MHB solution into each well5Each CFU/mL bacterial solution was cultured overnight at 37 ℃ and 150rpm, and the growth of the bacteria was measured at an OD of 600 nm.
The above MHB medium was replaced with YMB medium for fungal inoculation.
The in vitro antibacterial effect of auranofin (auranofin) and pentamidine (pentamidine) on clinically common bacteria and fungi was tested by the chessboard method (see fig. 2), and the Minimum Inhibitory Concentration (MIC) of the two drugs used alone and the Minimum Inhibitory Concentration (MIC) of the two drugs used in combination were measured, and the results are shown in table 1. The results show that the two drugs are not highly active against bacteria and fungi when used alone, but can greatly reduce the minimum inhibitory concentration when used in combination.
Meanwhile, we calculate the Fractional Inhibitory Concentration Index (FICI) of the two drugs when used in combination according to formula (1). When FICI is less than or equal to 0.5, the drug combination is considered to have a synergistic effect (synergy); when 0.5< FICI is less than or equal to 1.0, the pharmaceutical composition is considered to have an additive effect (additive); when FICI ≧ 4, the drug combinations are considered antagonistic to each other. As can be seen from the graph 2 and the table 1, the combination of the auranofin and the pentamidine has synergistic antibacterial effect on almost all tested bacteria and fungi, the pentamidine reduces the MIC of the auranofin on the bacteria or the fungi by 2-32 times, and the antibacterial activity is obviously enhanced. The antibacterial activity of the drug is particularly remarkable when the drug is used for treating multiple drug-resistant acinetobacter baumannii-1789, and the FICI is far lower than 0.5(FICI is 0.094).
In conclusion, the results of in vitro antibacterial experiments show that the pentamidine or auranofin has poor curative effect on common clinical bacteria and fungi when being singly administered, and the pentamidine or auranofin shows excellent antibacterial effect when being used in combination, thereby having obvious synergistic effect.
TABLE 1 synergistic antibacterial evaluation of combination of auranofin and pentamidine against different bacteria
Example 2 determination of the inhibition curves of combination of auranofin and pentamidine on multiple drug resistant A.baumann ni 1789 A.baumann
The MHB diluted auranofin (2.0,3.9,7.8,15.6 mu g/mL) and pentamidine (125 mu g/mL) and their drug combination (pentamidine 125 mu g/mL + auranofin 2.0,3.9,7.8,15.6 mu g/mL) and the blank group was MHB culture solution without drug, 10 was added5Culturing the CFU/mL bacterial solution at 37 ℃ and 150rpm, and detecting the growth condition of the multiple drug-resistant Acinetobacter baumannii A.baumannii 1789 at different concentrations for 0-8 h and 24h when the absorbance value is 600 nm.
As can be seen from fig. 3, pentamidine slowed the rate of bacterial growth but was not completely inhibited when compared to the blank control group when administered with auranofin alone, and substantially inhibited the bacterial growth when the auranofin reached a higher concentration of 15.6 μ g/mL, indicating that neither drug alone was sufficiently antimicrobial to completely kill the bacteria. In contrast, when auranofin was administered in combination with pentamidine, auranofin completely prevented bacterial growth even at 2 μ g/mL, showing complete bacteriostatic effects (the curves of the pentamidine and auranofin combination groups were all overlapped). Thus, the combination of auranofin and pentamidine completely inhibited bacterial growth and proliferation compared to the single administration.
Example 3 bactericidal kinetics assay of multiple drug resistant Acinetobacter baumannii 1789 with combination of auranofin and pentamidine
Bactericidal kinetics detection of multiple drug-resistant acinetobacter baumannii-1789: dilution of auranofin (2.0, 15.6. mu.g/mL) with pentamidine (125. mu.g/mL) and their drug combinations (pentamidine 125. mu.g/mL + auranofin 2.0. mu.g/mL) with MHB, blank controlThe group is MHB culture solution without medicine, and the concentration of the MHB culture solution added with the medicine is 105Placing the CFU/mL bacterial solution in a constant temperature shaking table, culturing at 37 ℃ and 150rpm, taking 10 mu L bacterial solution for dilution to an appropriate multiple at 0,0.5,1,2,4,8 and 24 hours, smearing on an agar plate, culturing at 37 ℃ for 24 hours, and counting.
As seen in FIG. 4, pentamidine (125. mu.g/mL) and auranofin (2.0. mu.g/mL) administered alone were not able to inhibit bacterial growth, with a growth trend similar to that of the untreated control blank. The auroform (15.6 mu g/mL) has obvious bacterial killing effect after being singly administered for 24 hours, and the sterilization rate is about 97 percent. However, when the concentration of the auranofin in the pharmaceutical composition is 2.0 mug/mL when the auranofin is used together with pentamidine (125 mug/mL), the pharmaceutical composition can completely kill bacteria within 4 hours, the sterilization rate is more than 99 percent, and a good synergistic sterilization effect is shown. Therefore, the experimental results show that the medicinal combination of auranofin and pentamidine can completely kill bacteria.
Example 4 hemolytic experiments of auranofin and pentamidine
Fixing the concentration of auranofin or pentamidine to 250 μ g/mL, continuously diluting another drug concentration with PBS twice at the maximum drug concentration of 250 μ g/mL, mixing 250 μ L of each drug, adding 500 μ L of collected mouse red blood cell solution, culturing at 37 deg.C for 2 hours with PBS as negative control and Triton X-100 as positive control. Centrifuging at 2200rpm at room temperature for 5min, collecting supernatant 100 μ L to 96-well plate, and detecting at absorbance value of 570 nm.
The result shows that no obvious hemolytic reaction exists when the pentamidine with the concentration of 250 mug/mL and the auranofin with the concentration of 0-250 mug/mL are used together; the combination of auranofin with the concentration of 250 mug/mL and pentamidine with the concentration of 0-250 mug/mL has no obvious hemolytic reaction. Thus, the composition of auranofin and pentamidine does not produce hemolysis, has little toxicity to mouse red blood cell solution, and shows good blood compatibility (see figure 5).
Claims (10)
1. A non-antibiotic antimicrobial composition comprising auranofin and pentamidine.
2. The non-antibiotic antimicrobial composition of claim 1, wherein the concentration of auranofin is 0.03-62.5 μ g/mL; the concentration of pentamidine is 0.25-62.5 mug/mL.
3. Use of a non-antibiotic antibacterial composition according to any one of claims 1 to 2 in the manufacture of an antibacterial medicament.
4. Use according to claim 3, wherein the bacteria are bacteria and/or fungi.
5. The use according to claim 4, wherein the bacteria are gram-negative or gram-positive bacteria.
6. The use of claim 4, wherein the fungus is Candida albicans.
7. The use according to claim 5, wherein the gram-negative bacteria are sensitive and/or resistant gram-negative bacteria.
8. Use according to claim 5, wherein the gram-positive bacterium is Staphylococcus aureus.
9. The use according to claim 7, wherein the sensitive gram-negative bacteria is any one or more of sensitive Escherichia coli, sensitive Acinetobacter baumannii and Enterobacter aerogenes.
10. The use of claim 7, wherein the drug-resistant gram-negative bacteria is any one or more of drug-resistant Escherichia coli, drug-resistant Acinetobacter baumannii and Acinetobacter pneumoniae.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011418654.8A CN112438989B (en) | 2020-12-07 | 2020-12-07 | Non-antibiotic antibacterial composition and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011418654.8A CN112438989B (en) | 2020-12-07 | 2020-12-07 | Non-antibiotic antibacterial composition and application thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112438989A true CN112438989A (en) | 2021-03-05 |
| CN112438989B CN112438989B (en) | 2021-10-12 |
Family
ID=74739657
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011418654.8A Active CN112438989B (en) | 2020-12-07 | 2020-12-07 | Non-antibiotic antibacterial composition and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112438989B (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102458543A (en) * | 2009-05-18 | 2012-05-16 | 3M创新有限公司 | Dry powder inhalers |
| CN105476984A (en) * | 2016-01-15 | 2016-04-13 | 四川医科大学 | Application of oridonin or derivative thereof to preparation of antibiotic sensitizer |
-
2020
- 2020-12-07 CN CN202011418654.8A patent/CN112438989B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102458543A (en) * | 2009-05-18 | 2012-05-16 | 3M创新有限公司 | Dry powder inhalers |
| CN105476984A (en) * | 2016-01-15 | 2016-04-13 | 四川医科大学 | Application of oridonin or derivative thereof to preparation of antibiotic sensitizer |
Non-Patent Citations (2)
| Title |
|---|
| MARIANA FELTRIN CANEVER等: "Screening and Identification of Pathogen Box® Compounds with anti-Trypanosoma evansi Activity", 《ACTA TROPICA》 * |
| RODOLFO GARCÍA-CONTRERAS等: "Editorial: Drug Re-purposing for the Treatment of Bacterial and Viral Infections", 《FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY》 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN112438989B (en) | 2021-10-12 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Michalopoulos et al. | The revival of fosfomycin | |
| RU2560846C1 (en) | Pharmaceutical compositions, containing sulbactam and beta-lactamase inhibitor | |
| CN115869306A (en) | Application of IOWH-032 in preparation of medicines for resisting gram-positive bacterial infection | |
| Chin et al. | Synergy of ciprofloxacin and azlocillin in vitro and in a neutropenic mouse model of infection | |
| Hoppe et al. | Comparison of erythromycin ethylsuccinate and co-trimoxazole for treatment of pertussis | |
| JPWO2010147145A1 (en) | Anti-gram negative bacteria agent | |
| CN110269857A (en) | Bactericidal composition of the Batan containing AVM hereinafter and application thereof | |
| EP2714034B1 (en) | Compositions comprising cefepime and tazobactam | |
| Kuck et al. | In vitro and in vivo activity of piperacillin, a new broad-spectrum semisynthetic penicillin | |
| CN112438989B (en) | Non-antibiotic antibacterial composition and application thereof | |
| US20060073156A1 (en) | Fosfomycin and n-acetylcysteine for the treatment of biofilms caused by escheric ia coli and other pathogens of the urinary tract | |
| CN113082026B (en) | Application of artemisinin derivative in preparation of polymyxin antibacterial synergist | |
| CN114617886B (en) | Compound and antibacterial application of pharmaceutically acceptable salt thereof | |
| Shah et al. | In vitro activity of piperacillin compared with that of carbenicillin, ticarcillin, ampicillin, cephalothin, and cefamandole against Pseudomonas aeruginosa and Enterobacteriaceae | |
| Auwera et al. | In-vitro activity of two new carbapenems FCE 22101 and CGP 31608 in comparison with imipenem | |
| CN110711192A (en) | Use of tryptophan for enhancing gram-negative bacteria bactericidal effect | |
| EP3919059B1 (en) | Composition for treating carbapenem antibiotic-resistant acinetobacter baumannii infection | |
| Pruekprasert et al. | In vitro activity of fosfomycin-gentamicin, fosfomycin-ceftazidime, fosfomycin-imipenem and ceftazidime-gentamicin combinations against ceftazidime-resistant Pseudomonas aeruginosa | |
| RU2672869C1 (en) | Antibacterial agent based on bacteriophage | |
| CN102125562B (en) | Medicinal composition for injection for treating superbug | |
| CN114028418B (en) | Antibacterial composition containing chitosan oligosaccharide and application thereof | |
| CN116621939B (en) | Application of antibacterial peptide LRGG in preparation of fluoroquinolone antibacterial synergist | |
| CN115337320B (en) | Application of HyG in reducing MIC of imipenem high-drug-resistance pseudomonas aeruginosa | |
| Ramirez-Ronda et al. | Treatment of urinary tract infection with norfloxacin: analysis of cost | |
| Smith et al. | Interaction of ciprofloxacin with ampicillin and vancomycin for Streptococcus faecalis |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |