CN116919954A - Application of oxazolidinone compound in preparation of medicines for inhibiting bacterial quorum sensing - Google Patents
Application of oxazolidinone compound in preparation of medicines for inhibiting bacterial quorum sensing Download PDFInfo
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- CN116919954A CN116919954A CN202310572472.3A CN202310572472A CN116919954A CN 116919954 A CN116919954 A CN 116919954A CN 202310572472 A CN202310572472 A CN 202310572472A CN 116919954 A CN116919954 A CN 116919954A
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- quorum sensing
- oxazolidinone compound
- pseudomonas aeruginosa
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- -1 oxazolidinone compound Chemical class 0.000 title claims abstract description 47
- 230000018612 quorum sensing Effects 0.000 title claims abstract description 47
- 230000001580 bacterial effect Effects 0.000 title claims abstract description 22
- 239000003814 drug Substances 0.000 title claims abstract description 19
- 230000002401 inhibitory effect Effects 0.000 title claims abstract description 16
- 229940079593 drug Drugs 0.000 title claims abstract description 11
- 238000002360 preparation method Methods 0.000 title abstract description 10
- 241000589517 Pseudomonas aeruginosa Species 0.000 claims abstract description 35
- 241000894006 Bacteria Species 0.000 claims description 17
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 10
- IZXIZTKNFFYFOF-UHFFFAOYSA-N 2-Oxazolidone Chemical class O=C1NCCO1 IZXIZTKNFFYFOF-UHFFFAOYSA-N 0.000 claims description 9
- 239000002775 capsule Substances 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 238000002347 injection Methods 0.000 claims description 2
- 239000007924 injection Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 5
- 238000009472 formulation Methods 0.000 claims 1
- 108090000623 proteins and genes Proteins 0.000 abstract description 19
- 206010059866 Drug resistance Diseases 0.000 abstract description 8
- 230000014509 gene expression Effects 0.000 abstract description 8
- 201000010099 disease Diseases 0.000 abstract description 5
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 5
- 150000001875 compounds Chemical class 0.000 abstract description 4
- 208000027096 gram-negative bacterial infections Diseases 0.000 abstract description 4
- 208000015181 infectious disease Diseases 0.000 abstract description 4
- 238000011866 long-term treatment Methods 0.000 abstract description 4
- 101100524676 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) rhlR gene Proteins 0.000 abstract description 3
- 230000007246 mechanism Effects 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 239000003242 anti bacterial agent Substances 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- 229940088710 antibiotic agent Drugs 0.000 abstract 1
- 244000052616 bacterial pathogen Species 0.000 abstract 1
- 230000007924 bacterial virulence factor Effects 0.000 abstract 1
- 230000036457 multidrug resistance Effects 0.000 abstract 1
- 208000024891 symptom Diseases 0.000 abstract 1
- 239000002126 C01EB10 - Adenosine Substances 0.000 description 12
- 229960005305 adenosine Drugs 0.000 description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 9
- 241000244206 Nematoda Species 0.000 description 9
- 239000000843 powder Substances 0.000 description 9
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 description 8
- 238000004458 analytical method Methods 0.000 description 7
- 239000001963 growth medium Substances 0.000 description 7
- 101710089384 Extracellular protease Proteins 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 235000013336 milk Nutrition 0.000 description 6
- 239000008267 milk Substances 0.000 description 6
- 210000004080 milk Anatomy 0.000 description 6
- 102000004169 proteins and genes Human genes 0.000 description 6
- 230000003115 biocidal effect Effects 0.000 description 4
- 239000002609 medium Substances 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Natural products CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- 208000032536 Pseudomonas Infections Diseases 0.000 description 3
- 230000000844 anti-bacterial effect Effects 0.000 description 3
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000011534 incubation Methods 0.000 description 3
- 230000006698 induction Effects 0.000 description 3
- 230000005764 inhibitory process Effects 0.000 description 3
- 230000003834 intracellular effect Effects 0.000 description 3
- 230000004060 metabolic process Effects 0.000 description 3
- 230000035755 proliferation Effects 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 150000003384 small molecules Chemical class 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000004083 survival effect Effects 0.000 description 3
- 230000008685 targeting Effects 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- 101100096647 Escherichia coli (strain K12) srmB gene Proteins 0.000 description 2
- 102000004157 Hydrolases Human genes 0.000 description 2
- 108090000604 Hydrolases Proteins 0.000 description 2
- QJPWUUJVYOJNMH-VKHMYHEASA-N L-homoserine lactone Chemical compound N[C@H]1CCOC1=O QJPWUUJVYOJNMH-VKHMYHEASA-N 0.000 description 2
- 101150026476 PAO1 gene Proteins 0.000 description 2
- 241000589516 Pseudomonas Species 0.000 description 2
- 101100137513 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) pqsA gene Proteins 0.000 description 2
- 101100137516 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) pqsD gene Proteins 0.000 description 2
- 101100468655 Pseudomonas aeruginosa (strain ATCC 15692 / DSM 22644 / CIP 104116 / JCM 14847 / LMG 12228 / 1C / PRS 101 / PAO1) rhlA gene Proteins 0.000 description 2
- 108700005075 Regulator Genes Proteins 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000001404 mediated effect Effects 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000035772 mutation Effects 0.000 description 2
- 101150088363 phzA gene Proteins 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 230000002797 proteolythic effect Effects 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 235000020183 skimmed milk Nutrition 0.000 description 2
- 230000001018 virulence Effects 0.000 description 2
- 108091032973 (ribonucleotides)n+m Proteins 0.000 description 1
- 108020004465 16S ribosomal RNA Proteins 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 231100000699 Bacterial toxin Toxicity 0.000 description 1
- 208000035473 Communicable disease Diseases 0.000 description 1
- 241001167795 Escherichia coli OP50 Species 0.000 description 1
- 239000006137 Luria-Bertani broth Substances 0.000 description 1
- 108700042017 Pseudomonas aeruginosa LasR Proteins 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000001147 anti-toxic effect Effects 0.000 description 1
- 238000003556 assay Methods 0.000 description 1
- 239000000688 bacterial toxin Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000009509 drug development Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000012851 eutrophication Methods 0.000 description 1
- 210000000987 immune system Anatomy 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000002054 inoculum Substances 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000009630 liquid culture Methods 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000013642 negative control Substances 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 238000003753 real-time PCR Methods 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
- 231100000765 toxin Toxicity 0.000 description 1
- 239000000304 virulence factor Substances 0.000 description 1
- 230000007923 virulence factor Effects 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
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/42—Oxazoles
- A61K31/421—1,3-Oxazoles, e.g. pemoline, trimethadione
-
- 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)
- 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 an oxazolidinone compound in preparation of a medicament for inhibiting bacterial quorum sensing. Solves the problems of few effective drug selections, long period and easy repetition of disease conditions of the traditional antibiotics for treating the multi-drug resistance pathogenic bacteria related infection. The action mechanism of the oxazolidinone compound provided by the invention comprises the following characteristics: three main control genes capable of simultaneously inhibiting pseudomonas aeruginosa quorum sensing systemlasR、rhlR、pqsRAnd the expression of the downstream functional genes can obviously inhibit the synthesis of bacterial virulence factors controlled by a pseudomonas aeruginosa quorum sensing system and relieve infection symptoms. The compound of the invention can be used for diseases requiring long-term treatment, such as multi-drug resistant gram-negative bacterial infection represented by pseudomonas aeruginosa, and is not easy to generate drug resistance.
Description
Technical Field
The invention relates to a high-efficiency quorum sensing small molecule inhibitor and application thereof. In particular to a novel application of an oxazolidinone compound for inhibiting the toxicity of multi-drug resistant gram-negative bacteria through high-efficiency inhibition of a quorum sensing system. The compound of the invention can be used for diseases requiring long-term treatment, such as multi-drug resistant gram-negative bacterial infection represented by pseudomonas aeruginosa, and is not easy to generate drug resistance.
Background
Oxazolidinone chemical structure and pseudomonas aeruginosaPseudomonas aeruginosa) The quorum sensing signal molecules of gram-negative bacteria have a certain similarity to the homoserine lactone parent nucleus structure. The structural formula of the oxazolidinone compound is shown in figure 1.
The quorum sensing is used for describing that after bacteria grow to a certain population density, individual bacteria can continuously receive homoserine lactone signal molecules secreted to the outside of cells by other individuals in a unit environment, and activate a complex intracellular regulation network of the bacteria so as to regulate release and metabolic pathways of virulence factors (such as extracellular protease, toxin substances and the like) in a large range, thereby obviously improving the survival suitability of the bacterial population. In view of the key role of bacterial quorum sensing systems mediated virulence systems in infectious diseases, achieving a reduction in bacterial toxicity by inhibiting bacterial quorum sensing systems and thus clearance by the host immune system is an antibiotic replacement drug development strategy. Unlike traditional antibiotic action mechanism, the strategy does not directly inhibit the growth and reproduction of bacteria, but inhibits the exertion of bacterial toxicity and reduces the damage of bacterial toxin to host tissues and organs. Targeting small molecule compounds developed based on signal molecules of a bacterial quorum sensing system directly act on quorum sensing middle control proteins, and if the middle control proteins influence the drug effect of the targeting small molecules through mutation, namely generate drug resistance, the change of the conformation of the middle control proteins also influences the binding of the targeting small molecules to natural signal molecules, so that the quorum sensing system is actively inhibited. Therefore, whether bacteria generate drug resistance through mutation or not, the application result of the targeted small molecule compound is that a bacterial quorum sensing system is inhibited, and the targeted small molecule compound is an anti-toxin strategy which is stable in evolution and difficult to generate drug resistance.
Disclosure of Invention
The invention aims to provide an application of an oxazolidinone compound in preparing a medicament for inhibiting multi-drug-resistant gram-negative pseudomonas aeruginosa quorum sensing.
The invention is realized in the following way:
application of oxazolidinone compound in preparation of medicines for inhibiting bacterial quorum sensing
The acting concentration of the oxazolidinone compound is 50-200 micromoles/L.
The chemical name of the oxazolidinone compound is 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxo oxazolidin-3-yl) phenyl) ethyl acetate.
The oxazolidinone compound is in a pharmaceutically acceptable preparation form, wherein the preparation form comprises tablets, granules, capsules, injections, sprays or other forms capable of being absorbed by human bodies.
The bacteria are gram negative bacteria.
The gram negative bacteria are pseudomonas aeruginosa.
The oxazolidinone compound and the gram negative bacteria quorum sensing common signal molecule have similar structural parent nucleus, can be targeted to bind with a plurality of central control proteins of the quorum sensing system, inhibit the generation of extracellular protease, and remarkably inhibit the expression of a plurality of central control genes and downstream functional genes of the quorum sensing system.
The bacteria are gram negative bacteria represented by pseudomonas aeruginosa model strain PAO 1.
The oxazolidinone compound provided by the invention comprises the following characteristics: can act on a plurality of central control proteins of the quorum sensing system at the same time, is effective at lower dosage, and can inhibit the quorum sensing system efficiently. The composition of the invention can be used for diseases requiring long-term treatment, such as multi-drug resistant gram-negative bacterial infection represented by pseudomonas aeruginosa, and is not easy to generate drug resistance.
The oxazolidinone compound can inhibit the expression of a plurality of central control genes and downstream functional genes of a bacterial quorum sensing system and inhibit the generation of bacterial extracellular protease.
The above-mentioned effects of oxazolidinones compounds of the invention are evaluated in vitro using pseudomonas aeruginosa model strain PAO1, and the results are shown in the examples.
In vitro, the oxazolidinone compound disclosed by the invention has no antibacterial activity on pseudomonas aeruginosa cultured under eutrophication conditions (such as LB culture medium), but can obviously inhibit the proliferation of pseudomonas aeruginosa in an environment (such as M9-adenosine culture medium) in which a quorum sensing system needs to be activated for growth. The oxazolidinone compound can obviously inhibit central control genes of pseudomonas aeruginosa quorum sensing systemlasRThe synthesis of extracellular protease, and simultaneously inhibit the expression of three central control genes and downstream key virulence related functional genes of the currently known pseudomonas aeruginosa quorum sensing system, and can effectively protect nematodes from being infected by pseudomonas aeruginosa.
The application of the oxazolidinone compound in preparing the medicine for inhibiting bacterial quorum sensing has the following advantages: completely different from the traditional antibiotic action mechanism, the method can avoid the direct action of multiple antibiotic drug resistance on a plurality of central control proteins of the quorum sensing system, and further effectively inhibit the toxic exertion mediated by the quorum sensing system. The oxazolidinone compound can be used for treating diseases requiring long-term treatment, such as multi-drug resistant gram-negative bacterial infection represented by pseudomonas aeruginosa, and drug resistance is not easy to generate.
Drawings
FIG. 1 is a structural formula of an oxazolidinone compound, ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxo-oxazolidin-3-yl) phenyl) acetate.
FIG. 2 is the growth effect of ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxooxazolidin-3-yl) phenyl) acetate on P.aeruginosa, A: LB medium; m9-adenosine medium.
FIG. 3 is an effect of ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxooxazolidin-3-yl) phenyl) acetate on induction of regulatory gene expression by a population of Pseudomonas aeruginosa.
FIG. 4 is a graph showing the protective effect of ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxooxazolidin-3-yl) phenyl) acetate on P.aeruginosa infection nematodes.
Detailed Description
The following describes the embodiments of the present invention in further detail with reference to examples. The following examples are illustrative of the invention and are not intended to limit the scope of the invention. The invention is intended to cover all possible alternatives, modifications and equivalents within the scope of the claims. The specific techniques or conditions not specified in the examples below are conventional techniques or conditions, or are described in the literature in this field, or are carried out in accordance with the product specifications.
Example 1
Oxazolidinone compound preparation for inhibiting pseudomonas aeruginosaP. aeruginosa，PAO 1) quorum sensing.
The oxazolidinone compound is ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxo-oxazolidin-3-yl) phenyl) acetate.
The oxazolidinone compound preparation is dry powder dissolved in dimethyl sulfoxide, and the structural formula of the oxazolidinone compound is shown in figure 2.
Antibacterial activity analysis:
the pseudomonas aeruginosa is treatedP. aeruginosa PAO1) （1.0×10 6 CFU) were inoculated into a common LB broth (Haibo Biotechnology Co., ltd.) and M9-adenosine (0.1%, w/v) medium (Sigma-Aldrich), respectively, and treated in groups50, 100 and 200 micromoles/L oxazolidinone compound preparations are respectively added into a culture medium, an equivalent amount of dimethyl sulfoxide is added into a control group, and the culture medium is cultured for 16 hours at 37 ℃ and then is subjected to optical density OD 600 The bacterial liquid density was measured as follows.
The analysis result of the antibacterial activity of the ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxo oxazolidin-3-yl) phenyl) acetate is shown in figure 3. In the LB culture medium, the bacterial liquid density of the oxazolidinone compound treated pseudomonas aeruginosa at each concentration is not changed significantly compared with that of a control group. Compared with a control group, in the M9-adenosine culture medium, the oxazolidinone compound can obviously inhibit the proliferation of pseudomonas aeruginosa. In view of the need for the metabolism of adenosine by pseudomonas aeruginosa to utilize quorum sensing central control geneslasRThe regulated intracellular hydrolase Nuh and the growth of the pseudomonas aeruginosa in the presence of the oxazolidinone compound are weakened under the condition that the adenosine is the only carbon source, which indicates that the quorum sensing system is inhibited and the proliferation is affected.
Analysis of oxazolidinone inhibition quorum sensing activity:
5. Mu.l of Pseudomonas aeruginosa (5.0X10 were added 6 CFU) were inoculated into M9-skimmed milk powder (0.5%, w/v) and M9-adenosine (0.1%, w/v) agar plates containing different concentration gradients of oxazolidinones (0, 50, 100, 200 μmol/L), and the diameters of proteolytic loops on the M9-skimmed milk powder plates were measured after 20 hours of incubation at 37 ℃ to examine the growth of pseudomonas aeruginosa on the M9-adenosine plates.
Ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxooxazolidin-3-yl) phenyl) acetate inhibition quorum sensing activity assays are shown in table 1. The compound can obviously inhibit the yield of extracellular protease of pseudomonas aeruginosa colonies on M9-skimmed milk powder culture plates and inhibit the growth of pseudomonas aeruginosa on M9-adenosine culture plates. Whereas the metabolism of pseudomonas aeruginosa requires the use of quorum sensing regulated extracellular proteases for skimmed milk powder, the metabolism of adenosine requires the use of quorum sensing central geneslasRRegulated intracellular hydrolase Nuh, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxo-oxazolidin-3-yl)The reduction of proteolytic loops of pseudomonas aeruginosa in the presence of phenyl) ethyl acetate compounds in the presence of skimmed milk powder as the sole carbon source and the reduction of growth in the presence of adenosine as the sole carbon source together indicate that the quorum sensing system is inhibited.
| Concentration of Compound (micromolar/L) | M9-skimmed milk powder (cm) | M9-adenosine 1 |
| 0 | 1.58±0.035 | + |
| 50 | 1.51±0.073* | - |
TABLE 1 influence of oxazolidinones on the quorum sensing system of Pseudomonas aeruginosa
1: ' represents normal growth; ' represents no growth or weak growth
Analysis of influence of oxazolidinone compounds on group induction regulation gene expression:
pseudomonas aeruginosa (1.0X10) 6 CFU) is inoculated in M9-skimmed milk powder (0.5%, w/v) liquid culture medium, 200 micromole/L oxazolidinone compound preparation is added into a treatment group, an equivalent dimethyl sulfoxide is added into a control group, bacterial cells are collected and total RNA is extracted after the culture is carried out for 16 hours at 37 ℃, and real-time fluorescence quantitative PCR is utilized to detect three group induction central control genes of pseudomonas aeruginosalasR,rhlR,pqsRAnd under itFunctional gene of gamelasB,rhlA,pqsA,pqsD,phzA,hcnAThe expression level of (2) was 16S rRNA as an internal gene.
The analysis result of the influence of the ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxo-oxazolidin-3-yl) phenyl) acetate on the expression of the quorum sensing regulatory gene is shown in figure 3. After the M9-skimmed milk powder culture solution is cultured, the oxazolidinone compound can obviously inhibit three quorum sensing central control genes of pseudomonas aeruginosa at the same timelasR,rhlR,pqsRAnd its downstream functional genelasB,rhlA,pqsA,pqsD,phzA,hcnAIs also significantly inhibited. The results comprehensively show that the oxazolidinone compound can inhibit the pseudomonas aeruginosa quorum sensing system with high efficiency.
Analysis of protection effect of oxazolidinone compounds on pseudomonas aeruginosa infection nematodes:
50. Mu.l of Pseudomonas aeruginosa (5.0X10 were added 7 CFU) was inoculated on PGS (peptone-glucose-sorbitol) plates, 200. Mu. Mol/L oxazolidinone compound test solution was added to the medium in the treatment group, equivalent DMSO was added to the control group, and after incubation at 37 ℃ for 24 hours, cooling was performed at room temperature, then 10 newly cultivated nematode adults (stage L4) were inoculated per plate, and incubation was continued at 25 ℃ and nematode survival was observed. The initial inoculum of the negative control group is escherichia coli OP50, and other culture conditions are consistent with those of the pseudomonas aeruginosa infection group.
The analysis of the protective effect of ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxooxazolidin-3-yl) phenyl) acetate on Pseudomonas aeruginosa infection nematodes is shown in FIG. 4. The killing effect of the pseudomonas aeruginosa on the nematodes in the control group is gradually enhanced along with the extension of the infection time, but in the oxazolidinone compound treatment group, the survival condition of the nematodes is obviously improved, and obvious statistical difference exists between the oxazolidinone compound treatment group and the untreated group, which shows that the oxazolidinone compound 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxo oxazolidin-3-yl) phenyl) acetic acid ethyl ester can better protect the nematodes from being infected by the pseudomonas aeruginosa.
Claims (6)
1. Application of oxazolidinone compounds in preparing medicines for inhibiting bacterial quorum sensing is provided.
2. The use of an oxazolidinone compound according to claim 1 for the manufacture of a medicament for inhibiting bacterial quorum sensing, wherein the oxazolidinone compound has an effective concentration of 50 to 200 μmol/L.
3. Use of an oxazolidinone compound according to claim 1 for the manufacture of a medicament for inhibiting bacterial quorum sensing, wherein the oxazolidinone compound is ethyl 2, 2-difluoro-2- (2-methoxy-6-methyl-4- (2-oxo-oxazolidin-3-yl) phenyl) acetate.
4. Use of an oxazolidinone compound for the manufacture of a medicament for inhibiting bacterial quorum sensing according to claim 1, wherein the oxazolidinone compound is in a pharmaceutically acceptable formulation comprising a tablet, granule, capsule, injection, spray or other form capable of being absorbed by the human body.
5. The use of an oxazolidinone compound according to claim 1 for the manufacture of a medicament for inhibiting quorum sensing in a bacterium, wherein the bacterium is a gram negative bacterium.
6. The use of an oxazolidinone compound for the manufacture of a medicament for inhibiting bacterial quorum sensing according to claim 5, wherein the gram negative bacterium is pseudomonas aeruginosa.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202310572472.3A CN116919954A (en) | 2023-05-22 | 2023-05-22 | Application of oxazolidinone compound in preparation of medicines for inhibiting bacterial quorum sensing |
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| Application Number | Priority Date | Filing Date | Title |
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| CN202310572472.3A CN116919954A (en) | 2023-05-22 | 2023-05-22 | Application of oxazolidinone compound in preparation of medicines for inhibiting bacterial quorum sensing |
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