CN113563220B - Antibacterial compound and application thereof - Google Patents
Antibacterial compound and application thereof Download PDFInfo
- Publication number
- CN113563220B CN113563220B CN202110707221.2A CN202110707221A CN113563220B CN 113563220 B CN113563220 B CN 113563220B CN 202110707221 A CN202110707221 A CN 202110707221A CN 113563220 B CN113563220 B CN 113563220B
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- escherichia coli
- antibacterial compound
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- compound
- antibacterial
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C233/00—Carboxylic acid amides
- C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
- C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
- C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
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- 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
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- 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
Abstract
The invention discloses an antibacterial agentThe compound and the application thereof belong to the fields of microbial infectious diseases and medicines. The structural formula of the antibacterial compound is shown in the formula, has a good inhibition effect on the growth of escherichia coli, has the application of resisting the escherichia coli, and can be used for preparing medicaments for resisting the escherichia coli and medicaments for preventing or treating escherichia coli infection. The invention discovers a novel antibacterial compound and provides a novel medicament for preventing or treating drug-resistant escherichia coli infection.
Description
Technical Field
The invention relates to the fields of microbial infectious diseases and medicines, in particular to an antibacterial compound and application thereof.
Background
Bacterial resistance seriously threatens global public health, and the development process of novel antibiotics is slow, so that the problem of bacterial resistance cannot be effectively solved. Antibiotic resistant bacteria pose a serious threat to modern medicine and human life and have therefore been identified by the World Health Organization (WHO) and other global institutions as major threats to society. Coli is the most common pathogenic bacteria, severely threatening the development of the farming industry and human health. Among them, the carbapenem-resistant enterobacteriaceae (CRE) has been classified as one of the urgent threats by the center for disease control and prevention (CDC), and almost half of hospitalized patients are suffering from blood infections due to these bacteria. Compared with the compound targeting the bacterial metabolic pathway, the compound synthesized by the outer membrane of the targeted bacteria has the advantages of stability, high efficiency and difficult mutation generation.
Disclosure of Invention
The invention aims to provide a novel antibacterial compound which has a good inhibition effect on escherichia coli. The invention also aims to provide the pharmaceutical application of the antibacterial compound.
The aim of the invention is achieved by the following technical scheme:
the invention takes peptidoglycan synthetic protein Mray of escherichia coli as a receptor for virtual screening, and screens a small molecular compound S1 with obvious inhibition effect on the growth of escherichia coli, and the structure of the small molecular compound S1 is shown as the following formula:
the small molecular compound S1 has the application of resisting escherichia coli, can be used for preparing medicaments for resisting escherichia coli, and can be used for preparing medicaments for preventing or treating escherichia coli infection. The application of the anti-escherichia coli is for the purpose of non-disease treatment.
An anti-Escherichia coli drug comprising the above small molecule compound S1.
A medicament for preventing or treating escherichia coli infection, comprising the small molecule compound S1.
Further, the escherichia coli is drug-resistant escherichia coli. Still further, the E.coli is E.coli PCN033.
The invention has the following advantages and beneficial effects: the invention discovers a novel antibacterial compound which has a good inhibition effect on the growth of escherichia coli. The invention provides a new medicine for preventing or treating drug-resistant escherichia coli infection.
Drawings
FIG. 1 is a graph of the results of homology modeling of the structure of the Mray protein.
FIG. 2 is a graph showing the effect of Compound S1 on E.coli growth.
Detailed Description
The following examples serve to further illustrate the invention but are not to be construed as limiting the invention. The technical means used in the examples are conventional means well known to those skilled in the art unless otherwise indicated.
Example 1
The necessary gene set of the escherichia coli genome is established by utilizing a homologous alignment method through the necessary genes of escherichia coli in DEG (http:// www.essentialgene.org /) and OGEE (http:// OGEE. Edgenius. Info/browse /) databases. And filtering out genes which have homology with human and pigs in the essential gene set of the escherichia coli through the data information of homologous genes of the human pig sources in the KEGG database. The genome of multi-resistant E.coli PCN033 was used as a reference genome, and 291 non-host homologous essential gene sets were identified and classified according to the metabolic pathway in KEGG. The five metabolic pathways of the candidate target concentrated genes are respectively fatty acid biosynthesis, terpene compound skeleton biosynthesis, peptidoglycan biosynthesis, RNA polymerase and DNA replication. Further analysis shows that the resolution of MraY, fabZ, ispU is below 3.0 Egypt, and the modeling standard is achieved. Further through literature investigation, it was found that the MraY protein is a protein involved in the synthesis of escherichia coli peptidoglycan, and its natural ligand is a redevelopment antibiotic. Thus, the MraY protein was selected as the receptor for virtual screening.
TABLE 1 analysis of candidate target spots
Example 2
The structure of the Mray protein of E.coli was homologously modeled using the Homology modeling module in MOE and according to the principle of lowest energy, using the Mray protein (PDB number: 5 ckr) structure in the PDB database as a template. FIG. 1A shows a simulated three-dimensional structure of the E.coli Mray protein, and FIG. 1B shows the distribution of dihedral angles for each amino acid.
Example 3
Using a Specs database provided by Tao Su (Shanghai) biochemical technology limited company in 2017, comprising 316970 small molecule compounds, constructing a small molecule pretreatment flow by using Pipeline Pilot 8.5 software, firstly removing solvent molecules and inorganic small molecules, retaining the largest fragments, then carrying out hydrogenation and charge treatment, then filtering out molecules with molecular weight more than 600, rotating the molecules with the number of more than 8, then calculating hydrogenation state under the conditions of pH of 2, 7.4 and 12 in sequence, and finally retaining the molecules after de-duplication. The receptor selects the position of the natural ligand of the receptor protein as an active cavity of the receptor, then a Protonate 3D tool is utilized in an AMBER99 force field (the protein selects the AMBER99 force field and the small molecule selects the MMFF94 force field), an electrostatic function is set to be a generalized Boen method under the conditions of 300K temperature, 7.0 pH and 1mol/L ion concentration, the intercept value of the electrostatic force is 15, the dielectric constant of a solute solvent is set to be 2 and 8, and after the Van der Waals force function adopts an 800R3 method, the protein result is subjected to hydrogenation charge. In the process of taking an active cavity where a natural ligand of the Mray protein is located as a molecular docking process, an active center of a receptor protein is screened through small molecules in a specs (https:// www.specs.net/snage. Phpsnpageid=home) database, a scoring function adopts London dG, a structure optimization method adopts Forcefield, and other parameters are set as default parameters.
The top 30 small molecules were selected according to scoring and tested for their effect on E.coli growth according to the standards of the American clinical and laboratory standards Committee (CLSI). The E.coli standard strain (ATCC 25922) was inoculated into LB medium, cultured overnight at 37℃in an incubator at 180rpm, and then 1:100 was transferred to MH medium and shaken to OD 600 The value was 0.6 and re-centrifuged with PBS buffer to a turbidity of about 0.5. 10 mu L of liquid medicine is added into a 96-well plate, then 90 mu L of prepared bacterial liquid is added into each well, and the final concentration of the medicine in each well is ensured to be 100 mu g/mL. Covering the sealing cover, marking, placing into a Bioscreen full-automatic growth curve analyzer, setting constant temperature at 37deg.C, slightly vibrating, and measuring OD every 1 hr 600 . Vibration was stopped 30 seconds before measurement, and after 16 hours incubation was completed, data were collected, saved, analyzed, and bacterial growth curves were plotted using GraphPad. Finally, a small molecule S1 which has obvious influence on the growth of escherichia coli is discovered, and a growth curve is shown in figure 2.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.
Claims (5)
1. Use of an antibacterial compound against escherichia coli, characterized in that: the application is for the purpose of non-disease treatment; the structural formula of the antibacterial compound is shown as follows:
2. an application of an antibacterial compound in preparing a medicament for resisting escherichia coli, which is characterized by comprising the following steps of: the structural formula of the antibacterial compound is shown as follows:
3. an application of an antibacterial compound in preparing a medicament for preventing or treating escherichia coli infection, which is characterized by comprising the following steps of: the structural formula of the antibacterial compound is shown as follows:
4. a use according to any one of claims 1-3, characterized in that: the escherichia coli is drug-resistant escherichia coli.
5. A use according to any one of claims 1-3, characterized in that: the escherichia coli is escherichia coli PCN033.
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| Application Number | Priority Date | Filing Date | Title |
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| CN202110707221.2A CN113563220B (en) | 2021-06-25 | 2021-06-25 | Antibacterial compound and application thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110707221.2A CN113563220B (en) | 2021-06-25 | 2021-06-25 | Antibacterial compound and application thereof |
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| CN113563220A CN113563220A (en) | 2021-10-29 |
| CN113563220B true CN113563220B (en) | 2023-08-29 |
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| CN202110707221.2A Active CN113563220B (en) | 2021-06-25 | 2021-06-25 | Antibacterial compound and application thereof |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105793424A (en) * | 2013-07-12 | 2016-07-20 | 亥姆霍兹感染研究中心有限公司 | Cystobactamides |
| CN110613710A (en) * | 2019-11-06 | 2019-12-27 | 中国医科大学 | Small molecule compound C29H22N2O8Application in E.coli meningitis |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2005016227A2 (en) * | 2003-08-14 | 2005-02-24 | Insight Biopharmaceuticals Ltd. | Methods and pharmaceutical compositions for modulating heparanase activation and uses thereof |
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- 2021-06-25 CN CN202110707221.2A patent/CN113563220B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105793424A (en) * | 2013-07-12 | 2016-07-20 | 亥姆霍兹感染研究中心有限公司 | Cystobactamides |
| CN110613710A (en) * | 2019-11-06 | 2019-12-27 | 中国医科大学 | Small molecule compound C29H22N2O8Application in E.coli meningitis |
Non-Patent Citations (1)
| Title |
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| RN：301675-18-3;Chemical Abstract Service;CA网络版STN Registry数据库 * |
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| CN113563220A (en) | 2021-10-29 |
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