阅读说明：本技术 一种抗菌化合物及其应用 (Antibacterial compound and application thereof ) 是由 谭臣 鲁浩 朱永为 王晨晨 鲁文嘉 王高岩 于 2021-06-25 设计创作，主要内容包括：本发明公开了一种抗菌化合物及其应用,属于微生物传染病及医药领域。本发明的抗菌化合物的结构式如下式所示,其对大肠杆菌的生长有很好的抑制作用,具有抗大肠杆菌的应用,可用于制备抗大肠杆菌的药物、制备预防或治疗大肠杆菌感染的药物。本发明发现了一种新型抗菌化合物,为预防或治疗耐药大肠杆菌感染提供了新的药物。(The invention discloses an antibacterial compound and application thereof, belonging to the fields of microbial infectious diseases and medicines. The antibacterial compound has a structural formula shown in the specification, has a good inhibition effect on the growth of escherichia coli, has an application of resisting escherichia coli, and can be used for preparing medicines for resisting escherichia coli and medicines for preventing or treating escherichia coli infection. The invention discloses a novel antibacterial compound, and provides a novel medicament for preventing or treating drug-resistant escherichia coli infection.)

1. An antimicrobial compound characterized by: the structural formula is as follows:

2. the use of the antibacterial compound of claim 1 against e.coli, characterized in that: the use is for non-disease treatment purposes.

3. Use of the antibacterial compound of claim 1 for the preparation of a medicament against e.

4. Use of the antibacterial compound of claim 1 for the preparation of a medicament for the prevention or treatment of e.

5. An anti-escherichia coli drug, which is characterized in that: comprising the antibacterial compound of claim 1.

6. A medicament for preventing or treating escherichia coli infection, characterized by: comprising the antibacterial compound of claim 1.

7. The use according to any one of claims 2 to 4 or the medicament according to claim 5 or 6, wherein: the Escherichia coli is drug-resistant Escherichia coli.

8. The use according to any one of claims 2 to 4 or the medicament according to claim 5 or 6, wherein: the Escherichia coli is Escherichia coli PCN 033.

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 drug resistance seriously threatens global public health, and the development process of novel antibiotics is slow, so that the problem of bacterial drug resistance cannot be effectively solved. Antibiotic-resistant bacteria pose a serious threat to modern medicine and human life, and have been identified as a major threat to society by global agencies such as the World Health Organization (WHO). Escherichia coli is the most common pathogenic bacterium, and seriously threatens the development of the breeding industry and human health. Among them, carbapenem-resistant enterobacteriaceae (CRE) has been classified as one of the urgent threats by the centers for disease control and prevention (CDC), and almost half of hospitalized patients cause blood infections due to these bacteria. Compared with the compound targeting the bacterial metabolic pathway, the compound synthesized by targeting the bacterial outer membrane has the advantages of stability, high efficiency and difficult variation.

Disclosure of Invention

The invention aims to provide a novel antibacterial compound which has good inhibition effect on escherichia coli. The invention also aims to provide pharmaceutical application of the antibacterial compound.

The purpose of the invention is realized by the following technical scheme:

the invention takes peptidoglycan synthetic protein Mray of escherichia coli as a receptor for virtual screening, and screens out a small molecular compound S1 which has obvious inhibition effect on the growth of the escherichia coli, and the structure of the small molecular compound is shown as the following formula:

the small molecular compound S1 has the application of resisting escherichia coli, can be used for preparing medicines resisting escherichia coli, and can be used for preparing medicines for preventing or treating escherichia coli infection. The application of the anti-Escherichia coli is the purpose of non-disease treatment.

An anti-Escherichia coli medicine comprises the small molecule compound S1.

A medicament for preventing or treating escherichia coli infection, which comprises the small molecule compound S1.

Further, the escherichia coli is drug-resistant escherichia coli. Further, the Escherichia coli is Escherichia coli PCN 033.

The invention has the following advantages and beneficial effects: the invention discloses 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 Mray protein.

FIG. 2 is a graph showing the effect of compound S1 on E.coli growth.

Detailed Description

The following examples are intended to further illustrate the invention but should not be construed as limiting it. Unless otherwise specified, the technical means used in the examples are conventional means well known to those skilled in the art.

Example 1

The essential gene set of the Escherichia coli genome is established by using a homologous alignment method through essential genes of Escherichia coli in DEG (http:// www.essentialgene.org /) and OGEE (http:// ogee.hedgehog. info/brown /) databases. Through the data information of homologous genes of a human source pig source in a KEGG database, genes which are homologous with human and pig in an escherichia coli essential gene set are filtered out. 291 necessary gene sets which are not homologous to the host are identified and classified according to the metabolic pathway in KEGG by using the genome of multi-drug resistant Escherichia coli PCN033 as a reference genome. The first five metabolic pathways of the candidate target set gene account for fatty acid biosynthesis, terpenoid skeleton biosynthesis, peptidoglycan biosynthesis, RNA polymerase and DNA replication. Further analysis shows that the resolutions of MraY, FabZ and ispU are all below 3.0 angstroms and reach the modeling standard. Further by literature investigations, it was found that the MraY protein is a protein involved in the synthesis of e.coli peptidoglycan and its natural ligand is a re-developed antibiotic. Therefore, the MraY protein was selected as the receptor for virtual screening.

TABLE 1 candidate target resolution

Example 2

Taking the MraY protein (PDB number: 5ckr) structure in the PDB database as a template, and carrying out homologous modeling on the MraY protein structure of the escherichia coli by utilizing a Homology modeling module in MOE according to the energy minimum principle. FIG. 1A shows the simulated three-dimensional structure of the E.coli Mray protein, and FIG. 1B shows the dihedral distribution of each amino acid.

Example 3

The method comprises the steps of using a Specs database provided by pottery (Shanghai) Biochemical technology Co., Ltd in 2017 and containing 316970 micromolecule compounds, constructing a micromolecule pretreatment process by using Pipeline Pilot 8.5 software, removing solvent molecules and inorganic micromolecules, reserving the largest fragment, carrying out hydrogenation and charging treatment, filtering out molecules with the molecular weight of more than 600 and the number of rotatable bonds of more than 8, calculating the hydrogenation state under the conditions of pH values of 2, 7.4 and 12 in sequence, and reserving the molecules after weight removal. The receptor selects the position of a natural ligand of a receptor protein as an active cavity of the receptor, and then a Protonate 3D tool is utilized in an AMBER99 force field (the protein selects an AMBER99 force field, and the small molecule selects an MMFF94 force field), under the conditions of 300K temperature, pH of 7.0 and ion concentration of 1mol/L, an electrostatic function is set to be a generalized Bonn method, the intercept value of 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 hydrogenated and charged. In the molecular docking process, an active cavity where a natural ligand of the Mray protein is located is used as an active center of a receptor protein, small molecules in specs (https:// www.specs.net/snpage. phpsnpageid ═ home) database are screened, a scoring function adopts London dG, a structure optimization method adopts Forcefield, and other parameters are set as default parameters.

The top 30 ranked small molecules were selected according to scoring and according to U.S. clinical and laboratory standardsCommittee (CLSI) standards, test the effect of small molecules on E.coli growth. Escherichia coli standard strain (ATCC25922) was inoculated into LB medium, cultured overnight in an incubator at 37 ℃ and 180rpm, transferred to MH medium at a ratio of 1:100, and shaken to OD₆₀₀The value was 0.6, and the suspension was centrifuged again and resuspended in PBS buffer until the McLeod's turbidity was around 0.5. 10 mu L of liquid medicine is added into a 96-well plate, and then 90 mu L of prepared bacterial liquid is added into each well, so that the final concentration of the medicine in each well is ensured to be 100 mu g/mL. Covering a sealing cover, marking, placing into a Bioscreen full-automatic growth curve analyzer, keeping the temperature at 37 deg.C, slightly vibrating, and measuring OD once every 1h₆₀₀. Vibration was stopped 30 seconds before measurement, incubation was terminated after 16h, collected, stored, data analyzed, and bacterial growth curves were plotted using GraphPad. Finally, a small molecule S1 was found that had a significant effect on e.coli growth, and the growth curve is shown in fig. 2.

The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.