CN110818684B - Inhibitor Lo-SH for resisting staphylococcus aureus virulence and biofilm formation and application thereof - Google Patents
Inhibitor Lo-SH for resisting staphylococcus aureus virulence and biofilm formation and application thereof Download PDFInfo
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Abstract
The invention provides an inhibitor Lo-SH for resisting staphylococcus aureus virulence and biofilm formation and application thereof, wherein the chemical structural formula of the inhibitor Lo-SH for resisting staphylococcus aureus virulence and biofilm formation is shown as a formula (1). The inhibitor Lo-SH for resisting the toxicity of staphylococcus aureus and the formation of biofilm has an inhibiting effect on the toxicity of staphylococcus aureus and the formation of biofilm, and can be used for preparing a medicament for inhibiting the toxicity of staphylococcus aureus and the formation of biofilm, or preparing a medicament for treating diseases caused by staphylococcus aureus, or preparing a disinfectant for medical instruments or medical appliances.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to an inhibitor Lo-SH for resisting staphylococcus aureus virulence and biofilm formation and application thereof.
Background
Staphylococcus aureus can infect different parts of the human body to cause various infectious diseases, from common skin diseases such as folliculitis, acne and hordeolum to deep and fatal diseases such as pneumonia, endocarditis, osteomyelitis and other metastatic complications. In the process of invading the host and inducing host infection by staphylococcus aureus, the staphylococcus aureus can secrete a plurality of virulence factors such as hemolysin, extracellular protease, leukocidin, phenol-soluble protein and the like, thereby assisting the invasion and damage of the staphylococcus aureus to the host and further inducing the occurrence of diseases. At present, with the wide use of antibacterial drugs, the emergence of drug-resistant bacteria, especially methicillin-resistant staphylococcus aureus (MRSA), brings difficulties to clinical treatment. Vancomycin and linezolid are few antibacterial drugs capable of treating MRSA infection at present, but at home and abroad, more and more vancomycin-insensitive staphylococcus aureus (VISA/hVISA) and linezolid drug-resistant strains are found, so that the selection of clinical antibacterial drugs is severely limited. In addition, staphylococcus aureus can be adhered to the surface of human tissue cells or medical implant materials to form a biofilm structure consisting of extracellular polysaccharide adhesion molecules, proteins, teichoic acid, extracellular DNA (eDNA) and the like, so that the sensitivity of bacteria to antibacterial drugs is reduced, attack and phagocytosis of host immune cells are avoided, and chronic infection and prolonged disunion are caused. The serious problem is that the infection in hospital related to staphylococcus aureus biofilm is increasing with the wide application of medical implant materials such as various catheters, dialysis technology, prosthetic joints and the like in recent years. At present, researches show that staphylococcus aureus resistant strains such as MRSA and the like also have stronger toxicity, can cause severe infectious diseases such as septic shock and endocarditis of patients to cause higher fatality rate, and also show that the resistant strains also have stronger biofilm formation capability. Therefore, in order to reduce the death of patients caused by the infection of the strains, inhibiting the virulence and biofilm formation of staphylococcus aureus becomes one of the difficulties and hot spots associated with bacteria to be urgently solved in recent years.
Disclosure of Invention
Aiming at the technical problems, the invention discloses an inhibitor Lo-SH for resisting the toxicity and biofilm formation of staphylococcus aureus and application thereof,
in contrast, the technical scheme adopted by the invention is as follows:
an inhibitor Lo-SH for resisting staphylococcus aureus virulence and biofilm formation, which has the following chemical structural formula:
wherein Lo-SH has a molecular formula of C 22 H 23 CIN 2 OS, a colorless and odorless transparent liquid at normal temperature, has the characteristics of high boiling point, good thermal stability and non-proton, and can be dissolved in most organic substances such as ethanol, propanol, benzene, chloroform and the like. The Lo-SH is a small molecular compound. The small molecular compound Lo-SH can obviously inhibit the toxicity and biofilm formation of staphylococcus aureus in vitro and in vivo; the small molecular compound does not influence the growth of bacteria; has no obvious toxicity to mammalian cells and no obvious hemolytic effect to human erythrocytes.
In the invention, the small molecular compound Lo-SH can be used for preparing a medical instrument or medical appliance disinfectant, and can be further used for modifying a chemical structure to prepare a novel medicament for resisting gram-positive bacteria infection.
The invention also discloses a medicament for resisting the toxicity of staphylococcus aureus and the formation of a biofilm, which comprises the inhibitor Lo-SH for resisting the toxicity of staphylococcus aureus and the formation of a biofilm.
Further, the medicament is liquid, and the concentration of Lo-SH in the medicament is not less than 25 mu M.
The invention also discloses application of Lo-SH in medicines for resisting the toxicity of staphylococcus aureus and biofilm formation, wherein the chemical structural formula of Lo-SH is shown as a formula (1).
Further, the medicament is liquid, and the concentration of Lo-SH in the medicament is not less than 25 mu M.
The invention also discloses application of Lo-SH in preparing a medicament for treating diseases caused by staphylococcus aureus, wherein the chemical structural formula of Lo-SH is shown as a formula (1).
The invention also discloses application of Lo-SH in preparing a medicine for resisting the toxicity of staphylococcus aureus and the formation of biofilm, wherein the medicine comprises Lo-SH, and the chemical structural formula of the Lo-SH is shown as a formula (1).
Further, the medicament is liquid, and the concentration of Lo-SH in the medicament is not less than 25 mu M.
The invention also discloses an application of Lo-SH in preparing a disinfectant for preparing medical instruments or medical appliances, wherein the disinfectant comprises Lo-SH, and the chemical structural formula of Lo-SH is shown as a formula (1).
Furthermore, lo-SH is prepared by adopting the following reaction route, namely desloratadine and mercaptopropionic acid are subjected to amidation reaction, and Lo-SH is obtained by dehydration. Preferably, the reaction temperature is not lower than 150 ℃.
Further, the mole ratio of desloratadine to mercaptopropionic acid is 1:1 to 1.5.
Or the reaction route is adopted, namely desloratadine and mercaptopropionyl chloride are dissolved in an organic solvent and react at the temperature of-5 to 60 ℃ under the action of an acid-binding agent.
Further, the organic solvent comprises one of dichloromethane, chloroform, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine or toluene.
Further, the acid binding agent is at least one of triethylamine, arsenicum sablimatum, potassium tert-butoxide, sodium methoxide, sodium ethoxide, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide.
Further, the mole ratio of desloratadine to mercaptopropionyl chloride is 1:1 to 1.5.
Although the compounds of the present invention may be administered directly without any formulation, the various compounds described are preferably used in the form of pharmaceutical preparations, the route of administration may be parenteral (e.g., intravenous, intramuscular) as well as oral.
Pharmaceutical compositions of the compounds of the invention were prepared as follows: the compounds of the present invention are combined with pharmaceutically acceptable solid or liquid carriers and optionally with pharmaceutically acceptable adjuvants and excipients using standard and conventional techniques to prepare microparticles or microspheres. Solid dosage forms include tablets, dispersible granules, capsules, sustained release tablets, sustained release pellets and the like. A solid carrier can be at least one substance that can act as a diluent, flavoring agent, solubilizing agent, lubricant, suspending agent, binder, disintegrating agent, and encapsulating agent. Inert solid carriers include magnesium phosphate, magnesium stearate, talc, lactose, pectin, propylene glycol, polysorbate 80, dextrin, starch, gelatin, cellulosic materials such as methyl cellulose, microcrystalline cellulose, low melting waxes, polyethylene glycols, mannitol, cocoa butter, and the like. Liquid dosage forms include solvents, suspensions such as injections, powders, and the like.
Compared with the prior art, the invention has the following beneficial effects:
by adopting the technical scheme of the invention, a novel small molecular compound Lo-SH with stronger inhibitory activity is obtained after modification and modification of a side chain group of loratadine, and in vitro and in vivo experiments of animals prove that the small molecular compound Lo-SH can effectively inhibit the toxicity and biofilm formation of staphylococcus aureus and has no toxicity to mammalian cells. The small molecular compound Lo-SH can be used for preparing a medicine for inhibiting the virulence of staphylococcus aureus and the formation of a biofilm, or preparing a medicine for treating diseases caused by staphylococcus aureus, or preparing a medical instrument or medical appliance disinfectant.
Drawings
FIG. 1 is a graph showing the inhibition of the formation of a biofilm of Staphylococcus aureus HG003 strain by Lo-SH, which is a sample of example 2 of the present invention.
FIG. 2 is a graph showing the results of OD570 measurements of inhibition of biofilm formation by Lo-SH against strain HG003 of Staphylococcus aureus in example 2 of the present invention. * P <0.001 (Student's t test) compared to control.
FIG. 3 is a graph showing the growth assay of HG003 plankton strains in example 2 of the present invention.
FIG. 4 is a graph showing the results of the detection of Lo-SH inhibition of biofilm formation by 16 clinical strains of Staphylococcus aureus in example 3 of the present invention. Compared with the control, the method has the advantages that, * P<0.05； *** P<0.001(Student’s t test)。
FIG. 5 is a graph showing the results of Lo-SH inhibition of pigment weakening in 5 strains of Staphylococcus aureus in example 3 of the present invention.
FIG. 6 shows that Lo-SH according to example 3 of the present invention inhibits the formation of Staphylococcus aureus (OD) from 5 strains of Staphylococcus aureus 450 Detection) result analysis graph; ** by comparison, P<0.01(Student’s t test)。
FIG. 7 shows that Lo-SH of example 3 of the present invention inhibits hemolytic activity (OD) of Staphylococcus aureus strain 5 550 Test) results analysis chart; by comparison of P<0.05；**P<0.01(Student’s t test)。
FIG. 8 is a graph analyzing the results of Lo-SH treatment of example 4 of the present invention for increasing the survival rate of mice infected with the lung of strain HG003 of Staphylococcus aureus. Lo-SH (140 mg/kg totally); * :P<0.05(Log-rank test)
Detailed Description
Preferred embodiments of the present invention are described in further detail below.
Example 1
Lo-SH is prepared by the following steps:
dissolving desloratadine in an organic solvent, taking triethylamine as an acid-binding agent, and adding an organic solution dissolved with mercaptopropionyl chloride, wherein the molar ratio of the desloratadine to the mercaptopropionyl chloride is 1:1 to 1.5, and stirring the mixture at the temperature of minus 5 ℃ for reaction to obtain reaction liquid containing Lo-SH. Wherein the organic solvent can be one of dichloromethane, trichloromethane, acetone, acetonitrile, tetrahydrofuran, DMF, pyridine or toluene. The mercaptopropionyl chloride is synthesized by a conventional method.
After the reaction is finished, pouring the reaction solution into cold water, fully shaking for layering, extracting an organic layer, and continuously washing for three times. The organic layer was dried and left to stand. Then filtered, and the solvent is evaporated under reduced pressure to obtain the compound Lo-SH. The product was purified by silica gel column chromatography for subsequent experiments.
Example 2
Test for inhibition of biofilm formation by Staphylococcus aureus with Compound Lo-SH.
Detecting the formation of a biofilm of the strain: the staphylococcus aureus strain is cultured in a TSB culture medium at 37 ℃ and 220rpm/min overnight for 10-12h. Bacterial suspension 1 was diluted with TSBG medium (TSB medium +0.5% glucose) to 200ul (with or without Lo-SH) and added to a 96-well plate (Costar 3599) at 200ul per well, and each strain was plated in 3 wells and incubated at 37 ℃ for 24h. Discarding supernatant, eluting with PBS for 3 times (200 ul/well/time), drying at room temperature, adding methanol, fixing for 15min (200 ul/well), discarding methanol, drying at room temperature, adding 0.5% crystal violet dye solution 100ul per well, dyeing at room temperature for 10min, eluting the crystal violet dye solution with clear water until running water is colorless, drying at room temperature, and reading OD on microplate reader 570 The value is obtained. The above experimental procedure was independently repeated 3 times, and the data were expressed as mean ± standard deviation (mean ± SD).
Detecting the growth of planktonic bacteria of the strain: after the strain was cultured overnight at 37 ℃ and 220rpm/min in MHB medium for 10-12h, it was diluted with fresh MHB medium 1 (with or without Lo-SH), cultured at 37 ℃ and 220rpm/min for 24h, and the OD was read on a microplate reader every 1h 600 The value is obtained.
As shown in figures 1 to 4, lo-SH can obviously inhibit the biofilm formation of standard staphylococcus aureus HG003 and 16 clinical isolates at the concentration of 25 mu M, but has no influence on the growth of planktonic bacteria.
Example 2
The compound Lo-SH inhibits the generation of staphylococcus aureus aureogenesis and hemolytic activity.
Detecting golden yellow pigment of the strain: after incubation with TSB medium at 37 ℃ for 48h (with or without Lo-SH), 3ml of the bacterial culture was centrifuged and washed twice with 0.01M Phosphate Buffered Saline (PBS). After the bacterial precipitation is washed by PBS, the supernatant is discarded, 300ul of methanol (100%) is added into the bacterial precipitation, the resuspended bacterial liquid is blown and beaten, the cell is shaken for 5 minutes after the resuspension, the cell is centrifuged (12000 r/min and 1-2 minutes), then the supernatant extract is sucked into a clean EP tube, then 300-350ul of methanol (100%) is added into the bacterial precipitation, the operation is repeated for 2 times, the extract is sucked out every time, finally about 1ml of the extract sucked together for 3 times is fully mixed, 200ul of the extract is added into a 96-well plate (3-well), and the OD450 value is measured on an enzyme-labeling instrument. The above experimental procedure was independently repeated 3 times, and the data were expressed as mean ± standard deviation (mean ± SD).
And (3) detecting hemolytic activity of the strain: strain 1. Mu.l of each strain supernatant and 1% rabbit erythrocytes were mixed in 1.5ml EP tubes, tritonX-100 as positive control (100% hemolysis), 1 XPBS as negative control, incubated at 37 ℃ for 15min, centrifuged for 15min, 100. Mu.l of supernatant was transferred to a new 96-well plate and the absorbance read at 550 nm. The above experimental procedure was independently repeated 3 times, and the data were expressed as mean ± standard deviation (mean ± SD). In fig. 5, the color of the control group is golden yellow, while the color of the present embodiment is off white.
As shown in FIGS. 5 to 7, lo-SH (25. Mu.M) can significantly inhibit the generation of Staphylococcus aureus of 5 strains, and significantly reduce the hemolytic activity of the strains.
Example 4
Test for increasing survival rate of mice infected with staphylococcus aureus lung by treating with compound Lo-SH.
A C57BL/6J mouse staphylococcus aureus lung infection model is constructed to evaluate the inhibition effect of Lo-SH on the toxicity of staphylococcus aureus. The method comprises the following steps: 6-8 week-old C57BL/6J mice (18-20 g/mouse) were selected, 15 mice per group. The mice were anesthetized by intraperitoneal injection of 11.8mg/L sodium pentobarbital at 100ul, and 1 hour after anesthesia, staphylococcus aureus HG003 strain (2.0x10) 9 cfu) were titrated into nose, 20ul bacteria solution/mouse, then the experimental mice started to inject Lo-SH into the abdominal cavity 2 times in 1 day, each dose is 10mg/kg, and the duration is 1 week, and the accumulated total dose reaches 140mg/kg. Mice were observed daily for survival. The above experimental procedures were independently repeated at least 2 times.
As shown in FIG. 8, the survival rate of mice infected with the lung of the HG003 strain of Staphylococcus aureus can be significantly improved by treating Lo-SH for 1 week and accumulating the dosage of 140mg/kg.
Example 5
Inhibition experiment of compound Lo-SH on growth of staphylococcus aureus
This example uses the standard tube dilution recommended by the Clinical and Laboratory Standards Institute (CLSI) of the United states, as follows:
1. bacteria were inoculated in fresh MH liquid medium and cultured overnight at 37 ℃.
2. Correcting the concentration of the bacterial liquid to 0.5 McLeod turbidity standard by using a fresh MH liquid culture medium, and then adding the MH liquid culture medium according to the ratio of 1:200 dilution, 1mL of Lo-SH (solvent DMSO final concentration is kept at 1%) with different concentration gradients, and incubation at 37 ℃ for 18 hours. As Lo-SH is dissolved in DMSO, 0.1% DMSO + bacteria is used as a control, and a sterile medium is used as a blank.
3. And taking out and comparing with a blank control, wherein the tube with the lowest concentration in which bacteria do not grow is the minimum inhibitory concentration of the compound.
The results show that Lo-SH has no inhibitory effect on the growth of Staphylococcus aureus.
Example 6
A cytotoxicity assay for detecting compound Lo-SH by MTT method comprising the steps of:
1. freshly cultured Vero cellsSeeded in 96-well plates at 100. Mu.L cells per well (approximately 5X 10) 4 Cells), 37 ℃,5% CO 2 The cells were incubated for 24 hours under conditions to allow the cells to grow into a monolayer.
2. Discarding the medium, adding 100. Mu.L/well fresh MEM medium containing varying concentrations of the compound Lo-SH (final concentration of DMSO solvent is maintained at 0.1%), loading each sample in 6 replicate wells, 37 ℃,5% CO 2 The culture was continued under the conditions for 24 hours. As Lo-SH is dissolved in DMSO, 0.1% DMSO + cells are used as a control.
3. Add 10. Mu.L of MTT marker per well, 37 ℃ C., 5% CO 2 Incubated under conditions for 4 hours.
4. Adding 100. Mu.L of a dissolving solution per well, 37 ℃ and 5% CO 2 Incubated overnight under conditions.
5. The 96-well plate was taken out to read the OD 570 Values, taking the mean of 6 wells per sample reading, calculate the inhibition rate of different concentrations of compound on Vero cell growth:
half inhibition amount CC 50 The values were calculated using the Logit method. Table 1 shows the toxic effect of Lo-SH compound on Vero cells.
TABLE 1 toxic Effect of Lo-SH on Vero cells results
The results show that no toxicity to Vero cells was observed.
Example 7
An erythrocyte hemolysis experiment comprises the following steps:
1. the isolated healthy human red blood cells were washed 3 times with sterile physiological saline and diluted to 5%.
2. Adding small molecule compound Lo-SH (solvent DMSO final concentration is kept at 1%) with different concentrations into 5% erythrocyte suspension, inoculating 200 μ l per well on 96-well plate, and taking three wells for each sample. As Lo-SH is dissolved in DMSO, 0.1% DMSO + cells are used as a negative control, 1% cell-permeable Triton-100+ cells are used as a positive control, and two common antibiotics, cefazolin and vancomycin, are used as controls. Incubate at 37 ℃ for 1 hour, centrifuge, and transfer 100. Mu.l of the supernatant to another clean 96-well plate, OD 570 Readings were taken, and each sample reading was averaged over triplicate wells.
Table 2 is the result of the toxic effect of compound Lo-SH on red blood cells.
TABLE 2 toxic Effect of Lo-SH on Red blood cells
The results show that: the small molecular compound Lo-SH has no hemolytic effect on human erythrocytes.
The foregoing is a further detailed description of the invention in connection with specific preferred embodiments and it is not intended to limit the invention to the specific embodiments described. For those skilled in the art to which the invention pertains, numerous simple deductions or substitutions may be made without departing from the spirit of the invention, which shall be deemed to belong to the scope of the invention.
Claims (7)
1. An inhibitor Lo-SH against virulence and biofilm formation of Staphylococcus aureus, comprising: the chemical structural formula is shown as formula (1):
2. a medicament for inhibiting staphylococcus aureus virulence and biofilm formation, comprising: which comprises an inhibitor of virulence and biofilm formation of s.aureus Lo-SH as claimed in claim 1.
3. The medicament for inhibiting staphylococcus aureus virulence and biofilm formation as claimed in claim 2, wherein the medicament comprises: the medicine is liquid, and the concentration of Lo-SH in the medicine is not less than 25 mu M.
Use of Lo-SH in the manufacture of a medicament for inhibiting Staphylococcus aureus virulence and biofilm formation, characterised in that: the chemical structural formula of Lo-SH is shown as the following formula (1):
use of Lo-SH for the preparation of a medicament for the treatment of a disease caused by Staphylococcus aureus, characterized in that: the chemical structural formula of Lo-SH is shown as the following formula (1):
6. use of Lo-SH according to claim 5 for the preparation of a medicament for the treatment of diseases caused by Staphylococcus aureus, characterized in that: the medicine is liquid, and the concentration of Lo-SH in the medicine is not less than 25 mu M.
The application of Lo-SH in preparing a disinfectant for medical instruments or medical appliances is characterized in that: the disinfectant comprises Lo-SH, and the chemical structural formula of the Lo-SH is shown as the following formula (1):
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