CN113750084A - New application of phthalazinone sulfate as NDM-1 inhibitor or antibiotic protective agent - Google Patents
New application of phthalazinone sulfate as NDM-1 inhibitor or antibiotic protective agent Download PDFInfo
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- CN113750084A CN113750084A CN202111065293.8A CN202111065293A CN113750084A CN 113750084 A CN113750084 A CN 113750084A CN 202111065293 A CN202111065293 A CN 202111065293A CN 113750084 A CN113750084 A CN 113750084A
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- Prior art keywords
- ndm
- phthalazinone
- beta
- antibiotic
- bacteria
- Prior art date
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Classifications
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- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
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Abstract
The invention discloses a new application of phthalazinone-acetate as an NDM-1 inhibitor or an antibiotic protective agent, belonging to the field of new medical application of phthalazinone-acetate. According to the invention, through NDM-1 enzyme inhibition test, a trace chessboard dilution method, a time-sterilization curve and other tests, the phthalazinone can obviously inhibit the activity of NDM-1 and recover the antibacterial activity of meropenem to NDM-1-producing escherichia coli, so that the phthalazinone can be used as an NDM-1 inhibitor, and the phthalazinone can be used in combination with beta-lactam antibiotics to reduce or even eliminate the hydrolysis of NDM-1 to the beta-lactam antibiotics and recover the sensitivity of drug-resistant bacteria to the beta-lactam antibiotics.
Description
Technical Field
The invention relates to a new pharmacological application of phthalazinone acetate, in particular to a new pharmacological application of phthalazinone acetate as an NDM-1 inhibitor or an antibiotic protective agent, belonging to the field of new pharmacological activity of phthalazinone acetate.
Background
The beta-lactam antibiotics have strong bactericidal activity, low toxicity and wide adaptation diseases, and are important medicaments for treating infectious diseases caused by bacteria at present. Beta-lactam antibiotics include carbapenems, cephalosporins, penicillins, and the like, all of which structurally have a beta-lactam ring that exerts antibacterial activity. With the widespread use of beta-lactam antibiotics, more and more bacteria are developing beta-lactamase mediated resistance.
The production of beta-lactamase, which catalyzes the cleavage of the C-N bond at the beta-lactam ring in beta-lactam antibiotics to open the ring, resulting in inactivation of the antibiotic, is one of the important mechanisms for inducing bacterial resistance. Based on amino acid sequence homology, beta-lactamase can be divided into serine-beta-lactamase and metallo-beta-lactamase, and the serine-beta-lactamase plays a catalytic role depending on serine of an active center and can be inhibited by clinically used antibiotics such as clavulanic acid, sulbactam, tazobactam and the like. The metallo-beta-lactamase plays a catalytic role by depending on zinc ions of an active center, can hydrolyze all beta-lactam antibiotics including carbapenems, widely exists in various gram-negative and positive pathogenic bacteria, and has no clinically effective inhibitor.
In 8 months 2010, a new Delhi metallo-beta-lactamase-1 (NDM-1) which hydrolyzes carbapenem drugs is reported in a J.Lancet.Scent, and is called as 'super bacteria' because NDM-1-producing bacteria have wide drug resistance to cause difficult infection treatment. The blaNDM-1 gene is positioned on a plasmid, can be independently replicated outside chromosomes and can be horizontally transferred among different strains, so that strains which are originally sensitive to antibiotics can obtain drug resistance. NDM-1 is metallo beta-lactamase which is discovered in recent years and has the widest influence range and the most serious harm degree, shows high drug resistance to almost all antibiotics, only tigecycline and polymyxin have certain inhibition effect on the antibiotics, and the continuously evolved mutant strains make clinical treatment harder. NDM-1 can hydrolyze beta-lactam antibiotics commonly used in clinic, and the inhibitor can inhibit the activity of NDM-1 enzyme, so that the beta-lactam antibiotics are protected, and the antibacterial effect of the beta-lactam antibiotics is recovered, therefore, the search for the inhibitor of NDM-1 is the most urgent requirement for inhibiting infection caused by 'super bacteria'.
The phthalylsulfonamide is a sulfonamide broad-spectrum bacteriostatic agent, slowly decomposes in intestines after being taken orally to release sulfonamidoacyl to generate an intestinal bacteriostatic action, has antibacterial action on gram positive bacteria and gram negative bacteria, and is mainly used for clinically treating bacillary dysentery, diarrhea, enteritis and infection prevention before and after intestinal tract operation. Until now, no report about the application of the phthalazinone-1 inhibitor is available at home and abroad.
Disclosure of Invention
The invention mainly aims to provide a new application of the phthalazinone-1 inhibitor or the antibiotic protective agent.
In order to achieve the above object, the technical solution adopted by the present invention comprises:
on the one hand, the invention discloses a new pharmacological application of the phthalazinone-acetate amide as an NDM-1 inhibitor, namely, the hydrolysis of NDM-1 on beta-lactam antibiotics is inhibited, and the antibacterial activity of the beta-lactam antibiotics on NDM-1-carrying positive bacteria is recovered. Thus, phthalazinone can be used as an antibiotic protectant, in particular as a protectant of beta-lactam antibiotics.
The invention provides a pharmaceutical composition for inhibiting pathogenic bacteria, which comprises an effective amount of antibiotics, an antibiotic protective agent and a pharmaceutically acceptable carrier or auxiliary material, wherein the antibiotics are preferably beta-lactam antibiotics; the antibiotic protective agent is phthalylsulfonamide.
The pharmaceutical composition for inhibiting pathogenic bacteria is prepared into clinically common preparations according to the conventional preparation method in the field, such as powder, granules, tablets, capsules, injections and the like, and is introduced into muscle, endothelium, subcutaneous, vein and mucosal tissues by injection, oral administration, nasal drip, eye drop, physical or chemical mediated methods, or is mixed or coated by other substances and then is introduced into the body.
The carrier or the auxiliary material refers to a carrier or an auxiliary material which is conventional in the pharmaceutical field, such as: diluents, disintegrants, lubricants, excipients, binders, glidants, fillers, surfactants, and the like; in addition, other adjuvants such as flavoring agents and sweeteners may also be added to the composition.
The diluent may be one or more ingredients that increase the weight and volume of the tablet; common diluents include lactose, starch, pregelatinized starch, microcrystalline cellulose, sorbitol, mannitol, and inorganic calcium salts. The most common of them are lactose, starch, microcrystalline cellulose.
The disintegrant can be one or more of crosslinked polyvinylpyrrolidone (with a total weight ratio of 2-6%), crosslinked sodium carboxymethylcellulose (with a total weight ratio of 2-6%), alginic acid (with a total weight ratio of 2-5%), and microcrystalline cellulose (with a total weight ratio of 5-15%). Wherein the preferred ratio is crosslinked polyvinylpyrrolidone (2-7% by weight) and crosslinked sodium carboxymethylcellulose (2-6% by weight). Most preferably crosslinked polyvinylpyrrolidone (in a ratio of 2-6% by weight relative to the total weight).
The lubricant comprises one or a mixture of stearic acid, sodium stearate, magnesium stearate, calcium stearate, polyethylene glycol, talcum powder and hydrogenated vegetable oil. Magnesium stearate is most preferred. The amount of the lubricant is in the range of 0.10 to 1% (by total weight), and is generally 0.25 to 0.75%, and preferably 0.5 to 0.7%.
The binder may be one or more ingredients that facilitate granulation. It may be starch slurry (10-30% by weight of the total binder), hydroxypropyl methylcellulose (2-5% by weight of the total binder), polyvinylpyrrolidone (2-20% by weight of the total binder), preferably ethanol aqueous solution of polyvinylpyrrolidone, and most preferably 50% ethanol aqueous solution of polyvinylpyrrolidone.
The glidant can be one or a mixture of more of superfine silica gel powder, talcum powder and magnesium trisilicate.
The surfactant may be one or more components that improve wetting and increase drug dissolution. Sodium lauryl sulfate is often used (the usual range is 0.2-6% by weight, based on the total weight).
The phthalazinone sulfate in the invention comprises a prototype, a pharmaceutically acceptable salt or a preparation containing the phthalazinone sulfate.
The beta-lactam in the present inventionThe representative drug of the amine antibiotics is meropenem, and the molecular formula is as follows: c17H25N3O5S, molecular weight is: 383.5.
the NDM-1 enzyme is a recombinant NDM-1 enzyme extracted from nature or prepared by using genetic engineering bacteria.
The "pathogenic bacteria" in the invention are preferably gram-negative or positive pathogenic bacteria, more preferably NDM-1 positive bacteria.
Phthalazinone, alternative name: phthalyl sulfoacetamide, cumamide, and carbobenzoyl sulfoacetamide, also known as cumamide. White crystalline powder, slightly smelly and slightly sour, with a melting point of 186-202 ℃, very slightly soluble in water, slightly soluble in ethanol, soluble in acetone and easily soluble in sodium hydroxide solution, and prepared by acylation of sulfanilamide and phthalic anhydride. The molecular formula is as follows: c16H14N2O6S, molecular weight: 362.4, having the formula:
the invention verifies that the phthalsultam can inhibit the activity of NDM-1 and recover the antibacterial activity of meropenem to NDM-1-carrying drug-resistant bacteria through NDM-1 enzyme inhibition tests, enzyme inhibition rate and half inhibition concentration tests, chessboard method determination minimum inhibitory concentration, time-sterilization curve methods and other tests, and the like, and the phthalsultam has wide medical application in treating bacterial infectious diseases.
Detailed description of the invention
The invention uses NDM-1 (PDB: 4EY2) crystal structure in protein database as target protein, applies computer aided drug design software GLIDE and MAESTRO, and calculates the binding free energy of the binding site of the phthalein-amide and NDM-1 ligand by molecular docking method. The docking product binding free energy is less than-10.0 Kcal/mol, and the phthalazinone is tightly bound in the active region of NDM-1 with zinc ion as the center, so the phthalazinone is considered as a candidate compound with potential NDM-1 inhibition effect.
On the basis, the invention detects the inhibition activity of the phthalazinone to NDM-1 enzyme, and the detection test result shows that the phthalazinone can inhibit the activity of the NDM-1 enzyme in a dose-dependent manner, the maximum inhibition rate is 87.5 percent, and the IC50 is 23.5 +/-1.3 mu M.
The test result of the minimum inhibitory concentration shows that the phthalsultam alone has no inhibitory effect, and the combined use of the phthalsultam and the meropenem can reduce the MIC value of the meropenem to NDM-1 positive escherichia coli by 4 times. FIC index shows that the joint use of the phthalazinone-sulfoacetate and the meropenem has obvious synergistic effect on inhibiting the strain producing NDM-1.
According to the test result of the time-sterilization curve, the combination of the phthalazinone and the meropenem can obviously inhibit the growth of NDM-1 positive escherichia coli.
Drawings
FIG. 1 is a diagram of the active area combination mode of a phthalylsulfonamide-NDM-1 composite system.
FIG. 2 is a time sterilization curve of phthalosulfamide in combination with meropenem on NDM-1 positive E.coli.
Detailed Description
The invention is further described below in conjunction with specific embodiments, the advantages and features of which will become apparent from the description. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be within the scope of the invention.
Test example 1 molecular docking test of phthalylsulfonamide and target protein NDM-1
The experiment uses the crystal structure of NDM-1 (PDB: 4EY2) in a protein database as a target protein, applies computer-aided drug design software GLIDE and MAESTRO, and calculates the binding free energy of the binding site of the phthalein-amide and NDM-1 ligand by adopting a molecular docking method. Molecular docking results found that the docking product binding free energy was less than-10.0 Kcal/mol, and that the phthalamide was tightly bound to the active region of NDM-1 centered on zinc ion (fig. 1), and therefore the phthalamide was considered as a candidate compound having a potential NDM-1 inhibitory effect.
Experimental example 2 expression of NDM-1 protein and isolation and purification
The gene sequence of blaNDM-1 is inserted into pET32 (alpha) plasmid through EcoRI and Xho I enzyme cutting sites to construct pET32 (alpha) -NDM-1 recombinant plasmid, and DNA sequencing verifies that the blaNDM-1 gene has no mutation in the connection process.
The recombinant plasmid is transferred into escherichia coli BL21(DE3) competent cells, screening is carried out through an ampicillin plate, a monoclonal colony is selected and inoculated into 5mL LB liquid culture medium, shaking is carried out at 37 ℃ and 180rpm overnight, 50% glycerol and bacterial liquid are mixed according to the proportion of 1:1, and the engineering bacteria E.coli BL21(DE3) -pET32 (alpha) -NDM-1 is preserved at-80 ℃.
Culturing the engineering bacteria in LB culture medium containing ampicillin at 37 deg.C and 180rpm to logarithmic growth phase with OD value of 0.6-0.8, inducing with isopropyl-beta-D-thiogalactoside (IPTG) with final concentration of 1mM at 37 deg.C for 4.5h, and centrifuging at 4 deg.C to collect bacteria.
The collected bacteria were resuspended in phosphate buffer (PBS, pH 8.0), the bacterial suspension was disrupted by an ultrasonic cell disruptor in ice bath, the bacterial lysate was centrifuged, the supernatant was collected and passed through a Ni-NTA His tag affinity column, and NDM-1 protein was isolated and purified by gradient elution using 0, 10, 20, 40, and 250mM imidazole. And finally, carrying out dialysis on the NDM-1 protein by using a dialysis bag with the molecular cut-off of 10KD for 36h to remove salt, concentrating by using an ultrafiltration tube with the molecular cut-off of 10KD, and detecting an NDM-1 protein expression and purification result by SDS-PAGE (sodium dodecyl sulfate-polyacrylamide gel electrophoresis) imprinting to obtain the NDM-1 recombinant protein with the purity of more than 90%.
Test example 3 inhibition of NDM-1 enzyme by phthalazinesulfonamide
The enzyme inhibition reaction system comprises 120 mu M meropenem as a substrate, 10mM 4-hydroxyethyl piperazine ethanesulfonic acid (HEPES, pH 8.0) as a buffer solution, NDM-1 enzyme in 3.0U and a phtaloacetamide solution with different concentration gradients, the incubation is carried out for 15min at the temperature of 30 ℃, and the enzyme activity is detected by using a microplate reader at the wavelength of 295 nm. Meanwhile, EDTA is used as a positive control, DMSO is used as a negative control, and a blank control group does not contain an inhibitor or an enzyme and is used as a bottom value of the system. Reactions were performed in 96-well plates, each reaction provided 3 replicate wells.
The specific process is as follows:
firstly, preparing a buffer solution for NDM-1 enzyme into a solution with the concentration of 3.0U, and incubating the solution at 30 ℃ for 10min to ensure that Zn is formed2+Fully occupy the active center; dissolving the phthalazinone acetate in a buffer solution to prepare a mother solution with the concentration of 100mM, then diluting the mother solution in a gradient manner, adding the diluted mother solution into NDM-1 enzyme, and incubating for 10min at 30 ℃ to ensure that the phthalazinone acetate and the enzyme are fully combined; adding 50 mu L of meropenem into a 96-pore plate reaction system, placing the mixture into an enzyme labeling instrument, oscillating and uniformly mixing the mixture, and incubating the mixture for 15min at the temperature of 30 ℃ to detect the 295nm ultraviolet absorption change. Calculating the inhibition rate of the phthalazinone-1 enzyme hydrolysis substrate by different concentrations, wherein the calculation formula of the inhibition rate is as follows:
inhibition (%). ratio (1-phthalazinone sample enzyme reaction rate/average enzyme reaction rate of negative control well) × 100%
The half-inhibitory concentration IC50 value of the phthalazinone to NDM-1 is calculated, and the result shows that the phthalazinone can inhibit the activity of NDM-1 enzyme in a dose-dependent manner, the maximum inhibition rate is 87.5%, and the IC50 is 23.5 +/-1.3 mu M.
Test example 4 test for minimum inhibitory concentration
2 mu.L of NDM-1 positive Escherichia coli is inoculated into 5mL of LB culture medium, and the culture is carried out at 37 ℃ and 180rpm shaking for activation for about 12h until the bacteria are in the late logarithmic phase. Taking the bacterial liquid into MH broth culture medium, adjusting the concentration of the bacterial liquid to 5 × 106CFU/mL, adopting trace broth dilution method to respectively carry out drug sensitivity test of phthalsultam and meropenem (concentration gradient is 1-2048 mu g/mL), and meanwhile, setting bacterial suspension without meropenem as positive control and MH broth as negative control. After the 96-well plate is cultured for 24h at 37 ℃, MIC results are read and are all operated in parallel for 3 times, and the MIC value of the medicine is the medicine concentration of a clear well in front of a turbid well in the 96-well plate.
Taking the activated and cultured bacterial liquid, matching a 96-pore plate by adopting a chessboard method, simultaneously detecting 77 possible concentration combinations, adding the phthalazinone and meropenem with different concentration combinations, placing the 96-pore plate in a constant-temperature biochemical incubator at 37 ℃ for incubation for 24h, carrying out an antibacterial activity experiment of the phthalazinone and meropenem combined with NDM-1 positive bacteria, and determining the minimum inhibitory concentration MIC value of the two combined applications. And simultaneously setting a negative control group and a positive control group, performing parallel operation for 3 times, and calculating a part of antibacterial concentration index FIC value according to the MIC value by the following calculation method:
FIC ═ MIC (combined Meropenem)/MIC (single Meropenem) + MIC (combined phthalazinone)/MIC (single phthalazinone)
When FICI is less than or equal to 0.5, the FICI and the FICI act synergistically; 0.5< FICI is less than or equal to 4, and the two are unrelated; FICI >4, both antagonistic.
TABLE 1 MIC and FIC values of meropenem in combination with phthalazinone for NDM-1 expressing positive E.coli
The test result of the minimum inhibitory concentration shows that the phthalsultam alone has no inhibitory effect, and the combined use of the phthalsultam and the meropenem can reduce the MIC value of the meropenem to NDM-1 positive escherichia coli by 8-32 times. FIC index shows that the joint use of the phthalazinone-sulfoacetate and the meropenem has obvious synergistic effect on inhibiting the strain producing NDM-1.
Test example 5 time-Sterilization Curve test
Selecting single colony from a pure culture plate of NDM-1 positive escherichia coli, inoculating the single colony in MH broth culture medium at 37 ℃ for culturing for 6-8 h, taking bacterial culture, and adjusting the concentration of the bacterial liquid to 5 multiplied by 10 by using a Mach turbidimeter and sterile physiological saline7CFU/mL, and 10-fold dilution in sterile MH broth to a final concentration of 106CFU/mL。
A blank control group without antibiotics, a meropenem group with the concentration of 8 mu g/mL and a combination group with the concentration of 32 mu g/mL of phthalein acephate are arranged. The test group and the control group were cultured at 37 ℃ under the same concentration of bacterial solution, a quantitative culture solution was taken out from each group at 0, 1, 3, 5, 7, 9, and 11 hours, and transferred to the corresponding agar medium, and after culturing at 37 ℃ for 18 to 24 hours, the number of colonies was counted, and a time-sterilization curve was plotted with the logarithm of the number of colonies as the ordinate and the culture time as the abscissa (FIG. 2).
According to the time-sterilization curve shown in fig. 2, it can be seen that the combination of phthalazinone and meropenem can significantly inhibit the growth of NDM-1 positive escherichia coli.
Claims (10)
1. Use of phthalazinone in the preparation of a neodrime-beta-lactamase-1 inhibitor.
2. The use of phthalazinone in the preparation of antibiotic protectants.
3. Use according to claim 2, characterized in that: the antibiotic is a beta-lactam antibiotic.
4. Use according to claim 3, characterized in that: the beta-lactam antibiotics comprise carbapenems, cephalosporins or penicillins.
5. Use according to claim 1 or 2, characterized in that: the phthalamide comprises a prototype, a pharmaceutically acceptable salt thereof, or a formulation comprising phthalamide.
6. A pharmaceutical composition for inhibiting pathogenic bacteria, comprising: a prophylactically or therapeutically effective amount of an antibiotic, an antibiotic protectant, and a pharmaceutically acceptable adjuvant or carrier; wherein the antibiotic protective agent is phthalylsulfonamide.
7. The pharmaceutical composition according to claim 6, wherein: the pathogenic bacteria are bacteria.
8. The pharmaceutical composition according to claim 7, wherein: the bacteria are gram-negative or gram-positive pathogenic bacteria, preferably NDM-1 positive bacteria.
9. The pharmaceutical composition according to claim 6, wherein: the beta-lactam antibiotics comprise carbapenems, cephalosporins or penicillins.
10. The pharmaceutical composition according to claim 6 or 9, characterized in that: the beta-lactam antibiotic is meropenem.
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| MURCIA-SOLER, MIGUEL等: "Discrimination and selection of new potential antibacterial compounds using simple topological descriptors", JOURNAL OF MOLECULAR GRAPHICS & MODELLING, vol. 21, no. 5, pages 375 - 390, XP002986362, DOI: 10.1016/S1093-3263(02)00184-5 * |
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