CN106377757B - Application of oxygen-containing hydrocarbon derivative as synergist of polymyxin - Google Patents
Application of oxygen-containing hydrocarbon derivative as synergist of polymyxin Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition containing a polymyxin synergist and application thereof. The oxygen-containing hydrocarbon derivatives containing 4-18 carbon atoms, including fatty alcohol, fatty acid and fatty glyceride, can be used as a polymyxin synergist, particularly as a synergist for inhibiting sensitive strains of polymyxin and a drug resistance reversal agent of polymyxin, and discloses a medicinal composition of the polymyxin synergist.
Description
Technical Field
The invention belongs to the field of biomedicine, and particularly relates to an application of oxygen-containing hydrocarbon derivatives as a synergistic agent of polymyxin.
Background
Polymyxin is a polypeptide antibiotic extracted from a polymyxin fermentation broth, and mainly comprises five different components of polymyxin A, B, C, D, E and the like. Among them, polymyxin B is used in clinical human medicine and is considered as the ultimate weapon for humans against carbapenem-resistant Enterobacteriaceae bacteria, and polymyxin E is one of the most widely used growth promoters for animal antibiotics. With the widespread use of antibiotics, bacterial resistance has become a global medical problem, especially with the problem of multidrug resistance (MDR) in gram-negative bacteria. Recent reports of coliform resistance mediated by the new resistance gene MCR-1 of polymyxin and the possibility of its horizontal transmission have led to a global panic discussion of bacterial resistance, and there is a fear that polymyxin will be breached as the last line of defense in the chemotherapy of human bacterial diseases. Over the past decades, attempts have been made to delay or eliminate bacterial resistance, but significant progress has been made. Therefore, the development of a composition capable of eliminating the drug resistance of polymyxin is of great significance in improving the effect of polymyxin and prolonging the service life thereof. In addition, because the systemic toxicity of the polymyxin is very high and the polymyxin cannot be used at high dose, if a compound pharmaceutical preparation (especially an injection) is developed by the components with synergistic interaction, the method has practical significance for reducing the toxic and side effects of the polymyxin and improving the safety and curative effect of the medicine.
Disclosure of Invention
The invention aims to provide a drug for treating diseases caused by infection of polymyxin sensitive bacteria or drug-resistant bacteria, wherein oxygen-containing hydrocarbon derivatives containing 4-18 carbon atoms are used as a synergistic agent of polymyxin.
The polymyxin synergist is a novel non-antibiotic polymyxin synergist and is an oxygen-containing hydrocarbon derivative containing 4-18 carbon atoms.
The oxygen-containing hydrocarbon derivative containing 4-18 carbon atoms is used as a synergistic agent of polymyxin in preparation of a medicine for treating diseases caused by infection of polymyxin sensitive bacteria or drug-resistant bacteria.
In a synergistic technical scheme, the oxygen-containing hydrocarbon derivative containing 4 to 18 carbon atoms is a linear chain or branched chain saturated or unsaturated fatty alcohol containing 4 to 18 carbon atoms, and the structure of the oxygen-containing hydrocarbon derivative is shown as a formula I:
wherein R is1Is selected from C3-17Linear or branched saturated alkyl, C3-17A linear or branched unsaturated alkyl group.
In a synergistic technical scheme, R is1Preferably selected from C9-11Linear or branched saturated alkyl, C9-11A linear or branched unsaturated alkyl group.
In another synergistic technical scheme, the oxygen-containing hydrocarbon derivative containing 4 to 18 carbon atoms is a linear chain or branched chain saturated or unsaturated fatty aldehyde containing 4 to 18 carbon atoms, and has a structure shown as a formula II:
wherein R is2Is selected from C3-17Linear or branched saturated alkyl, C3-17A linear or branched unsaturated alkyl group.
In another synergistic embodiment, the fatty aldehyde is preferably a linear or branched, saturated or unsaturated fatty aldehyde containing from 10 to 12 carbon atoms.
In another synergistic technical scheme, the oxygenated hydrocarbon derivative containing 4 to 18 carbon atoms is a linear or branched chain saturated or unsaturated fatty acid containing 4 to 18 carbon atoms, and has a structure shown in a formula III:
wherein R is3Is C3-17Straight-chain or branched saturated alkyl or C3-17A linear or branched unsaturated alkyl group.
In another synergistic technical scheme, R is3Preferably C9-11Straight-chain or branched saturated alkyl or C9-11A linear or branched unsaturated alkyl group.
In another synergistic technical scheme, the oxygen-containing hydrocarbon derivative containing 4 to 18 carbon atoms is an esterified derivative of a linear or branched saturated or unsaturated fatty acid containing 4 to 18 carbon atoms, the structure of which is shown as a formula IV:
wherein R is4Is selected from C3-17Linear or branched saturated alkyl, C3-17A linear or branched unsaturated alkyl group; r5Is selected from C1-18Linear or branched saturated alkyl, C1-18Linear or branched unsaturated alkyl, C1-18Straight or branched chain hydroxy-substituted alkyl.
Further, the esterified derivative of the straight chain or branched chain saturated or unsaturated fatty acid containing 4-18 carbon atoms is glyceride thereof.
In another synergistic embodiment, the glyceride of a saturated or unsaturated fatty acid, straight or branched, containing from 4 to 18 carbon atoms is preferably a monoglyceride of that fatty acid.
In another synergistic embodiment, the glyceride of a saturated or unsaturated fatty acid, straight or branched, containing from 4 to 18 carbon atoms is preferably a diglyceride of the fatty acid.
In another synergistic embodiment, the glyceride of a linear or branched, saturated or unsaturated fatty acid containing from 4 to 18 carbon atoms is a triglyceride of the fatty acid.
In another synergistic embodiment, the carbonyl end of the esterified derivative of a linear or branched, saturated or unsaturated fatty acid having from 4 to 18 carbon atoms is preferably a carbonyl group having from 10 to 12 carbon atoms.
The invention can combine oxygen-containing hydrocarbon derivatives containing 4-18 carbon atoms with polymyxin to form the pharmaceutical composition.
The invention provides a pharmaceutical composition, which comprises the polymyxin synergist containing the oxygen-containing hydrocarbon derivative with 4-18 carbon atoms and polymyxin.
In one embodiment, the pharmaceutical composition further comprises a pharmaceutically acceptable excipient, carrier, adjuvant, vehicle or any combination thereof.
In one embodiment, the pharmaceutical composition further comprises polymyxin.
In another embodiment, the polymyxin is selected from polymyxin a, polymyxin B, polymyxin C, polymyxin D, polymyxin E, and the like.
In another embodiment, the polymyxin is preferably polymyxin B.
In another embodiment, the polymyxin is preferably polymyxin E.
The invention also provides application of the oxygen-containing hydrocarbon derivative containing 4-18 carbon atoms as a synergistic agent of polymyxin in preparation of a medicine for treating diseases caused by infection of polymyxin sensitive bacteria or drug-resistant bacteria.
In one embodiment, the pharmaceutical composition containing the polymyxin synergist is used for preparing a medicament comprising the polymyxin synergist, a pharmaceutically acceptable carrier, an excipient, a solvent and an adjuvant.
In another embodiment, the pharmaceutical composition comprising the polymyxin synergist is used for preparing a medicament comprising one of polymyxin, the polymyxin synergist, a pharmaceutically acceptable carrier, an excipient, a solvent and an adjuvant.
In another embodiment, the medicament prepared from the pharmaceutical composition containing the polymyxin synergist can be orally administered, injected or topically administered for treating diseases caused by infection of polymyxin sensitive bacteria or drug-resistant bacteria.
In one technical scheme, the medicine for treating diseases caused by the polymyxin sensitive bacteria or the drug-resistant bacteria is used for treating diseases caused by infection of the polymyxin sensitive bacteria or the drug-resistant bacteria of human beings, and comprises wound surfaces, urinary tracts, eyes, ears, trachea, skin mucosa, intestinal infection, septicemia, peritonitis, meningitis and the like.
In another technical scheme, the medicament for treating the diseases caused by the polymyxin sensitive bacteria or the drug-resistant bacteria is used for treating the diseases caused by the infection of the polymyxin sensitive bacteria or the drug-resistant bacteria in the cultured animals.
In vitro and in vivo biological experiment results show that the oxygen-containing hydrocarbon derivatives with 4-18 carbon atoms contained in the medicinal composition have weak inhibitory activity on polymyxin sensitive bacteria or drug-resistant bacteria, and when the composition is combined with polymyxin, the polymyxin has a synergistic effect on the inhibitory activity on the polymyxin sensitive bacteria or the drug-resistant bacteria.
Any embodiment of any aspect of the invention may be combined with other embodiments, as long as they do not contradict. Furthermore, in any embodiment of any aspect of the invention, any feature may be applicable to that feature in other embodiments, so long as they do not contradict. The foregoing merely outlines certain aspects of the invention, but is not limited to these aspects. These and other aspects will be more fully described below.
The term "comprising" as used herein is intended to be open-ended, meaning that certain elements not specified may be included in addition to the elements recited.
The term "alkyl" as referred to herein is a hydrocarbon group formed by removing one hydrogen atom from an alkane molecule; "C3-17The "straight-chain or branched saturated alkyl group" means that the alkyl group is a straight-chain hydrocarbon group or a branched hydrocarbon group having 3 to 17 carbon atoms and no unsaturated bond; "C3-17The straight-chain or branched-chain unsaturated alkyl group' represents a straight-chain hydrocarbon group or a branched-chain hydrocarbon group containing 3 to 17 carbon atoms and having one double bond; "C1-18Straight or branched hydroxy-substituted alkyl "refers to straight or branched chain hydrocarbon groups of 1 to 18 carbon atoms substituted with one or more hydroxy groups.
Polymyxin is five antibacterial polypeptides found in a polymyxa culture solution, including A, B, C, D, E and the like, has similar antibacterial spectra and wide range, has strong antibacterial effect on most gram-negative bacteria such as pseudomonas aeruginosa, escherichia coli, klebsiella pneumoniae, haemophilus, enterobacter, salmonella, shigella, bordetella pertussis, pasteurella, vibrio and the like, and common drug-resistant strains include partial strains of escherichia coli, pseudomonas aeruginosa, salmonella, shigella, klebsiella and the like.
The polymyxin synergistic agent is an oxygen-containing hydrocarbon derivative containing 4-18 carbon atoms, which is selected from straight-chain or branched-chain saturated or unsaturated fatty alcohol containing 4-18 carbon atoms, straight-chain or branched-chain saturated or unsaturated fatty aldehyde containing 4-18 carbon atoms, and straight-chain or branched-chain saturated or unsaturated fatty acid containing 4-18 carbon atoms, and the structures of the oxygen-containing hydrocarbon derivative are respectively shown as a formula I, a formula II and a formula III:
wherein R is1、R2And R3Is C3-17Straight-chain or branched saturated alkyl or C3-17A linear or branched unsaturated alkyl group; and may also be selected from esterified derivatives of straight or branched chain saturated or unsaturated fatty acids containing from 4 to 18 carbon atoms.
The straight or branched chain saturated or unsaturated fatty alcohol containing 4-18 carbon atoms is selected from propanol, butanol, n-pentanol, hexanol, heptanol, octanol, nonanol, decanol, undecanol, lauryl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol or the corresponding isomeric alcohols thereof, and the like, and the corresponding carbon atoms of these alcohols containing an unsaturated fatty alcohol having a chain end or double bond in the chain.
The straight chain or branched chain saturated or unsaturated fatty acid containing 4-18 carbon atoms is selected from propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid or corresponding isomeric acids thereof, and unsaturated fatty acids containing a chain end or a double bond in the chain, corresponding to the number of carbon atoms of the acids.
The linear or branched saturated or unsaturated fatty aldehyde containing 4-18 carbon atoms is selected from butyraldehyde, valeraldehyde, caproaldehyde, heptaldehyde, caprylic aldehyde, nonanal, undecanal, lauric aldehyde, myristic aldehyde, palmitic aldehyde, stearyl aldehyde, isomeric aldehydes corresponding to the aldehydes, and the like, and unsaturated fatty aldehydes containing a chain end or chain double bond corresponding to the number of carbon atoms of the aldehydes.
The esterified derivatives of linear or branched, saturated or unsaturated fatty acids having 4 to 18 carbon atoms are selected from propionic acid, butyric acid, valeric acid, caproic acid, enanthic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, or the isomeric acids thereof, or the esterification products of unsaturated fatty acids having one chain end or double bond in the chain, corresponding to the number of carbon atoms, with monohydric or polyhydric alcohols having 1 to 18 carbon atoms, such as the methyl, ethyl, propyl, butyl, amyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, lauryl, myristyl, palmityl, stearyl, monoglycerides, diglycerides, triglycerides and the like.
The oxygen-containing hydrocarbon derivative containing 4-18 carbon atoms is a petrochemical fine chemical product, and the linear or branched chain saturated or unsaturated fatty acid containing 4-18 carbon atoms can be prepared from linear or branched chain saturated or unsaturated fatty alcohol containing 4-18 carbon atoms or fatty aldehyde through oxidation, and further generates esterification reaction with alcohol to generate the esterified derivative. The selection of esterification reaction conditions such as feeding ratio, reaction temperature, catalyst and the like is controlled within a certain range, and the reaction of the fatty acid and the polyalcohol is controlled to be mono-esterification, di-esterification and the like, such as the preparation of fatty acid monoglyceride, fatty acid diglyceride and fatty acid triglyceride and the like.
The invention relates to oxygen-containing hydrocarbon derivatives containing 4-18 carbon atoms, which comprise linear or branched chain saturated or unsaturated fatty alcohol containing 4-18 carbon atoms, linear or branched chain saturated or unsaturated fatty aldehyde containing 4-18 carbon atoms, linear or branched chain saturated or unsaturated fatty acid containing 4-18 carbon atoms, esterified derivatives of linear or branched chain saturated or unsaturated fatty acid containing 4-18 carbon atoms and the like, and the Minimum Inhibitory Concentration (MIC) of each compound on polymyxin sensitive bacteria and drug-resistant bacteria and the minimum inhibitory concentration of polymyxin on the polymyxin sensitive bacteria and the drug-resistant bacteria under the culture condition of the hydrocarbon derivatives containing 4-18 carbon atoms with the same concentration are determined by a microdilution method in the research of in vitro biological experiments. The experimental result shows that the esterified derivatives of all the linear or branched saturated or unsaturated fatty alcohols containing 4 to 18 carbon atoms, the linear or branched saturated or unsaturated fatty aldehydes containing 4 to 18 carbon atoms, the linear or branched saturated or unsaturated fatty acids containing 4 to 18 carbon atoms and the linear or branched saturated or unsaturated fatty acids containing 4 to 18 carbon atoms have weak inhibitory activity on polymyxin sensitive bacteria (MIC <4.0ppm) and drug-resistant bacteria (MIC >4.0ppm), and the MIC is more than or equal to 800 ppm; all the linear chain or branched chain saturated or unsaturated fatty alcohol containing 4-18 carbon atoms and the linear chain or branched chain saturated or unsaturated fatty acid containing 4-18 carbon atoms act on a test strain together with polymyxin under the same concentration during in vitro biological experiment research, the action effect of the polymyxin on sensitive bacteria is enhanced by 10-20 times, the action effect on drug-resistant strains is more obvious and enhanced by about 50 times, and the synergistic effect on the polymyxin sensitive bacteria and the effect on drug resistance reversion of the polymyxin resistant bacteria are obviously shown; however, the esterified derivatives of linear or branched, saturated or unsaturated fatty acids containing 4 to 18 carbon atoms act in vitro with polymyxin, the effect of polymyxin on sensitive or resistant bacteria being largely identical or similar to that of the individual application test of polymyxin, and surprisingly the esterified derivatives have a synergistic effect in vitro, such as monoglycerides of the fatty acids and diglycerides of the fatty acids, on polymyxin when free hydroxyl groups are present.
The oxygenated hydrocarbon derivatives containing 4-18 carbon atoms, which are provided by the invention, comprise straight-chain or branched-chain saturated or unsaturated fatty alcohol containing 4-18 carbon atoms, straight-chain or branched-chain saturated or unsaturated fatty aldehyde containing 4-18 carbon atoms, straight-chain or branched-chain saturated or unsaturated fatty acid containing 4-18 carbon atoms, esterified derivatives of straight-chain or branched-chain saturated or unsaturated fatty acid containing 4-18 carbon atoms, and the like, and after the experimental mice are subjected to intramuscular injection of experimental strains in vivo in the research of biological experiments, the combined treatment of all oxygenated hydrocarbon derivatives containing 4-18 carbon atoms and polymyxin, which are provided by the invention, is carried out, and the survival rate of the mice in the experimental process is counted. The experimental result shows that compared with a blank non-administration toxicity attacking group and a polymyxin administration positive control group, the experimental group combines with the polymyxin in vitro to obtain the fatty acid monoglyceride without synergistic effect or drug resistance reversal effect on the polymyxin, and the synergistic effect is shown in an in vivo treatment experiment.
Further, the oxygen-containing hydrocarbon derivatives containing 4-18 carbon atoms in the invention comprise linear or branched chain saturated or unsaturated fatty alcohol containing 4-18 carbon atoms, linear or branched chain saturated or unsaturated fatty aldehyde containing 4-18 carbon atoms, linear or branched chain saturated or unsaturated fatty acid containing 4-18 carbon atoms, esterified derivatives of linear or branched chain saturated or unsaturated fatty acid containing 4-18 carbon atoms and the like, and are combined with polymyxin in treatment experiments of mammals such as weaned piglets, intramuscular injection is carried out to fresh culture broth of edema type escherichia coli of experimental animals, and the death rate of experimental groups during the experiment is observed and counted. The experimental results show that all the hydrocarbon derivatives containing 4-18 carbon atoms have synergistic effect on polymyxin in vivo.
The invention relates to the application of a pharmaceutical composition containing a polymyxin synergist of oxygen-containing hydrocarbon derivatives containing 4-18 carbon atoms in preparing a medicament for treating diseases caused by infection of polymyxin sensitive bacteria or drug-resistant bacteria.
The medicine for treating diseases caused by polymyxin sensitive bacteria or drug-resistant bacteria infection is used for treating diseases caused by polymyxin sensitive bacteria or drug-resistant bacteria infection of human or animals. The topical preparation is in form of solution, emulsion or injection, and can be used for treating skin, ear and eye infection or oral cavity disinfection caused by sensitive bacteria, intestinal infection, septicemia, urinary tract infection, burn or wound infection, meningitis, peritonitis, endocarditis, infantile severe pertussis and skin mucosa infection caused by polymyxin sensitive bacteria or drug-resistant bacteria. In addition, the medicinal composition can also contain other treatment components except polymyxin, such as antibiotics, antituberculosis drugs, antifungal drugs, antiviral drugs, antiparasitic drugs, antitumor drugs, cardiovascular and cerebrovascular system drugs, nervous system drugs, respiratory system drugs, digestive system drugs, immune system drugs and the like, and is used for treating other complex diseases.
The pharmaceutical compositions disclosed herein are prepared using techniques and methods known to those skilled in the art. The medicaments prepared from the compositions disclosed herein are prepared using techniques and procedures known to those skilled in the art, for example, by mixing the components involved with pharmaceutically acceptable excipients, carriers, adjuvants, vehicles, or combinations thereof, at ambient temperature and atmospheric pressure.
The medicaments prepared from the pharmaceutical compositions of the present invention for treating diseases caused by infection with polymyxin-sensitive or resistant bacteria are generally in dosage forms suitable for administration to a patient by the desired route, including those suitable for the following routes of administration, such as oral administration: tablets, capsules, caplets, pills, troches, powders, syrups, suspensions, solutions, emulsions, and the like; parenteral administration: sterile solutions, suspensions, reconstituted powders and the like; transdermal administration: transdermal patches and the like; rectal or luminal administration: suppositories and lotions; inhalation dosage form: aerosols, solutions, dry powders, etc. and topical administration: creams, ointments, lotions, solutions, pastes, sprays, foams, gels, and the like. In one embodiment, the pharmaceutical composition or medicament may be in an oral dosage form. In another embodiment, the pharmaceutical composition or medicament may be in the form of an inhalation formulation. In another embodiment, the pharmaceutical composition or medicament of the present invention may be in a form for topical administration. In another embodiment, the pharmaceutical composition or medicament may be administered nasally.
The invention discovers for the first time that oxygen-containing hydrocarbon derivatives containing 4-18 carbon atoms, including fatty alcohol, fatty acid and fatty glyceride, can be used as a polymyxin synergist, particularly as a polymyxin inhibition sensitive strain synergist and a polymyxin drug resistance reversal agent, provides more effective application space for the application of polymyxin, and has very important application value in the pharmaceutical field and the animal breeding field.
The specific implementation mode is as follows:
the following examples are further illustrative of the present invention and are not intended to be limiting thereof.
Example 1: in vitro biological research of the oxygen-containing hydrocarbon derivatives on the synergistic effect of polymyxin.
Experimental samples: polymyxin E (19000IU/mg), polymyxin B (6000IU/mg), butyric acid, caproic acid, caprylic acid, pelargonic acid, capric acid, undecanoic acid, lauric acid, stearic acid, undecylenic acid, neodecanoic acid, decanol, lauryl alcohol, decanal, lauryl aldehyde, glycerol monodecanyl ester, glycerol monolauryl ester and decanoic acid decyl ester.
Experimental strains: coli 3Y-9 (sensitive to polymyxin E), E3D-5 and salmonella CU0208 (resistant to polymyxin E), pseudomonas aeruginosa B545 and shigella 4082 (resistant to polymyxin B).
The experimental method comprises the following steps: each experimental sample was tested for in vitro Minimum Inhibitory Concentration (MIC) against the experimental strain by microdilution method, as shown in table 1. And simultaneously testing the minimum inhibitory concentration of polymyxin E or polymyxin B to different strains when 100ppm of oxygen-containing hydrocarbon and hydrogen derivatives are respectively added in the culture, and comparing the minimum inhibitory concentration with the MIC value of polymyxin without related oxygen-containing hydrocarbon and hydrogen derivatives to judge the synergistic degree of the polymyxin E or polymyxin B. The test results are shown in tables 1 and 2.
The experimental results are as follows: the oxygen-containing hydrocarbon derivatives have weak inhibition effect on escherichia coli, pseudomonas aeruginosa, salmonella and shigella (table 1); the oxygen-containing hydrocarbon derivatives can reduce the in vitro minimum inhibitory concentration of polymyxin to corresponding strains by 2-4 times for colibacillus sensitive to polymyxin, and the maximum in vitro minimum inhibitory concentration of polymyxin to different strains can be reduced by 64 times for different derivatives of drug-resistant strains (Table 2).
TABLE 1 in vitro minimum inhibitory concentrations (MIC, ug/ml) of polymyxin and oxygenated hydrocarbon derivatives against gram-negative bacteria such as Escherichia coli
TABLE 2 minimum inhibitory concentrations (MIC, ug/ml) of polymyxin against different strains in vitro at 100ppm of oxygenated hydrocarbon derivatives
Note: under the condition of different oxygen-containing hydrocarbon derivatives of 100ppm, the minimum inhibitory concentration of polymyxin E to escherichia coli and salmonella and the minimum inhibitory concentration of polymyxin B to pseudomonas aeruginosa and shigella in vitro are tested.
Example 2 dose study of synergistic bacteriostatic action of capric acid on polymyxin
Experimental samples: polymyxin E, polymyxin B, capric acid;
experimental strains: coli 3Y-9 (sensitive to polymyxin E), E3D-5 and salmonella CU0208 (resistant to polymyxin E), pseudomonas aeruginosa B545 and shigella 4082 (resistant to polymyxin B).
The experimental method comprises the following steps: the minimum inhibitory concentration of polymyxin E or polymyxin B against the corresponding strains in vitro when they contained varying concentrations of capric acid in culture was tested by the microdissection method.
The experimental results are as follows: capric acid has weak inhibitory activity on related test strains (table 1); under the combined application of capric acid with different concentrations, the minimum inhibitory concentration of polymyxin to the corresponding strains is reduced along with the increase of the capric acid concentration, and an obvious existing dose effect relationship is presented (table 3).
TABLE 3 minimum inhibitory concentration (MIC, ug/ml) of polymyxin against different bacteria in vitro in the presence of different concentrations of capric acid
Note: and testing the minimum inhibitory concentration of polymyxin E to escherichia coli and salmonella and the minimum inhibitory concentration of polymyxin B to pseudomonas aeruginosa and shigella in vitro under the conditions of different capric acid concentrations.
Example 3 animal testing: research on synergistic effect of capric acid and glycerol monodecanoate on polymyxin B in mice
Experimental samples: capric acid, glycerol monodecanyl ester;
experimental animals: the weight of the mouse is 18-22g, and the mouse is half male and female and 140;
the experimental method comprises the following steps: 140 mice with similar body weight were randomly divided into 7 groups of 20 mice each, half each of the males and females, and each test group of mice was injected with different drugs 1 hour before and 8 hours after challenge according to table 4, and the drugs were used for 3 days in succession. Infection of Pseudomonas aeruginosa B545 strain by intraperitoneal injection 1 hour after first administration7CFU/mouse, the mortality of each test group was observed within 1 week after challenge infection.
The experimental results are as follows: the mouse challenge test result shows that both the capric acid and the glycerol monodecanyl ester can synergistically enhance the effect of polymyxin B on pseudomonas aeruginosa, and the death rate of the test mouse is reduced. (Table 4).
TABLE 4 test results of the synergistic effect of capric acid and glyceryl monodecanoate on polymyxin B in mice
Note: polymyxin B (2 mg/kg body weight) and capric acid (300 mg/kg body weight) were mixed and then intramuscular injection was carried out, and group 7 polymyxin B (2 mg/kg body weight) and glycerol monodecanoate (300 mg/kg body weight) were mixed and then intramuscular injection was carried out.
Example 4 animal testing: research on cooperative control of piglet edema disease by using glycerol monodecanyl ester and polymyxin E
Experimental samples: polymyxin E (colistin sulfate), glycerol monodecanyl ester, and Escherichia coli 3D-5 strain (piglet edema type Escherichia coli);
experimental animals: the grown three-element hybrid weaned piglets are 180-head and 24-day-old, and have similar body weights;
the experimental method comprises the following steps: 180 24-day-old three-element weaned piglets were randomly divided into 7 groups of 30. The feed is customized nursing powder without any medicine. The piglets in each test group were intramuscularly administered with different drugs 1 hour before and 8 hours after challenge according to table 5, with the drugs being administered for 3 days in succession. 1 hour after the first administration, the strain 3D-5 of Escherichia coli is attacked and infected by intramuscular injection5×108CFU/mouse, the mortality of each test group was observed within 1 week after challenge infection.
The experimental results are as follows: the combined application of the glycerol monodecanyl ester and the colistin sulfate has more remarkable treatment effect on the piglet edema disease than the single application of the glycerol monodecanyl ester or the colistin sulfate, and the glycerol monodecanyl ester and the colistin sulfate show obvious synergistic effect. (Table 5)
TABLE 5 test results for the synergistic control of edema disease in piglets with glyceryl monodecanoate and polymyxin E
Note: 6 is intramuscular injection of a mixture of colistin sulfate (in an amount of 2mg/kg body weight) and glycerol monodecanoate (in an amount of 200mg/kg body weight).
Claims (4)
1. The application of oxygen-containing hydrocarbon derivatives containing 10-12 carbon atoms as a synergistic agent of polymyxin in the preparation of medicines for treating diseases caused by infection of polymyxin sensitive bacteria or drug-resistant bacteria;
the oxygen-containing hydrocarbon derivative is fatty acid containing 10-12 carbon atoms, the structure of which is shown as formula III:
wherein R is3Is selected from C9-11Straight chain saturated alkyl, C9-11A linear unsaturated alkyl group;
the sensitive bacteria or the drug-resistant bacteria are escherichia coli, salmonella, pseudomonas aeruginosa or shigella;
the polymyxin is selected from polymyxin B or polymyxin E.
2. Use according to claim 1, characterized in that the fatty acid containing 10 to 12 carbon atoms is selected from capric acid, undecanoic acid, lauric acid or unsaturated fatty acids containing a terminal or intrachain double bond corresponding to the number of carbon atoms of these acids.
3. The use of claim 1, wherein the medicament for treating diseases caused by infection with polymyxin-sensitive bacteria or drug-resistant bacteria is a medicament for treating diseases caused by infection with polymyxin-sensitive bacteria or drug-resistant bacteria for human or animal use.
4. The use of claim 3, wherein the disease caused by infection with polymyxin-sensitive bacteria or drug-resistant bacteria includes wound, urinary tract, eye, ear, trachea, skin mucosa, intestinal tract infection and septicemia, peritonitis and meningitis.
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| CN201811326275.9A CN109512998A (en) | 2016-03-04 | 2016-03-04 | The application of synergetic effect additive of the esterification derivative of oxygen-containing hydrocarbon derivative as polymyxins |
| CN201610124829.1A CN106377757B (en) | 2016-03-04 | 2016-03-04 | Application of oxygen-containing hydrocarbon derivative as synergist of polymyxin |
| CN201811326331.9A CN109512999B (en) | 2016-03-04 | 2016-03-04 | Use of aliphatic alcohols containing oxygenated hydrocarbon derivatives as a synergist for polymyxins |
| PCT/CN2016/077921 WO2017147958A1 (en) | 2016-03-04 | 2016-03-30 | Use of oxygen-containing hydrocarbon derivative as polymyxin synergist |
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| CN201811326275.9A Division CN109512998A (en) | 2016-03-04 | 2016-03-04 | The application of synergetic effect additive of the esterification derivative of oxygen-containing hydrocarbon derivative as polymyxins |
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| CN201610124829.1A Active CN106377757B (en) | 2016-03-04 | 2016-03-04 | Application of oxygen-containing hydrocarbon derivative as synergist of polymyxin |
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| WO2019036770A1 (en) * | 2017-08-24 | 2019-02-28 | University Of South Australia | Antimicrobial compositions and methods of use |
| CN107753470B (en) * | 2017-10-09 | 2021-04-27 | 武汉大学 | Small molecule inhibitor of polymyxin drug-resistant protein and application thereof |
| CN109568494B (en) * | 2019-01-22 | 2021-11-19 | 浙江中医药大学 | Application of bletilla striata alcohol extract in preparation of polymyxin antibacterial synergist |
| CN112755174B (en) * | 2021-02-26 | 2022-11-18 | 沈阳药科大学 | Polymyxin derivatives, preparation method and application thereof |
| CN115813890B (en) * | 2022-11-30 | 2024-02-23 | 扬州大学 | Application of dendrobinol as polymyxin adjuvant in preparation of medicines for treating bacterial infectious diseases |
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| HU199682B (en) * | 1988-04-01 | 1990-03-28 | Egyt Gyogyszervegyeszeti Gyar | Process for producin synergetic veterinary composition |
| US6238682B1 (en) * | 1993-12-13 | 2001-05-29 | The Procter & Gamble Company | Anhydrous skin lotions having antimicrobial components for application to tissue paper products which mitigate the potential for skin irritation |
| US5587358A (en) * | 1994-05-09 | 1996-12-24 | Asahi Kasei Kogyo Kabushiki Kaisha | Potentiators of antimicrobial activity |
| US6319958B1 (en) * | 1998-06-22 | 2001-11-20 | Wisconsin Alumni Research Foundation | Method of sensitizing microbial cells to antimicrobial compound |
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| FI20085469A0 (en) * | 2008-02-08 | 2008-05-16 | Northern Antibiotics Oy | Polymyxin derivatives with short fatty acid tails and their uses |
| GB0813211D0 (en) * | 2008-07-18 | 2008-08-27 | E Therapeutics Plc | Antibacterial combination therapy for the treatment of gram positive bacterial infections |
| EA201591954A1 (en) * | 2013-04-12 | 2016-04-29 | Вайом Байосайнсиз Пвт. Лтд. | COMPOSITION AND COMPOSITION OF ANTI-MICROBAL MEANS, METHODS OF THEIR RECEPTION AND METHODS OF TREATING MICROBIAL INFECTIONS |
| CN104922100B (en) * | 2013-12-31 | 2018-04-06 | 广州英赛特生物技术有限公司 | β Japan cypress amphyl and its application in animal specific antiseptic and feeding antimicrobial growth accelerator is prepared |
| CN105030744B (en) * | 2015-07-09 | 2019-04-19 | 广州英赛特生物技术有限公司 | Application of the substituted benzene guanidine derivatives as polymyxins antibiotic synergist |
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| CN106377757A (en) | 2017-02-08 |
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| WO2017147958A1 (en) | 2017-09-08 |
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