CN101426507A - Use of polyamines with antibiotics - Google Patents
Use of polyamines with antibiotics Download PDFInfo
- Publication number
- CN101426507A CN101426507A CNA2006800185586A CN200680018558A CN101426507A CN 101426507 A CN101426507 A CN 101426507A CN A2006800185586 A CNA2006800185586 A CN A2006800185586A CN 200680018558 A CN200680018558 A CN 200680018558A CN 101426507 A CN101426507 A CN 101426507A
- Authority
- CN
- China
- Prior art keywords
- antibiotic
- polyamino acid
- compositions
- antibacterial
- curee
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
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- 239000003242 anti bacterial agent Substances 0.000 title claims abstract description 38
- 229940088710 antibiotic agent Drugs 0.000 title abstract description 20
- 229920000768 polyamine Polymers 0.000 title abstract 2
- 230000003115 biocidal effect Effects 0.000 claims abstract description 182
- 239000000203 mixture Substances 0.000 claims abstract description 44
- 238000000034 method Methods 0.000 claims abstract description 43
- 206010034133 Pathogen resistance Diseases 0.000 claims abstract description 4
- 239000002253 acid Substances 0.000 claims description 151
- 230000000844 anti-bacterial effect Effects 0.000 claims description 42
- PFNFFQXMRSDOHW-UHFFFAOYSA-N spermine Chemical compound NCCCNCCCCNCCCN PFNFFQXMRSDOHW-UHFFFAOYSA-N 0.000 claims description 34
- ATHGHQPFGPMSJY-UHFFFAOYSA-N spermidine Chemical compound NCCCCNCCCN ATHGHQPFGPMSJY-UHFFFAOYSA-N 0.000 claims description 24
- 150000003952 β-lactams Chemical class 0.000 claims description 19
- 230000000694 effects Effects 0.000 claims description 18
- 229940063675 spermine Drugs 0.000 claims description 17
- KIDHWZJUCRJVML-UHFFFAOYSA-N putrescine Chemical compound NCCCCN KIDHWZJUCRJVML-UHFFFAOYSA-N 0.000 claims description 16
- VHRGRCVQAFMJIZ-UHFFFAOYSA-N cadaverine Chemical compound NCCCCCN VHRGRCVQAFMJIZ-UHFFFAOYSA-N 0.000 claims description 14
- 239000002552 dosage form Substances 0.000 claims description 12
- 229940063673 spermidine Drugs 0.000 claims description 12
- WIIZWVCIJKGZOK-RKDXNWHRSA-N chloramphenicol Chemical compound ClC(Cl)C(=O)N[C@H](CO)[C@H](O)C1=CC=C([N+]([O-])=O)C=C1 WIIZWVCIJKGZOK-RKDXNWHRSA-N 0.000 claims description 10
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- MHWLWQUZZRMNGJ-UHFFFAOYSA-N nalidixic acid Chemical compound C1=C(C)N=C2N(CC)C=C(C(O)=O)C(=O)C2=C1 MHWLWQUZZRMNGJ-UHFFFAOYSA-N 0.000 claims description 9
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Abstract
Compositions and methods for affecting antibiotic resistance, for improving the overall efficacy of antibiotics, and for killing bacteria are included herein involving the use of polyamines to sensitize bacteria and resistant bacterial strains to hydrophilic antibiotics and to reduce bacterial resistance to such antibiotics.
Description
Technical field
Present invention relates in general to the Drug therapy field and the sterilization reagent field of bacterial infection.More particularly, compositions and the method that the present invention relates to influence antibiotic effect and improve antibiotic overall efficacy and killing bacteria.
Background technology
Antibiotic and other antibacterial have been widely used for saving life that is difficult the number meter and the severe complication that reduces multiple disease and infection.After being extensive use of above 50 years, the antibacterial effect of many antibacterial is just in variation, and wherein partly cause is because antibacterial has produced resistance.Especially, antibiotic excessively and be extensive use of and be considered to promote the evolution tolerance, this makes under antibacterial can survive in the most effective medicine.Resistance to antibacterial provides the existence facility and has made that infection is difficult to eliminate more for microorganism.
The increase day by day that bacterial resistance occurs has improved catches the more risk of severe infections disease in hospital or other place.For example, along with the raising of the pathogen that causes disease, cure at more difficult quilt at present such as diseases such as pulmonary tuberculosis, gonorrhea, malaria and juvenile's ear infections to traditional antibiotic resistance.For the resistance of hospital's medicine of containing the patient who suffers from serious disease is the problem of difficulty especially, if there are not these patients of antibiotic help strong or that toxicity is bigger can't resist infection.Unfortunately, has the antibacterial that Johnson ﹠ Johnson more deposits ability, even if under this antibacterial also can survive, this made this problem become even worse in having the strongest known antibiotic environment owing to produced.These have the patient that stronger drug-fast antibacterial continues tormenting fragility in the hospital just.The result of this infection is that antibiotic resistance causes longer hospital stays, higher mortality rate and the health care cost that increases day by day.
Thus, always all need be in order to improve bioactive compositions of antibiotic and method.Equally also need to tackle the compositions and the method for effective treatment of the antibiotic resistance of antibacterial.Except other content, involved in the present invention is exactly these demands.
Summary of the invention
First and foremost, the invention provides the method and composition that is used to improve antibacterial and disinfectant effect.Wherein be used to improve antibiotic and the exemplary process of antibacterium and Resistant strain effect thereof and compositions are comprised use polyamino acid, kill or suppress antibacterial thereby take antibiotic again so that antibacterial or strains become responsive to antibiotic.General principles of the present invention provides the method that can significantly improve antibiotic and disinfectant antibacterial effect.
The present invention roughly comprise by separately or and antibiotic use the bacterial infection that the polyamino acid of effective dose is treated the patient together.In an illustrative treatment, can use polyamino acid simultaneously and thereby antibiotic induces them to be in appropriate level separately by exogenous replenishing to the curee, the sensitivity antibiotic that becomes then can kill or suppress antibacterial better so that polyamino acid can make bacterial antibiotic.In another illustrative treatment, can before using antibiotic therapy or after treatment a period of time, use polyamino acid to the curee.In another illustrative treatment, before using polyamino acid, treat earlier with antibiotic, make the resistant strain of antibacterial or antibacterial become responsive using polyamino acid subsequently to antibiotic.Like this and antibiotic simultaneously, the curee is used polyamino acid prior to antibiotic and/or after antibiotic.
The all compositionss of the present invention are included in polyamino acid and the antibiotic that effective dose is gone up in treatment.Polyamino acid and/or antibiotic given dose depend on the persistent period of employed antibiotic, employed polyamino acid, the disease of being treated or infection and treatment.Generally speaking, dosage can be according to these factor and is different.Preferred dosage is polyamino acid and/or antibiotic effective lowest dose level on the treatment meaning.Can adopt and allow doctor or veterinary participate in method in the medical judgment process to determine rational dosage.Polyamino acid and antibiotic effective form of medication, method of application and dosage can be determined by experience, can judge this according to techniques well known.
An advantage of the present invention is that it allows to adopt the antibiosis of some low concentration usually to reach therapeutic effect.For example based on can reduce to treat the time limit, shorten be in intensive care unit or be in hospital or the clinic in time and the reasons such as reduction of serious hospital infection (in hospital, the infecting) risk followed, the present invention also helps improving life quality.
If read the specific descriptions of following preferred implementation in conjunction with the accompanying drawings, those skilled in the art can more easily understand the present invention.
Description of drawings
Table shown in the accompanying drawing 1 has been described under various concentration polyamino acids, chemical substance and/or antibiotic situation the minimum inhibiting value to Pseudomonas aeruginosa.
Table shown in the accompanying drawing 2 has been described the sensitivity of clinical isolates Pseudomonas aeruginosa to the compositions be made up of multiple antibiotic and polyamino acid.
Table shown in the accompanying drawing 3 has been described escherichia coli and the salmonella typhimurium strain sensitivity to the compositions be made up of multiple antibiotic and polyamino acid.
Accompanying drawing 4 has shown the time series analysis figure that kills Pseudomonas aeruginosa PAO1 in the human serum.
Accompanying drawing 5 illustrates beta-lactam enzymatic activity reduction in the various cells after the compositions-treated of antibiotic and polyamino acid formation.
Accompanying drawing 6 illustrates agent interfering and handles beta-lactam enzymatic activity in the various kinds of cell of back.
Accompanying drawing 7 illustrates after the compositions-treated of antibiotic and various polyamino acid formation, only can detect extremely low-level beta-lactam enzymatic activity.
Table shown in the accompanying drawing 8 has been described the sensitivity of coli strain to the compositions of ciprofloxacin and various polyamino acids.
The specific embodiment
The preferred embodiment for the present invention comprises compositions and the method that improves antibiotic and other antibacterial effect.Be used to improve antibiotic among the present invention and the exemplary process of antibacterium and Resistant strain effect thereof and compositions are comprised use polyamino acid, kill or suppress antibacterial thereby take antibiotic again so that antibacterial or strains become responsive to antibiotic.This paper has done qualification to general principles of the present invention, and the method that can significantly improve antibiotic and disinfectant antibiotic effect is provided.
More especially, use separately or particularly use various polyamino acids with hydrophilic antibiotics with antibiotic, find that unexpectedly it can reduce antibacterial to this antibiotic resistance, and killed resistant strain, and improved this antibiotic effect.Since before research shown that natural polyamino acid (for example cadaverine, spermidine and spermine) can not make enterobacteria become responsive to hydrophilic antibiotics and natural polyamino acid had not both had antibacterial toxicity and do not have the sensitization activity yet, prior art was not paid close attention to the method that adopts the especially natural polyamino acid of polyamino acid and is made bacterial antibiotic become responsive thus.The discovery polyamino acid can make such as Pseudomonas aeruginosa (Pseudomonas aeruginosa), escherichia coli (Escherichia coli), bacillus subtilis (bacillus subtilis) and staphylococcus aureus bacterial antibiotics such as (Staphylococcus aureus) and disinfectant and become responsive after experimentizing with various antibiotic (comprising hydrophilic antibiotics) and polyamino acid.
An illustrative embodiment of the present invention comprise by the polyamino acid of using effective dose separately or and its be applied the bacterial infection for the treatment of the patient with antibiotic.In an illustrative treatment, can use polyamino acid simultaneously and thereby antibiotic induces them to be in an amount of level separately by exogenous replenishing to the curee, thereby the sensitivity antibiotic that becomes then can kill or suppress antibacterial better so that polyamino acid can make bacterial antibiotic.In another illustrative treatment, can before with antibiotic therapy or after treatment a period of time, use polyamino acid to the curee.In another illustrative treatment, before using polyamino acid, treat earlier with antibiotic, make the resistant strain of antibacterial or antibacterial become responsive using polyamino acid subsequently to antibiotic.Like this and antibiotic simultaneously, the curee is used polyamino acid prior to antibiotic and/or after antibiotic.
For example, do not produce enough effects if use the antibiotic of a period of time, that polyamino acid that just can use a period of time comes sensitized bacteria and improves antibiotic effect.Similarly, after using the antibiotic of a period of time, use polyamino acid so that improve antibiotic effect.Another embodiment is, thereby can improve antibiotic effect using the antibiotic polyamino acid that applies simultaneously of certain hour.Similarly, the curee who is applied suffer from anaphylaxis or other to different treatments under the situation of preferred antibiotics sensitivity, be considered to deleterious and then can apply polyamino acid simultaneously and improve antibiotic effect using the certain hour antibiotic.Among another embodiment, can before using a period of time antibiotic, use polyamino acid so that make bacterial antibiotic become responsive in advance.
The selected polyamino acid and the antibiotic that all comprise dose therapeutically effective in all generally compositions of the present invention.Concrete polyamino acid and/or antibiotic agent amount depend on used antibiotic, used polyamino acid, the disease of being treated or infection (comprising the bacterial infection or and the order of severity of resistance), the persistent period of curee's quantity and situation, compositions discharge rate and treatment.Dosage can change with these factors generally.Preferred dose is polyamino acid and/or antibiotic effective lowest dose level on the treatment meaning.Can adopt and allow doctor or veterinary participate in method in the medical judgment process to determine rational dosage.Polyamino acid and antibiotic effective form of medication, method of application and dosage can be determined by experience, can judge this according to techniques well known.
Because some antibiotic uses are subjected to system toxicity or expensive restriction, reduce the required antibiotic concentration of effective treatment and then can reduce toxicity and/or treatment cost, and the antibiotic that can allow to use antibiotic more widely like this and/or use alternative type.Thereby for example and antibiotic use polyamino acid can avoid the side effect of some antibiotic and/or antibacterial together from the dosage that reduces the treatment reagent contain antibiotic and/or antibacterial in fact.Because the reduction of serious hospital infection (infecting in the hospital) risk that shortens the course of treatment, reduces to stay in intensive care unit or stay in the overall time of hospital and followed, thereby the present invention can be used for improving life quality equally.
Be applicable to that polyamino acid of the present invention comprises natural polyamino acid, preferably those belong to nontoxic native compound and/or are present in polyamino acid in general animal and/or the human body with high level.The polyamino acid that is selected for the preferred embodiment for the present invention is natural polyamino acid.These natural polyamino acids comprise for example cadaverine, putrescine, spermidine, spermine and nor-spermidine and nor-spermine etc.Preferred polyamino acid comprises spermine and spermidine, and these polyamino acids are found can be than putrescine and cadaverine sensitized bacteria more effectively.The analog of synthetic and other polyamino acid also are applicable to the present invention and need not to rely on over-drastic experiment to obtain.
Can be used for schematic polyamino acid of the present invention is spermine, and this polyamino acid shows antibacterial have been weakened antibiotic resistance and the best effect that improves antibiotic effect.Shown in this paper embodiment, this polyamino acid can sensitize resistant bacteria and and the various antibiotic bacterial infection of coming together effectively to treat.And because this polyamino acid is nontoxic and exist natively in the human body to the mankind, this polyamino acid can safety is applied to human patients.The result of embodiment can be extrapolated to other polyamino acid.
Be applicable to that antibiotic of the present invention comprises the material that can suppress growth of microorganism or kill microorganisms, its can be synthetic also can be natural.This class antibiotic comprises beta-Lactam antibiotic, Macrolide, monoamine rhzomorph, rifomycins, Tetracyclines, chloromycetin, clindamycin, lincomycin, fusidinic acid, novobiocin, fosfomycin, fucidin, capreomycin, Methacolimycin sulfonate (colismethate), Gramicidin, minocycline, doxycycline, bacitracin, erythromycin, nalidixan, vancomycin and trimethoprim.The example of beta-Lactam antibiotic comprise ampicillin, azlocillin, aztreonam, Carbenicillin, cefoperazone, ceftriaxone, Cefalorne cefaloridine, cephalosporin thiophene,, cloxacillin, latamoxef, benzylpenicillin, piperacillin and ticarcillin.Other antibiotic comprises that cationic peptide also is applicable to the present invention.
Antibiotic of the present invention further comprises and contains one or more antibacterial or antibiotic compositions or Therapeutic Method.For example, first and second antibiotic that can adopt series (one after another person) or parallel (while or combination) to use in the present invention, it is also included within the antibiotic implication.In one embodiment, the first and second antibiotic combinations can be, for example, and penicillin and such as aminoglycosides such as gentamycin, vancomycins.In a preferred embodiment, antibiotic composition comprises that at least two kinds of mutual different antibiotic and every kind of antibiotic are preferably from different class of antibiotic.
What one skilled in the art will readily appreciate that is to adopt Therapeutic Method known and exploitation in the future to use polyamino acid and/or antibiotic composition.Said composition can be made preparation so that use by how various route of administration.In optimal way, antibiotic product is made into to be suitable for oral form, and it comprises various formation ball shapes or the such dosage form of graininess, and ball or granule are made into whole drug products subsequently, for example, and capsule or be embedded in the tablet or be suspended in the oral liquid.
In addition, in the preparation oral delivery system, the antibiotic of various dosage forms and polyamino acid product can be made into tablet, and tablet is separately all put into capsule to produce whole antibiotic product.Like this, for example, antibiotic product can comprise first dosage form of instant release type, also can comprise at least a antibiotic other tablet that is used for delaying to discharge, wherein antibiotic and polyamino acid discharge from tablet separately at different time, discharge whole antibiotic in the time bar of expectation thereby be implemented in from antibiotic product.For slow release, according to prior art as can be known, it can come the sustained release time by the thickness of antibiotic concentration in the controlling packet tegillum and/or bag tegillum.
In this mode, antibiotic part and polyamino acid part can discharge or discharge at different time simultaneously.For example, respectively, the tablet of rapid release (at first discharge) both can be that antibiotic also can be a polyamino acid and the tablet that slowly discharges (second discharges) can be polyamino acid or antibiotic.In addition, also can comprise the tablet of slow release (the 3rd also a large amount of release), it comprises required antibiotic and/or polyamino acid.This type of release system allows medical practitioner's decision at first to discharge antibiotic or polyamino acid.Selectively, can be combined in antibiotic and polyamino acid in the single tablet, perhaps also may reside in but release simultaneously in the tablet separately.
In addition, polyamino acid or polyamino acid and antibiotic compositions also can be designed to use with other external form of ointment form and disinfectant.For example, to be made into the form effect of antimicrobial lotion good especially for polyamino acid and antibiotic compositions.In one embodiment, the external method of application can adopt at least two kinds of different dosage forms, every kind of dosage form each self-contained antibiotic and polyamino acid, and can be by preparing the dosage form that is used for the external method of application at oil-in-water powder or Water-In-Oil powder.In this dosage form, the immediate release dosage form form is in the continuous phase, and slow release formulation then is present in the discontinuous phase.Also can be made into to apply the prescription of multiple dosage form.For example, can make Water-In-Oil-oil-in-water powder, the water that comprises first slow release formulation that wherein comprises the oil that promptly is interpreted into branch and be continuous phase then is dispersed in the oil.Ointment can be creaminess or emulsion form or be similar to other non-dissolve dosage form that those are used for topical administration.Also can form the pastel that is easy to apply, jelly, paste, soap shape thing or the like such as the mineral of the cellulose of synthetic polymer, fatty acid, soap and ester, aliphatic alcohol, modification or modification, so that directly be used on the skin of user by liquid carrier.
Also can pass through in suitable solvent, to add the reactive compound of aequum, and add other composition after the various degerming after filtration listed above as required, prepare aseptic parenteral solution thus.Preparation is used to make the sterilized powder of aseptic parenteral solution if desired, and preferred manufacturing procedure is vacuum drying and Freeze Drying Technique, and it can produce the active component powder, and this powder also has the existing any required composition of aforementioned filtration sterilization solution.This solution can be the compositions of antibiotic and polyamino acid.Selectively, can independent sequentially administration of antibiotics and polyamino acid injection.This solution optionally comprises the microsphere or the Nano microsphere of antibiotic and polyamino acid, and wherein microsphere or Nano microsphere are in vivo with certain speed stripping active substance.
In body, using, can be estimated that suitable polyamino acid also can use together with antibiotic under conditions in vitro.For example, polyamino acid can be used with antibiotic together so that food preservation is more of a specified duration fresher in food industry.In this application, polyamino acid can help antibiotic to suppress the antibacterial that causes food decay, extends the shelf life thus.Can be used for blood, cell or tissue so that these materials have less antibacterial or do not have antibacterial such as, polyamino acid again.In this application, polyamino acid helps antibiotic to suppress to cause blood, the contaminated antibacterial of cell or tissue, prolongs the effective life of blood, cell or tissue thus.
Polyamino acid and antibiotic one work or the mechanism that strengthens antibiotic resistance is still understood as yet fully, and this effect can not be pushed into all polyamino acids.It is believed that polyamino acid works by influencing efflux pump (eflux pump).In addition, can believe that polyamino acid can work by influencing penicillin-binding protein.Preferred antibiotic is those antibiotic that act on together that pass through these mechanism.Yet polyamino acid can influence Drug resistance treatment and improve antibiotic effect that cutter system is unimportant really.
Embodiment
Reference data and example are set forth antibiotic effect and can be strengthened because of the compositions of using polyamino acid or containing polyamino acid in this part.More particularly, the present invention is further elaborated with reference to following non-limiting examples.
Material and method substantially
Experimental growth conditions
Various bacterial isolateses comprise Pseudomonas aeruginosa and escherichia coli (E.coli), grow in Luria-Bertani (LB) agarose/meat soup or Mueller-Hinton (MH) agarose/broth bouillon.Growth curve is determined by the upgrowth situation of antibacterial under the condition of various chemical substances, polyamino acid and/or antibiotic existence.Inoculated bacteria is cultivated in the incubator of air and Controllable Temperature immediately.Extract sample aliquot in per four hours and under 600nm, detected optical density.Antibiotic, chemical substance and/or polyamino acid are dissolved in distilled water or the solvent and are after this using the disposable membrane filtration of 0.4 μ m.
Lethal time is analyzed
Various bacteria samples lethal times are analyzed.At first, make tested antibacterial in the Mueller-Hinton culture medium, grow to middle logarithmic (log) phase.Cell at room temperature carefully is diluted in the sodium phosphate buffer that contains polyamino acid (for example spermine).Organize in contrast, cell is diluted in the sodium phosphate that does not contain any other chemical compound.Extract sample aliquot at a certain time interval and be coated in the LB agarose plate and 37 ℃ of following overnight incubation.Determine the percentage ratio of the bacterium colony of survival with respect to matched group.
Minimal inhibitory concentration (MIC) value
In Mueller-Hinton meat soup, adopt standard agar doubling dilution law technology and meat soup dilution technology to determine the bacterial strain MIC value of the various compositions-treated formed through polyamino acid and antibiotic.Do not find that visual muddy lowest concentration of drug is confirmed as MIC.Also adopt the antibiotic diffusion analysis to come to proving conclusively by agar dilution and the resulting result of meat soup dilution technology.
Beta-lactamase is analyzed
Adopt spectrophotography to be that the beta-lactam enzymatic activity of substrate has been done definite with Nitrocefin (nitrocefin).After beta-lactamase was extracted from cell, the molar extinction coefficient of employing 20500 came the beta-lactam enzymatic activity is monitored by the change of absorbance under the 486nm.Hydrolysis degree is the reflection of untamed enzyme amount.
The structure of lacZ::ampC promoter fusions and beta galactosidase analysis
Extracting genomic DNA and be used for the pcr amplification of ampC (PA1110) promoter region from various antibacterials such as for example Pseudomonas aeruginosa PAO1, amplimer is to being 5`-ggaagtcctccagccgcggcag-3`/5`-ggcgtcctttgtcgttggctgcatgagaaa-3` (500bps fragment).This 500bps PCR fragment is through centrifugal column purification and insert wide host range and transcribe fusion vector, pQF50, and it produces plasmid pAU16R.DNA sequence of being inserted and position are determined by the nucleic acid sequencing method.
The culture that comprises pAU16R contains or does not contain in the MH broth bouillon of spermine (10mM and 20mM) diluted 100 times at 20mL.Culture is cultivated 3h with 350rpm down at 37 ℃.Add antibiosis in the culture and usually induce the ampC gene, culture was additionally cultivated one hour under the same conditions.Use the centrifuging collecting cell, wash once, and resuspended in phosphate buffer (pH7.0).With 8,000ib/in
2Cell breakage instrument (French pressure) handle cell and destroy cell and prepare the soluble cell extract to measure μ-galactosidase activity.Employing is that the Coomassie brilliant blue method (Brandford method) of standard is measured protein concentration with the bovine serum albumin.The outer membrane permeability is analyzed
Detect by release and to realize the analysis of outer membrane permeability the beta-lactamase of chromosome coding.At first, stationary phase cells is diluted in the MMP broth bouillon of 20mL preheating with 1:59 and in incubator, cultivates 5h down at 37 ℃ with 350rpm.Adding Carbenicillin (20 μ g/mL) with after beta-lactamase is induced, this culture is the extra cultivation of 5h again.5, centrifugal 10min harvesting also washs 1 time with the sodium phosphate buffer of 0.05mM pH7.2 under the 000xg.This cell ball carries out resuspended in the identical buffer of 5mL and is divided into the every sample aliquot of 1mL.By in every part of sample, add 1,5,10, the method for 20mM EDTA, spermidine, spermine and arginine (in contrast) comes outside membrane permeability is analyzed.This analysis also can be undertaken by add 1,5,10,20 μ g/mL PMBN in every sample aliquot.Reactant mixture is at room temperature cultivated 5min, and centrifugal (15000xg) 20min at full speed immediately, then with the source of supernatant as beta-lactamase.Determine the beta-lactam enzymatic activity according to the supernatant that adopts 300 μ L as mentioned above.
Be used in combination polyamino acid and multiple antibiotic and can more effectively tackle the Pseudomonas aeruginosa bacterial infection with antibiotic than single.These results show that polyamino acid and certain antibiotics are united use can bacteria growing inhibiting and have synergistic function, and wherein polyamino acid and certain antibiotics unites to use and improve antibiotic effect.In addition, these results show that the concentration that can select specific polyamino acid thoroughly suppresses bacterial resistance.
Fig. 1 shows the resistant strain (P.aeurginosaPAO1) that polyamino acid can the sensitization Pseudomonas aeruginosa.Generally speaking, the spermine of 20mM spermidine, putrescine, cadaverine and 1mM can make Pseudomonas aeruginosa that 14 beta-lactams, chloromycetin, nalidixan and trimethoprim are become responsive.Under the situation that various polyamino acids (spermidine, spermine, putrescine and cadaverine) exist, to all obviously reductions of MIC value (2-64 doubly) of all beta-lactam antibiotics, chloromycetin, nalidixan and trimethoprim.Spermidine and spermine have better sensibilization than putrescine and cadaverine under the employed concentration of present embodiment.Exist or do not exist under the situation of polyamino acid, constant to the MIC value of hydrophilic antibiotics (erythromycin, novobiocin and fusidinic acid).In addition, polyamino acid also can make the ciprofloxacin resistant strain that Carbenicillin, chloromycetin and nalidixan are become responsive.
Because the dissociant with very high MIC value becomes responsive to antibiotic under the situation that polyamino acid exists, this embodiment demonstration can be by uniting antibiotic such as use such as ciprofloxacin, beta-lactam, chloromycetin, nalidixan and trimethoprim and polyamino acid so that more effectively tackle Pseudomonas aeruginosa.
The interpolation of higher concentration polyamino acid can further improve antibacterial sensitization and antibiotic effect.In order further to detect the influence of polyamino acid to antibiotic MIC value, the polyamino acid of employing variable concentrations is determined the MIC value to Carbenicillin.The polyamino acid that table 1 has disclosed higher concentration can reduce the MIC value of higher level.MIC value in the table has been repeated 3 times and has all obtained identical value.No matter all MIC results reduce or constant, all through the detection of antibiotic inhibition zone.
Pseudomonas aeruginosa PAO1 is to the MIC value of Carbenicillin under the situation of table 1. variable concentrations polyamino acid
Embodiment 3
The resistant strain of Pseudomonas aeruginosa (or clinical isolates) becomes responsive by the multiple combination of antibiotic and polyamino acid.Reference strain Pseudomonas aeruginosa PAO1 is proved to be with aforesaid identical the MIC value of Carbenicillin, chloromycetin and nalidixan.Under the situation that polyamino acid exists, except bacterial strain T6268 to the Carbenicillin, clinical isolates is all much higher than reference strain PAO1 to the MIC value of Carbenicillin, nalidixan.
Especially especially, as shown in Figure 2, clinical isolates will be hanged down 2-32 doubly to the MIC value of Carbenicillin, chloromycetin and nalidixan than the value that does not adopt polyamino acid to obtain.Unhoped-forly be, reference strain PAO1 is more much higher than the MIC value of clinical isolates to the MIC value of chloromycetin, the scope that exceeds 4-16 doubly between (Fig. 2).Under the situation that polyamino acid exists, clinical isolates is much the same or exceeds 4 times the MIC value of ciprofloxacin, gentamycin and polymyxin B.This embodiment has confirmed that polyamino acid and antibiotic combination can reduce the MIC value of different strains.
Polyamino acid and antibiotic being used in combination can sensitization E.coli bacterial strain and Salmonella typhimurium (Salmonella typhimuium) bacterial strains.The sensitivity that multiple E.coli bacterial strain (K10 that for example is separated to from europathogenic patient, K12 and C921-61) and Salmonella typhimurium LT2 (S.typhimurium LT2) demonstrate beta-lactam (ampicillin, azlocillin, Carbenicillin, oxazacillin, benzylpenicillin, piperacillin and ticarcillin) and 7 kinds of other antibiotic (chloromycetin, erythromycin, fusidinic acid, kanamycin, novobiocin, spectinomycin and tetracycline) strengthens.
As shown in Figure 3, E.coli bacterial strain and Salmonella (S.typhimurium) are stronger 4 times than the situation of not using polyamino acid to the sensitivity of most beta-lactam antibiotics under the situation that polyamino acid exists.Similarly, E.coli bacterial strain (K10 and K12) also can be strong 4 times to most other antibiotic sensitivity under the situation that polyamino acid exists.Based on this, this embodiment shows that polyamino acid and antibiotic combination can reduce the MIC value of different bacterium.
Polyamino acid and antibiotic combination can make anti-methicillinum staphylococcus aureus (methicillin-resistant Staphylococcus aureus) (MRSA) beta-lactam be become responsive.The MRSA clinical isolates, staphylococcus aureus Mu5, demonstrating has higher resistance to beta-lactam, and to the medium resistance of vancomycin.Especially especially, table 2 shows that external source spermine (1mM and still less) can make staphylococcus aureus Mu50 again to beta-lactam become responsive (for example, the reduction of oxazacillin MIC value is above 100 times).Known gold Staphylococcus aureus Mu5 can express the coded high-level penicillin-binding protein 2A by mecA, and this is the molecular mechanism that Methicillin resistance produces.Because glycopeptide antibiotic class (for example vancomycin) is considered to the appearance that the clinical use of last line of defense vancomycin of MRSA has then caused the dual resistant strain of vancomycin/methicillinum, this embodiment shows that polyamino acid and multiple antibiotic combination can tackle these super resistance bacterium.
Table 2. spermine antagonism methicillinum staphylococcus aureus (MRSA) Mu50 is to the influence of antibiotics sensitivity
Embodiment 6
Polyamino acid can make antibacterial that the antibiotic in the human serum is become responsive.Fig. 4 has shown the beta-lactam sensitivity tests result of polyamino acid mediation in the human serum.Separately existing in polyamino acid in the human serum can kill in the 24h under not having any exogenous antibiotic situation and surpass two kinds of E.coli bacterial strains (K10 and K12) of 99%; Yet Pseudomonas aeruginosa PAO1 and Salmonella typhimurium LT2 be well-grown (data not shown goes out) still under the same conditions.
As shown in Figure 4, no matter exist or do not have the 2mM spermine, the growth of Pseudomonas aeruginosa PAO1 can not be affected in the human serum.In addition, the Carbenicillin that adds 16 μ g/mL in the serum has separately then caused initial inhibition, and this inhibition can be accompanied by the recovery fully of growth.Yet when the Carbenicillin with 16 μ g/mL added the spermine of 2mM together, the inoculation bacterium above 99% all was killed in 24h.Similarly the result also can obtain (data not shown goes out) with Salmonella typhimurium LT2.
These human serum positive findingses have supported polyamino acid and antibiotic combination meeting to produce the conclusion of Expected Results preferably in human body.
Embodiment 7
This embodiment shows that the cell polyamino acid can not change the permeability of adventitia or make cell or outer membrane rupture.Whether employing is assessed the adventitial cell barrier to beta-lactam enzymatic activity measurement in free cell filter liquor or the full cell and can be changed along with the rising of antibiotics sensitivity.If handle with polymyxin B, have realized that the cationic peptide antibiotic can improve the permeability of adventitia, when in cell suspending liquid, applying the antibiotic of 100 μ g/mL, can detect significantly full cell beta-lactam enzymatic activity.
Fig. 5 shows that when applying the antibiotic of 100 μ g/mL in cell suspending liquid the cell of handling through polymyxin B can show significant full cell beta-lactam enzymatic activity.Fig. 6 can detect pericentral siphon beta-lactamase (the periplasmic β-lactamase) be released in the suspension that causes owing to outer membrane rupture after being presented at and adding 0.5mM EDTA, and the activity of being surveyed from whole cell can prove that the enzyme that discharges has increased after adding 1mM EDTA, and the permeability of outer membrane has also increased thereupon.Fig. 7 shows adding 20mM spermidine or spermine (data not shown goes out) and only detects low-level beta-lactam enzymatic activity afterwards.These results show that polyamino acid does not probably play a role by the ruptured cell adventitia or by changing outer membrane permeability.
The antibiotics sensitivity of polyamino acid mediation can not be subjected to the influence of divalent ion or salt.Because research has before shown that the physiological concentration of divalent ion or salt can exert an influence to the antibiotic antimicrobial susceptibility of some type, measures polyamino acid under variable concentrations divalent ion or the salt action and antibiotic composition.
As shown in table 3, the rising of divalent ion or salinity can not cause remarkable influence to the antimicrobial susceptibility based on polyamino acid.For example, this embodiment shows that the compositions of spermine and spermidine still keeps its activity under the situation that the 10mM spermidine exists.The rising of divalent ion or salinity can not exist the carbenicillin susceptibility under the situation to produce appreciable impact to the 10mM spermidine.Similarly the result also can be at Pseudomonas aeruginosa, and Salmonella observes on salmonella typhi and the anti-methicillinum staphylococcus aureus Mu50 (MRSA).
Table 3. magnesium chloride, calcium chloride and sodium chloride are to the influence of E.coli K10 to carbenicillin susceptibility
Polyamino acid and multiple antibiotic compositions have improved the effect to the resistant strain of multiple E.coli.As shown in Figure 8, polyamino acid has improved multiple E.coli resistant strain to multiple antibiotic sensitivity.As shown in Figure 8, the adding MIC value along with exogenous polyamino acid has reduced 3 times.
Polyamino acid and multiple antibiotic compositions have improved the effect to the Salmonella typhimurium resistant strain.In this embodiment, polyamino acid has improved the Salmonella typhimurium resistant strain to multiple antibiotic antimicrobial susceptibility.As shown in table 4, the MIC value has reduced 3 times.
Table 4. polyamino acid is to the influence of Salmonella typhimurium LT2 antibiotics sensitivity
Embodiment 11
Polyamino acid and multiple antibiotic combination have improved the effect to staphylococcus aureus 700699 resistant strains.In this embodiment, polyamino acid has strengthened 700699 pairs of multiple antibiotic antimicrobial susceptibilities of staphylococcus aureus.As shown in table 5, the MIC value has reduced 3 times.
Table 5. polyamino acid is to the influence of 700699 pairs of antibiotics sensitivities of MRSA staphylococcus aureus
To the specific descriptions of aforementioned preferred implementation and accompanying drawing is not limit for illustrative and explanation order only, neither be used for limiting the scope of the invention and spirit.Selection and description to embodiment are in order to explain the principle and the practical application thereof of invention to greatest extent.Those skilled in the art can recognize can be under the situation that does not break away from the scope of the invention and spirit to description described invention implement multiple modification.
Claims (27)
1, a kind ofly be used for improving the method for antibiotic in curee's effect, it comprises the steps:
A) curee is used at least a polyamino acid; And
B) this curee is used at least a antibiotic.
2, method according to claim 1 is characterized in that, and is better than independent described at least a antibiotic effect with the described at least a antibiotic effect of described at least a polyamino acid combination.
3, method according to claim 1 is characterized in that, by the curee being used described at least a polyamino acid, is used to suppress the required described at least a antibiotic amount of curee's bacterial infection thereby reduce.
4, method according to claim 1 is characterized in that, described at least a antibiotic is hydrophilic.
5, method according to claim 1 is characterized in that, described at least a antibiotic is a beta-lactam.
6, method according to claim 1 is characterized in that, described at least a antibiotic is selected from by penicillin, cephalosporin, monoamine rhzomorph, and the group that compositions constituted.
7, method according to claim 1 is characterized in that, described at least a polyamino acid comprises the polyamino acid of natural generation.
8, method according to claim 1 is characterized in that, described at least a polyamino acid is selected from by cadaverine, putrescine, spermidine, spermine, nor-spermidine and nor-spermine and group that compositions constituted thereof.
9, method according to claim 1 is characterized in that, described at least a polyamino acid comprises the polyamino acid through the natural generation of chemical modification.
10, method according to claim 1 is characterized in that, described at least a polyamino acid comprises the polyamino acid that is derived from putrescine.
11, method according to claim 1 is characterized in that, it is good that described at least a antibiotic and described at least a polyamino acid are used in combination the effect that tackles bacterial resistance when having than the described at least a antibiotic of independent use.
12, method according to claim 1 is characterized in that, uses described at least a polyamino acid before using described at least a antibiotic.
13, method according to claim 1 is characterized in that, describedly at least aly uses described at least a polyamino acid again after antibiotic applying.
14, method according to claim 1 is characterized in that, described at least a antibiotic and described at least a polyamino acid are applied to the curee together.
15, method according to claim 1 is characterized in that, described at least a antibiotic comprises multiple antibacterial.
16, method according to claim 1 is characterized in that, the artificial analog of the polyamino acid that described at least a polyamino acid is natural generation.
17, method according to claim 1 is characterized in that, described at least a antibiotic is taken with peroral dosage form.
18, method according to claim 1 is characterized in that, described at least a polyamino acid is taken with peroral dosage form.
19, a kind of inventive compositions that is used to handle antibacterial comprises:
A) at least a polyamino acid;
B) at least a antibiotic; And
C) acceptable carrier on the materia medica.
20, compositions according to claim 19 is characterized in that, described at least a polyamino acid is derived from putrescine.
21, compositions according to claim 19, it is characterized in that, described at least a polyamino acid is selected from one group of material, and this group comprises: beta-Lactam antibiotic, the amino sugar amine, Macrolide, the monoamine rhzomorph, rifomycins, Tetracyclines, chloromycetin, clindamycin, lincomycin, imipenum, fusidinic acid, novobiocin, fosfomycin, fucidin, neomycin, polymyxin, capreomycin, Methacolimycin sulfonate, colistin, Gramicidin, minocycline, doxycycline, vancomycin, bacitracin, kanamycin, nalidixan and trimethoprim.
22, compositions according to claim 19 is characterized in that, described at least a antibiotic is hydrophilic.
23, compositions according to claim 19 is characterized in that, described at least a antibiotic is a beta-lactam.
24, compositions according to claim 19 is characterized in that, described at least a antibiotic comprises the different antibiotic combination.
25, compositions according to claim 19 is characterized in that, described at least a antibiotic comprises dissimilar antibiotic combinations.
26, compositions according to claim 19 is characterized in that, described at least a antibiotic acts on antibacterial by the efflux pump that influences antibacterial.
27, compositions according to claim 19 is characterized in that, described at least a antibiotic can be to penicillin-binding protein generation effect.
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| US11058110B2 (en) | 2017-12-12 | 2021-07-13 | International Business Machines Corporation | Polymers with antimicrobial functionalities |
| US11525036B2 (en) | 2017-12-12 | 2022-12-13 | International Business Machines Corporation | Chemical compositions with antimicrobial functionality |
| US11617367B2 (en) | 2017-12-12 | 2023-04-04 | International Business Machines Corporation | Antimicrobial polymers capable of supramolecular assembly |
| CN110179990B (en) * | 2019-06-13 | 2023-02-10 | 湖北凌晟药业有限公司 | Ceftibuten composition, granules thereof and preparation method of granules |
| CN110179990A (en) * | 2019-06-13 | 2019-08-30 | 湖北凌晟药业有限公司 | A kind of preparation method of Ceftibuten composition and its granule and the granule |
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