KR101649675B1 - Composition for antibiotics against Staphylococcus aureus - Google Patents

Composition for antibiotics against Staphylococcus aureus Download PDF

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KR101649675B1
KR101649675B1 KR1020150098159A KR20150098159A KR101649675B1 KR 101649675 B1 KR101649675 B1 KR 101649675B1 KR 1020150098159 A KR1020150098159 A KR 1020150098159A KR 20150098159 A KR20150098159 A KR 20150098159A KR 101649675 B1 KR101649675 B1 KR 101649675B1
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South Korea
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staphylococcus aureus
present
compound
composition
cells
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KR1020150098159A
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Korean (ko)
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석영재
김연란
윤지희
이주연
안진희
강승규
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서울대학교산학협력단
한국화학연구원
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/01Hydrocarbons
    • A61K31/015Hydrocarbons carbocyclic
    • AHUMAN NECESSITIES
    • A23FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23KFODDER
    • A23K20/00Accessory food factors for animal feeding-stuffs
    • A23K20/10Organic substances
    • A23K20/111Aromatic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate

Abstract

The present invention relates to a pharmaceutical composition comprising 2- [7- (benzyloxy) -1- (2-chlorobenzyl) -6-4 (dimethylamino) phenyl] naphthalen-2-yl) oxy] acetic acid, The present invention discloses an antimicrobial composition for Staphylococcus aureus containing a cargo, and the composition according to the present invention can be usefully used for the control of Staphylococcus aureus or for the prevention or treatment of various diseases caused thereby.

Description

Composition for antibiotics against Staphylococcus aureus < RTI ID = 0.0 >

The present invention relates to an antimicrobial composition for Staphylococcus aureus.

Staphylococcus aureus is a gram-positive, tuberous anaerobic bacterium that forms cell clumps (lumps) as it grows, and is generally present in the skin and nasal surface of healthy people and livestock. It produces exothermic exotoxin causing food poisoning. It also releases toxins (luocosidine), hemolysin, and coagulase enzymes that kill phagocytes, causing it to escape the resistance of infected host cells and cause pyogenic infections. Recently, MRSA (methicillin-resistant Staphylococcus aureus), which is resistant to most antibiotics in the hospital, has appeared. The MRSA is resistant to antibiotics such as penicillin, which has been used for about 50 years as a prescription medicine for bacterial infections. Patients hospitalized in hospitals and medical institutions are infected by internal infection, and they are infected with human beings through physical contact. If they become infected through trauma or cause pneumonia, life is dangerous enough.

Methicillin-resistant Staphylococcus aureus can only be treated with vancomycin. However, Vancomycin-resistant Staphylococcus aureus (VRSA), resistant to vancomycin, is resistant to most antibiotics that treat Staphylococcus aureus infections. Therefore, no antibiotics currently in use are effective and therefore cause sepsis and lead to death It is possible. Therefore, it is urgent to develop antibiotics which are effective against not only Staphylococcus aureus but also resistant bacteria.

Korean Patent Publication No. 2011-0015867 discloses a novel compound effective for Staphylococcus aureus with an antimicrobial composition containing as an active ingredient an extract of a bark extract of Aspergillus oryzae. Korean Patent Laid-Open Publication No. 2013-0090295 also discloses a novel compound Novel compounds which are effective against methicillin-resistant Staphylococcus aureus for antimicrobial compounds are disclosed.

However, it is necessary to develop new substances that are effective for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) as well as conventional staphylococcal infections, and which are harmless to humans even at high doses.

The present invention is directed to providing Staphylococcus aureus antibiotics that are capable of controlling Staphylococcus aureus but are not toxic to cells.

In one embodiment, the present invention provides a pharmaceutical composition comprising 2- [7- (benzyloxy) -1- (2-chlorobenzyl) -6-4 (dimethylamino) phenyl] naphthalen-2-yl) oxy] acetic acid, Or a solvate thereof. The present invention also provides a pharmaceutical composition for antibiosis against Staphylococcus aureus.

In another embodiment, the present disclosure is also directed to a method of treating Staphylococcus aureus comprising 2- [7- (benzyloxy) -1- (2- chlorobenzyl) -6-4 (dimethylamino) phenyl] naphthalen-2-yl) oxy] acetic acid A cosmetic composition for antibacterial use is provided.

In another embodiment, the present invention is also directed to a method of treating Staphylococcus aureus comprising 2- [7- (benzyloxy) -1- (2- chlorobenzyl) -6-4 (dimethylamino) phenyl] naphthalen-2-yl) oxy] The present invention provides a composition for antibiotic animal feed addition.

In another aspect, the present invention provides a method of controlling methicillin-resistant Staphylococcus aureus in an invitro characterized by the use of a compound of formula (I).

The compositions and methods according to the present invention have sterilizing or controlling effects on Staphylococcus aureus including methicillin resistant Staphylococcus aureus or vancomycin resistant Staphylococcus aureus.

The compound of formula 1 of the present invention is a substance showing 100% growth inhibition against Staphylococcus aureus, particularly methicillin-resistant Staphylococcus aureus. The MIC is 1.95 μM and is harmless to human cell lines even at a dose of 10 times or more of that of conventional antibiotics. Therefore, the composition containing the compound of formula (1) of the present invention is effective for preventing or treating various infectious diseases caused by Staphylococcus aureus.

FIG. 1 shows the results of an experiment of cytotoxicity of the compound of Chemical Formula 1 in human neuroblastoma (SH-SY5Y) according to one embodiment of the present invention. The vertical axis indicates the cell viability (%) after 24 hours of treatment of the compound. The abscissa indicates that the A400 is 7- (benzyloxy) -6- (4-dimethylamino) phenyl) naphthalene-2-ol (MIC: 3.9 μM) at 40 μM and A40 is 4 μM of the above compound; B400 is 40 μM of the compound of Formula 1 (MIC: 1.95 μM), B40 is 4 μM of the above compound; C400 was prepared by dissolving 40 μM of (S) -2 - ((4 '- (2-benzylbenzofuran-3- yl) - [1,1'- biphenyl] -4- yl) oxy) MIC: 3.9 [mu] M) and C40 is 4 [mu] M of the above compound; D400 was prepared by dissolving 40 μM of (R) -2 - ((4 '- (2-benzylbenzofuran-3- yl) - [1,1'- biphenyl] -4- MIC: 3.9 [mu] M), and D40 means 4 [mu] M of the above compound. The test compound was not treated in the control.
FIG. 2 shows the results of an experiment on cytotoxicity of the compound of Chemical Formula 1 in human embryonic kidney (HEK293) according to one embodiment of the present invention. The horizontal axis and the vertical axis are as shown in FIG. No compound was treated in the control group.
FIG. 3 shows the results of an experiment for cytotoxicity of the compound of Chemical Formula 1 in human hepatocellular carcinoma (HepG2) according to one embodiment of the present invention. The horizontal axis and the vertical axis are as shown in FIG. The vertical axis indicates the cell survival rate (%). The abscissa indicates that A40 is 7- (benzyloxy) -6- (4-dimethylamino) phenyl) naphthalene-2-ol (MIC: 3.9 μM) at 40 μM; B40 is 40 [mu] M of the compound of Formula 1 (MIC: 1.95 [mu] M), B4 is 4 [mu] M of the above compound; C40 was prepared by adding 40 μM of (S) -2 - ((4 '- (2-benzylbenzofuran-3- yl) - [1,1'- biphenyl] -4- yl) oxy) MIC: 3.9 [mu] M) and C4 is 4 [mu] M of the above compound; D40 is a mixture of 40 μM of (R) -2 - ((4 '- (2-benzylbenzofuran-3- yl) - [1,1'- biphenyl] -4- yl) oxy) MIC: 3.9 [mu] M), and D4 means 4 [mu] M of the above compound. No compound was treated in the control group.

The present invention relates to a novel use of the compound of formula (I) as an antimicrobial agent against Staphylococcus aureus.

In one embodiment, the present invention provides a compound of formula (I), which is 2- [7- (benzyloxy) -1- (2- chlorobenzyl) -6-4 (dimethylamino) phenyl] An antimicrobial composition for Staphylococcus aureus comprising a pharmaceutically effective salt thereof or a solvate thereof.

[Chemical Formula 1]

Figure 112015066860512-pat00001

This compound has a protein phosphatase activity as disclosed in Korean Patent No. 0622667 with Compound No. 6.

It has now been found that the compound of formula (I) has antimicrobial activity against Staphylococcus aureus.

Staphylococcus aureus in which the compound according to the present invention is effective includes Methicillin Resistant Staphylococcus aureus (MRSA) and Vancomycin Resistance Staphylococcus aureus (VRSA). Compounds according to the present invention are described in Clin Microbiol Infect. 2008 Mar; 14 Suppl 2: 3-9. doi: 10.1111 / j.1469-0691.2008.01923.x., MRSA as well as VRSA can be used.

A "pharmaceutically effective salt" herein is a pharmaceutically acceptable acid addition salt or base addition salt thereof, or a solvate thereof.

Pharmaceutically acceptable salts include those therapeutically active non-toxic addition salts which may be formed by the compounds of formula I and which are treated with suitable organic or inorganic bases to render their therapeutically active non-toxic metal or amine moieties Salt form (salt addition salt). Suitable basic bases include, for example, ammonium salts, alkali and alkaline earth metal salts, especially lithium salts, potassium, magnesium and calcium salts, salts with organic salts such as benzathine, N-methyl-D-glucamine, Salts, and salts with amino acids such as, for example, arginine and lysine.

Also included are quaternary ammonium salts of the compounds of Formula 1 herein. The quaternary ammonium salt can be obtained by reacting a basic nitrogen present in the compound of formula (I) with a suitable quaternizing agent. The quaternizing agents include alkyl halides, aryl halides, or aryl alkyl halides, such as methyl iodide, benzyl iodide, alkylcfluoromethanesulfonate, alkyl methanesulfonate, and alkyl p-toluenesulfonate . Quaternary ammonium salts carry a positively charged nitrogen, and pharmaceutically acceptable counter ions include chloro, bromo, iodo, trifluoroacetate, and acetate ions.

Conversely, the compound in the form of the salt may be converted to the free form by treatment with an appropriate acid.

Also included are all possible solvates which may be prepared from the compounds of formula (1) herein. Solvates include hydrates, alcoholates, and the like.

The 'Staphylococcus aureus' is not only a food poisoning but also a cause of purulent diseases such as skin inflammation, ear infections and cystitis. 'Methicillin-resistant Staphylococcus aureus' is a bacterium resistant to all beta-lactam antibiotics including methicillin It is a bacterium that causes symptoms such as high fever, chills, and low blood pressure if it is infected in a hospital or a medical institution through a trauma after surgery or after surgery.

The pharmaceutical composition of the present invention may be administered simultaneously or sequentially, and may be administered in combination with other pharmacologically active ingredients for treating the aforementioned diseases.

The pharmaceutical composition of the present invention may be formulated in a suitable form together with a commonly used pharmaceutically acceptable carrier. &Quot; Pharmaceutically acceptable " refers to compositions which are physiologically acceptable and which, when administered to humans, do not normally cause allergic reactions such as gastrointestinal disorders, dizziness, or the like. Examples of pharmaceutically acceptable carriers include, for example, water, suitable oils, saline, aqueous carriers for parenteral administration such as aqueous glucose and glycols, etc., and may further contain stabilizers and preservatives. Suitable stabilizers include antioxidants such as sodium hydrogen sulfite, sodium sulfite or ascorbic acid. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben and chlorobutanol. In addition, the composition according to the present invention may contain various additives such as a suspending agent, a solubilizer, a stabilizer, an isotonic agent, a preservative, an adsorption inhibitor, an interface activator, a diluent, an excipient, a pH adjuster, An antioxidant, and the like. Pharmaceutically acceptable carriers and formulations suitable for the present invention, including those exemplified above, are described in detail in Remington ' s Pharmaceutical Sciences, Current Edition.

The composition of the present invention may be prepared in a unit dosage form by formulating it using a pharmaceutically acceptable carrier and / or excipient according to a method which can be easily carried out by a person having ordinary skill in the art to which the present invention belongs. Into a capacity container. The formulations may be in the form of solutions, suspensions or emulsions in oil or aqueous media, or in the form of powders, granules, tablets or capsules.

The method of administration of the pharmaceutical composition of the present invention can be easily selected according to the formulation, and can be administered to mammals such as livestock, human, and the like in various routes. For example, it may be formulated in the form of powders, tablets, pills, granules, dragees, hard or soft capsules, liquids, emulsions, suspensions, syrups, elixirs, external preparations, suppositories, sterilized injection solutions, Or parenterally, and parenteral administration may be particularly preferable.

Formulations for parenteral administration include sterilized aqueous solutions, non-aqueous solutions, suspensions, emulsions, freeze-dried preparations, and suppositories. Examples of the non-aqueous solvent and suspending agent include propylene glycol, polyethylene glycol, vegetable oil such as olive oil, injectable ester such as ethyl oleate, and the like. As a base for suppositories, witepsol, macrogol, tween 61, cacao paper, laurin, glycerol, gelatin and the like can be used.

The dosage of the pharmaceutical composition of the present invention may vary depending on the patient's body weight, age, sex, health condition, diet, administration time, administration method, excretion rate and severity of disease, 60 kg), it is about 1 ng to 10 mg / day, especially about 1 μg to 1 mg / day. It will be apparent to those skilled in the art that doses may be additive or subtracted, as the dosage can vary depending on various conditions, and thus the dose is not intended to limit the scope of the invention in any way.

The number of administrations can be administered once or several times a day within a desired range, and the administration period is not particularly limited.

In another aspect, the present invention provides a cosmetic composition for the treatment of Staphylococcus aureus infectious disease comprising the compound of formula (1). The cosmetic composition of the present invention may be prepared in any form conventionally produced in the art and may be in the form of solutions, suspensions, emulsions, pastes, gels, creams, lotions, powders, soaps, Oils, powder foundations, emulsion foundations, wax foundations and sprays, but are not limited thereto. The ingredients included in the cosmetic composition of the present invention include, in addition to the active ingredient and the carrier ingredient, ingredients conventionally used in cosmetic compositions and may contain conventional additives such as antioxidants, stabilizers, solubilizers, vitamins, . ≪ / RTI >

In another embodiment, the composition of the present invention is provided in the form of a composition for animal feed addition. The composition of the present invention can be used as an animal feed additive for the purpose of preventing or improving bacterial infectious diseases in animals.

In another aspect, the present invention provides a method of controlling methicillin-resistant Staphylococcus aureus in an invitro characterized by the use of a compound of formula (I).

Hereinafter, the present invention will be described in detail with reference to the following examples. However, the following examples are illustrative of the present invention, and the contents of the present invention are not limited by the following examples.

Example

Example 1. Killing effect on Staphylococcus aureus

The compound of formula (1) was prepared according to the method described in Korean Patent No. 0622667. From the 62.5 μM to 0.122 μM, double-diluted serial dilution method was used at various concentrations as described in the description of the drawing.

Minimal inhibitory concentration (MIC) was determined according to the criteria of CLSI (Clinical and Laboratory Standards Institute) as follows to verify the antimicrobial effect of the compounds according to the present invention on Staphylococcus aureus.

Methicillin resistance Staphylococcus aureus ( MRSA , MRSA NCCP 14769) was streaked on BBL TM Müller Hillton agar plates (1.5% agar) to obtain independent colonies. And cultured in a 37 ° C incubator for 24 hours. About 3-5 similar shaped colonies were selected and transferred to an SPL 50ml tube containing 5ml MH liquid medium. And cultured at 37 ° C in a shaking incubator until a 0.5McFarland turbidity standard (0.08-0.13 at OD 625nm) was reached. During the incubation time, compound 1 was diluted stepwise from 96.5 μM into 96-well plates, and 10 μl of each compound was diluted to a concentration of 5 × 10 5 CFU / ml rapidly within 15 min. 90 占 diluted bacterial culture was dispensed into a 96-well polystyrene plate. And cultured in an incubator at 37 ° C for 24 hours. The absorbance (OD) was measured in a 96-well plate reader and the cell culture condition was measured to determine the MIC. No compound was treated in the control group. The bacterial growth was determined by measuring the absorbance at 600 nm. At the beginning of the experiment, the number of all bacteria was uniformly inoculated at about 0.05, and the incubation was started. After 24 hours, the absorbance was measured, The results of the compound treated groups were compared. The MIC of Compound 1 was 1.95 μM (1.07 μg / ml) or. The MIC of vancomycin is 2 ug / ml, but the MIC of Compound 1 is 1.07 ug / ml, which is comparable to vancomycin, even when treated with a smaller amount of antimicrobial agent.

Example 2. Cytotoxicity test

2-1. Toxicity analysis of SH-SY5Y (human neuroblastoma)

Mammalian cell line SH-SY5Y cells (ATCC CRL-2266 占) were cultured in a 96 well polystyrene plate in a 37 占 incubator for 24 hours using 0.2% FBS medium. Confluency and cell status were confirmed by microscopy. Cells washed with 0.2% FBS were incubated with 1 × 10 4 cells / well in an amount of 100 μl each. Compound (1) was administered at a concentration of MIC, MIC 10-fold in 96 wells. And cultured in a 37 ° C incubator for 24 hours. After washing once with the culture medium, cells were removed from the wells using trypsin. Dead cells (PI-positive, red fluorescence) stained by living cells (no signal, bright field counting) and PI (Propidium iodide) were counted in 3 or more (3 to 4) The number of viable cells was converted into% in the total number of cells by adding the numbers, and the cell viability was measured. The cell death rate was calculated as the number of dead cells in the whole cell count in terms of%. The results are shown in FIG. As indicated, antibiotics according to the present invention were found not to be toxic to eukaryotic cells at high concentrations.

2-2. Toxicity analysis of HEK 293 (human embryonic kidney) and HepG2 (human hepatocellular carcinoma)

In a 96-well polystyrene plates HEK 293 (ATCC ® CRL-1573 ™) or HepG2 (ATCC ® HB-8065 ™ ) cells, respectively 0.2% FBS medium 37 ℃ incubator using a cultured for 24 hours. Confluence and cell status were confirmed by microscopy. Cells washed with 0.2% FBS were incubated with 1 × 10 4 cells / well in an amount of 100 μl each. The compound of FIG. 1 was administered at a concentration of MIC and MIC 10-fold in 96 wells, respectively. And cultured in a 37 ° C incubator for 24 hours. After washing once with the culture medium, cells were removed from the wells using trypsin. Accustain Kit (NanoEnTek Inc.) was used according to the manufacturer's method to determine whether the cells were alive. In summary, 50 μl of Accustain T solution and 50 μl of Accustain N solution were added to each well. Then, the cell mixture was loaded 12 μl into Accuchip 4X, and the survival rate of the sample cells and the number of living cells and dead cells were measured with an ADAM-Mc automatic cell counter (NanoEnTek Inc.). The results are shown in FIGS. 2 and 3, respectively. As indicated, antibiotics according to the present invention were found not to be toxic to eukaryotic cells at high concentrations.

Claims (5)

Phenyl] naphthalen-2-yl) oxy] acetic acid, a pharmaceutically effective salt thereof, or a solvate thereof, can be obtained by reacting 2- [7- (benzyloxy) -1- (2- chlorobenzyl) A pharmaceutical composition for antimicrobial use against Staphylococcus aureus.
The pharmaceutical composition according to claim 1, wherein said Staphylococcus aureus is methicillin-resistant Staphylococcus aureus or vancomycin-resistant Staphylococcus aureus.
The cosmetic composition for antimicrobial use of Staphylococcus aureus comprising 2- [7- (benzyloxy) -1- (2-chlorobenzyl) -6-4 (dimethylamino) phenyl] naphthalen-2-yl) oxy] acetic acid.
Antibiotic animal feed supplementation for Staphylococcus aureus comprising 2- [7- (benzyloxy) -1- (2-chlorobenzyl) -6-4 (dimethylamino) phenyl] naphthalen-2-yl) oxy] acetic acid / RTI >
A method for controlling methicillin-resistant Staphylococcus aureus in vitro using the compound of formula (1) according to claim 1.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020171636A1 (en) * 2019-02-22 2020-08-27 서울대학교산학협력단 Antibacterial composition against staphylococcus aureus and mycobacterium tuberculosis

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100622667B1 (en) * 2004-08-31 2006-09-19 한국화학연구원 Naphthyloxyacetic acid derivatives
KR20110015867A (en) * 2009-08-10 2011-02-17 중앙대학교 산학협력단 Anti-bacterial composition comprising extract from barks of alnus pendula matsum

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR100622667B1 (en) * 2004-08-31 2006-09-19 한국화학연구원 Naphthyloxyacetic acid derivatives
KR20110015867A (en) * 2009-08-10 2011-02-17 중앙대학교 산학협력단 Anti-bacterial composition comprising extract from barks of alnus pendula matsum

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Bioorganic & Medicinal Chemistry Letters, 2013, vol. 23, pp. 2001~2006
Bioorganic & Medicinal Chemistry Letters, 2013, vol. 23, pp. 2001~2006 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020171636A1 (en) * 2019-02-22 2020-08-27 서울대학교산학협력단 Antibacterial composition against staphylococcus aureus and mycobacterium tuberculosis
KR20200102762A (en) * 2019-02-22 2020-09-01 서울대학교산학협력단 Composition for antibiotics against staphylococcus aureus and mycobacterium
KR102198101B1 (en) * 2019-02-22 2021-01-04 서울대학교산학협력단 Composition for antibiotics against staphylococcus aureus and mycobacterium

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