US20170204052A1 - Novel antimicrobial compound and use thereof - Google Patents

Novel antimicrobial compound and use thereof Download PDF

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US20170204052A1
US20170204052A1 US15/311,245 US201515311245A US2017204052A1 US 20170204052 A1 US20170204052 A1 US 20170204052A1 US 201515311245 A US201515311245 A US 201515311245A US 2017204052 A1 US2017204052 A1 US 2017204052A1
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microorganism
genus
composition
antibiotic
present
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Won Gon Kim
Hyun Ju Kim
Yu Jin KIM
Kyung Yun Cho
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Korea Research Institute of Bioscience and Biotechnology KRIBB
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/64—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C233/67—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
    • C07C233/75—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a six-membered aromatic ring
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/56—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/44—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/58—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C235/64—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton with carbon atoms of carboxamide groups and singly-bound oxygen atoms bound to carbon atoms of the same non-condensed six-membered aromatic ring with carbon atoms of carboxamide groups and singly-bound oxygen atoms, bound in ortho-position to carbon atoms of the same non-condensed six-membered aromatic ring having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to an antimicrobial compound and a microorganism having an antimicrobial activity, and more specifically, to a novel compound having an antimicrobial activity, an isomer thereof, a derivative, or pharmaceutically acceptable salt thereof; a microorganism of the genus Corallococcus producing the same; an antimicrobial composition containing the same; a pharmaceutical composition for preventing or treating microbial infections containing the composition; an antimicrobial quasi-drug composition; an antimicrobial food composition; an antimicrobial feed composition for livestock or fish; and a method for preparing the compound.
  • VRSA vancomycin-resistant Staphylococcus aureus
  • MRSA vancomycin-resistant Enterococcus
  • VRE vancomycin-resistant Enterococcus
  • VISA vancomycin intermediate-resistant S. aureus
  • the present inventors have made efforts to discover a novel antibiotic material, and as a result, they have newly identified a Myxobacteria microorganism producing a strong antibiotic material, isolated and purified the antibiotic material with purity from the culture broth of the microorganism, determined the chemical structure of the antibiotic material, and confirmed that the antibiotic material has an antimicrobial activity not only in gram-positive and gram-negative microorganisms but also in antibiotic-resistant microorganisms, thereby completing the present invention.
  • An object of the present invention is to provide a compound represented by the following Formula 1 or 2, an isomer thereof, a derivative, or a pharmaceutically acceptable salt thereof.
  • Another object of the present invention is to provide a microorganism of the genus Corallococcus having an antimicrobial activity, wherein the microorganism produces the compound represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide an antimicrobial composition containing the compound represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof, a microorganism of the genus Corallococcus producing the same, a spore of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof.
  • Still another object of the present invention is to provide a method for treating at least one disease selected from the group consisting of (i) to (iii) below, including administering the composition to a subject in need thereof:
  • bacteremia sepsis, urinary tract infection, pneumonia, pleural empyema, tympanitis, mastoiditis, meningitis, osteomyelitis, arthritis, peritonitis, pericarditis, cellulitis, typhus, and acute gastroenteritis.
  • Still another object of the present invention is to provide a method for preparing compounds represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • Still another object of the present invention is to provide a use of the above compounds, an isomer thereof, a derivative, or a pharmaceutically acceptable salt thereof, a microorganism of the genus Corallococcus producing the same, a spore of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof for the preparation of pharmaceutical drugs for treating at least one disease selected from the group consisting of (i) to (iii) above.
  • the microorganism of the genus Corallococcus producing coralmycins A and B which are novel compounds of the present invention, have very strong antimicrobial activities against not only the gram-positive and gram-negative microorganisms but also antibiotic-resistant microorganisms, such as MRSA, QRSA, VRE, and VISA, and Acinetobacter baumannii, which is a multidrug-resistant microorganism. Therefore, the present invention can be very useful for prevention, treatment, and alleviation of various microbial infections, and thus can be widely applied to the medical supply, quasi-drug, food, and feed industries.
  • FIG. 1 a shows an image of cells of a Corallococcus coralloides M23 microorganism.
  • FIG. 1 b shows an image of the shape of fruiting bodies of a Corallococcus coralloides M23 microorganism.
  • the present invention provides a compound represented by the following Formula 1 or 2, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • the Corallococcus coralloides M23 microorganism (Accession No. KCTC18279P), which is a microorganism of the genus Corallococcus , was identified, and two different compounds with antimicrobial activities produced by the microorganism were purified and identified.
  • coralmycin A a novel compound represented by Formula 1 above
  • coralmycin B a novel compound represented by Formula 2 above
  • KCTC18279P was deposited to the Korean Collection for Type Cultures (KCTC), which is an international depositary authority under the Budapest Treaty, and assigned the Accession No. KCTC12812BP. Accordingly, in the present invention, KCTC18279P and KCTC12812BP can be interchangeably used as the Accession No. of the Corallococcus coralloides M23 microorganism.
  • the compounds of the present invention may include isomers, a derivative thereof or a pharmaceutically acceptable salt thereof having the same activities as those of the compounds represented by Formula 1 or 2 above, but are not limited thereto.
  • isomers refers to a relationship of molecules which have the same chemical formula but are not the same.
  • types of isomers include structural isomers, geometrical isomers, optical isomers, and stereoisomers.
  • Structural isomers are compounds which have the same chemical constitution but differ in the three-dimensional orientations of their atoms and groups in space; in which optical isomers (i.e., enantiomers) refer to two stereoisomers of a compound which have mirror images that are not superimposable with each other, and diastereomers refer to two or more stereoisomers of a compound which have an achiral center but whose molecules are not mirror images of each other.
  • the isomers of Formula 1 or 2 above may be those represented by Formula 3 or 4 below, but are not limited thereto.
  • the term “derivative” refers to a compound in which an atom or atomic group of a compound is substituted with a different atom or atomic group.
  • the derivatives of coralmycin A or coralmycin B are compounds having an antimicrobial activity in which the atom or atomic group of coralmycin A or coralmycin B are substituted with a different atom or atomic group.
  • the derivatives may be those in which the hydrogen atom in a hydrocarbon or heterocycle is substituted with a different group or a functional group is substituted with a different functional group.
  • the term “pharmaceutically acceptable salt” refers to any of all organic or inorganic addition salts of the compound, which do not diminish the advantageous effects of the compounds represented by Formula 1 or 2 above, in a concentration which is relatively non-toxic to patients, and has an unharmful and effective action.
  • Acid addition salts may be prepared by a conventional method, for example, dissolving a compound in an excess amount of an aqueous acid solution and precipitating the resulting salt in a water-miscible organic solvent (e.g., methanol, ethanol, acetone, or acetonitrile).
  • a water-miscible organic solvent e.g., methanol, ethanol, acetone, or acetonitrile.
  • An equimolar amount of a compound and an acid or alcohol in water e.g., glycol monomethylether
  • the mixture may be dried by evaporation or the precipitate may be subjected to suction filtration, but is not limited thereto.
  • organic acids and inorganic acids may be used as a free acid.
  • the inorganic acids may include hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, and tartaric acid; organic carbonic acids such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid, vanillic acid, hydroiodic acid, etc., but are not limited thereto.
  • a pharmaceutically acceptable metal salt may be prepared using a base.
  • An alkali metal salt or alkali earth metal salt may be prepared, for example, by dissolving a compound in an excess amount of an alkali metal hydroxide or alkali earth metal hydroxide solution, filtering a non-dissolved compound salt obtained therefrom, and evaporating the filtrate, followed by drying.
  • examples of a pharmaceutically acceptable metal salt to be prepared may include sodium, potassium, or calcium salts, but are not limited thereto.
  • a corresponding silver salt may be prepared by reacting an alkali metal or alkali earth metal salt with an appropriate silver salt (e.g., silver nitrate), but the preparation method is not limited thereto.
  • the pharmaceutically acceptable salts of the compounds represented by Formula 1 or 2 above may include salts of an acidic or basic group that can be present in the compounds of Formula 1 or Formula 2, unless instructed otherwise.
  • the pharmaceutically acceptable salts may include sodium, calcium, or potassium salts of a hydroxyl group, etc.
  • other pharmaceutically acceptable salts of an amino group may include hydrobromide, sulfate, hydrogen sulfate, phosphate, hydrogen phosphate, dihydrogen phosphate, acetate, succinate, citrate, tartrate, lactate, mandelate, methanesulfonate (mesylate), p-toluenesulfonate (tosylate), etc., and they can be prepared by a preparation method known in the art.
  • any pharmaceutically acceptable salt which exhibits the same antimicrobial activity as the compounds of Formula 1 or 2 above can be used without limitation.
  • the present invention provides a microorganism of the genus Corallococcus having an antimicrobial activity, where the microorganism can produce the compounds represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof.
  • the microorganism of the genus Corallococcus may belong to the scope of the present invention without limitation, as long as the microorganism can produce compounds represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof thereby having antimicrobial activities.
  • the microorganism may be Corallococcus coralloides, and more specifically, a Corallococcus coralloides M23 microorganism with the Accession Number of KCTC18279P, but is not limited thereto.
  • a physiological and morphological examination was performed for the identification of a Corallococcus coralloides M23 microorganism purely isolated from a soil sample.
  • the microorganism was confirmed to be a gram-negative Bacillus with a length of about 4 ⁇ m ( FIG. 1 a ), which showed vegetative growth feeding on E. coli and migrated with gliding motility.
  • the microorganism formed its unique fruiting bodies in WC medium (10 mM 3-[N-morpholino]propanesulfonic acid (pH 7.6), 0.1% CaCl 2 .2H 2 O, 1.5% agar) ( FIG. 1 b ).
  • DNA was extracted from the microorganism and analyzed by PCR. As a result, it was confirmed that the nucleotide sequence of 16S rDNA of the M23 microorganism showed a similarity of 99.86% to that of 16S rDNA (Accession Number DQ768120) of the standard microorganism of Corallococcus coralloides (DSM 2259 (T)).
  • the M23 microorganism was identified based on the physiological and morphological characteristics and the analysis of the nucleotide sequence of 16S rDNA, and the M23 microorganism was deposited to the Korean Collection for Type Culture (KCTC) located at 25 Gwahak-ro, Yuseong-gu, Daejeon, Korea, on Apr. 2, 2014, under Accession No. KCTC 18279P.
  • KCTC Korean Collection for Type Culture
  • the present invention provides a culture broth of the microorganism of the genus Corallococcus.
  • the culture broth of the present invention may be a culture broth of a microorganism of the genus Corallococcus, and more specifically, a culture broth of the Corallococcus coralloides M23 microorganism with the Accession Number of KCTC18279P, but is not limited thereto. Since the compounds represented by Formula 1 or Formula 2 have an antimicrobial activity, the culture broth of the microorganism of the genus Corallococcus producing the above compounds will also have the antimicrobial activity.
  • the term “culture broth” refers to the entire medium including a cultured microorganism obtained by culturing the microorganism of the genus Corallococcus of the present invention, specifically the Corallococcus coralloides M23 microorganism, in medium which can provide nutrients for growth and survival of the microorganism, for a particular period of time; a metabolite thereof; remaining nutrients, etc., and the culture solution in which the microorganism is removed after culturing is also included.
  • the microorganism of the genus Corallococcus and the Corallococcus coralloides M23 microorganism are microorganisms having an antimicrobial activity
  • the microorganism of the genus Corallococcus or the Corallococcus coralloides M23 microorganism, and a culture broth thereof can be used as an antimicrobial composition.
  • the present invention provides an antimicrobial composition containing the compound represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof, a microorganism of the genus Corallococcus producing the same, a spore of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof.
  • the microorganism may be a Corallococcus coralloides microorganism, and more specifically, the Corallococcus coralloides M23 microorganism with the Accession Number of KCTC18279P, but is not limited thereto.
  • the compounds represented by Formula 1 or Formula 2 have very strong antimicrobial activities against antibiotic-resistant microorganisms, gram-positive microorganisms, and gram-negative microorganisms, and thus a composition containing a microorganism of the genus Corallococcus producing the same, a spore of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof will also have a very strong antimicrobial activity.
  • the term “extract” refers to a resulting product obtained by extracting a target material using water, a low-grade alcohol having 1 to 4 carbon atoms (e.g., methanol, ethanol, propanol, butanol, etc.), an organic solvent (e.g., hexane, acetone, chloroform, methyl acetate, etc.), a mixed solvent thereof, etc., and the resulting product includes all of an extract, a dilution or concentrate of the extract, a dried product obtained by drying the extract, or a crude purified or purified product, etc.
  • the extract is a resulting product obtained by extracting a microorganism of the genus Corallococcus using an organic solvent, and the extract may include an antimicrobial compound provided in the present invention, but is not limited thereto.
  • the term “fraction” refers to a resulting product obtained by a fractionation method which separates particular components or particular groups from a mixture containing various constituting components.
  • the fraction may be a resulting product obtained by subjecting the extract of microorganism of the genus Corallococcus to solvent fractionation using a solvent such as n-hexane, ethyl acetate, etc.
  • the fraction may include both a polar solvent fraction and a non-polar solvent fraction, and specifically, a methanol fraction, an ethyl acetate fraction, etc., may be used as well.
  • antimicrobial or “antimicrobial activity” refer to properties that can resist against microorganisms such as bacteria and fungi, and more specifically, to the characteristics that antibiotic materials or the like being inhibiting the growth or proliferation of microorganisms.
  • antimicrobial and antimicrobial activity may be used as characteristics to inhibit the growth or proliferation of antibiotic-resistant or antibiotic-susceptible gram-positive microorganisms; antibiotic-resistant or antibiotic-susceptible gram-negative microorganisms; etc., but the uses of these terms are not particularly limited thereto.
  • the antibiotic-resistant microorganism may be a microorganism having a resistance to at least one antibiotic selected from the group consisting of penicillin antibiotics, methicillin antibiotics, quinolone antibiotics, vancomycin antibiotics, carbapenem antibiotics, and aminoglycoside antibiotics, and specifically, the microorganism may be methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant Staphylococcus aureus (QRSA), vancomycin resistant enterococcus (VRE), vancomycin intermediate-resistant S. aureus (VISA), or multidrug-resistant Acinetobacter baumannii, but is not limited thereto.
  • MRSA methicillin-resistant Staphylococcus aureus
  • QRSA quinolone-resistant Staphylococcus aureus
  • VRE vancomycin resistant enterococcus
  • VRE vancomycin intermediate-resistant S. aureus
  • VISA vancomycin intermediate-resistant S. aureus
  • the antimicrobial activities of coralmycin A against MRSA, QRSA, and multidrug-resistant Acinetobacter baumannii were confirmed, and the antimicrobial activities of coralmycin B against MRSA and multidrug-resistant Acinetobacter were confirmed (Tables 2 and 4).
  • the gram-positive microorganisms may be a microorganism of the genus Staphylococcus, the genus Bacillus, the genus Streptococcus, or the genus Enterococcus
  • the gram-negative microorganisms may be a microorganism of the genus Salmonella, the genus Acinebacter, the genus Escherichia, the genus Pseudomonas, or the genus Klebsiella, but the microorganisms are not particularly limited thereto.
  • the gram-positive microorganisms may be Staphylococcus aureus, MRSA, QRSA, Bacillus subtilis, Bacillus cereus, Streptococcus pneumoniae, Enterococcus faecalis, or Staphylococcus epidermidis
  • the gram-negative microorganisms may be Salmonella typhimurium, Acinebacter calcoaceticus, Escherichia coli, Pseudomonas aeruginosa, Klebsiella aerogenes, Acinetobacter baumannii, or Klebsiella pneumoniae, but the microorganisms are not particularly limited thereto.
  • a microorganism of the genus Staphylococcus refers to a microorganism which belongs to the genus Micococcaceae and the microorganism includes Staphylococcus aureus, Staphylococcus epidermidis, Staphylococcus saprophyticus, etc., and is called Staphylococcus.
  • the microorganism of the genus Staphylococcus is present in the gastrointestinal tract, and additionally, in the skin or mucous membranes of humans or animals. Examples of the microorganisms isolated from people with diseases include S. aureus, S. epidermidis, S. saprophyticus, S. haemolyticus, S. hominis, S. warneri, etc.
  • the microorganism of the genus Staphylococcus may include any microorganism without limitation that can be used as a target of antimicrobial compounds provided in the present invention.
  • Staphylococcus aureus an exemplary microorganism of the genus Staphylococcus, is a gram-positive facultative anaerobe which is generally present in the skin and on the nasal surface of healthy people or cattle.
  • Staphylococcus aureus produces heat-resistant exotoxins which cause food poisoning and secretes a toxin (leukocidin), hemolysins, coagulase, etc., which kill phagocytes, and is thereby capable of escaping the resistance of the infected host cells and causing purulent infections.
  • MRSA and QRSA which are microorganisms recently reported to show a resistance to most antibiotic materials within hospitals, etc., also belong to Staphylococcus aureus.
  • Staphylococcus epidermidis an exemplary microorganism of the genus Staphylococcus
  • Staphylococcus epidermidis is a gram-positive bacterium and can cause sepsis, urinary tract infection, endocarditis, etc.
  • the composition can cause the apoptosis of the microorganisms that belong to the genus Staphylococcus, the above diseases caused by a microorganism of the genus Staphylococcus can be treated using the composition.
  • a microorganism of the genus Bacillus is a collective term referring to rod-shaped bacteria.
  • the microorganism is present in various environments in nature such as living environments of people, soils, etc. About 148 species are known at present and some are known to cause food poisoning.
  • the microorganism of the genus Bacillus can include without limitation any microorganism that can be used as a target of antimicrobial compounds provided in the present invention.
  • the microorganism of the genus Bacillus may be specifically Bacillus subtilis or Bacillus cereus, but is not limited thereto.
  • the composition can cause the apoptosis of microorganisms that belong to the genus Bacillus, the above disease caused by a microorganism of the genus Bacillus can be treated using the composition.
  • a microorganism of the genus Streptococcus is a gram-positive microorganism of the genus Streptococcaceae and it is one of the pathogens causing pyogenic infection, etc.
  • the microorganism of the genus Streptococcus can include without limitation any microorganism that can be used as a target of antimicrobial compounds provided in the present invention.
  • the Streptococcus pneumoniae is a gram-positive diplococcus and it is a pathogen causing pneumonia, pleural empyema, tympanitis, mastoiditis, bacteremia. meningitis, osteomyelitis, arthritis, peritonitis, pericarditis, cellulitis, etc.
  • the composition can cause the apoptosis of microorganisms that belong to the genus Streptococcus, the above diseases caused by a microorganism of the genus Streptococcus can be treated using the composition.
  • a microorganism of the genus Salmonella is a gram-negative microorganism and is one of the pathogens causing typhus, acute gastroenteritis, food poisoning, etc.
  • the microorganism of the genus Salmonella can include without limitation any microorganism that can be used as a target of antimicrobial compounds provided in the present invention.
  • the microorganism of the genus Salmonella may be specifically Salmonella typhimurium, but is not limited thereto.
  • the composition can cause the apoptosis of microorganisms that belong to the genus Salmonella, the above diseases caused by a microorganism of the genus Salmonella can be treated using the composition.
  • a microorganism of the genus Acinebacter may include any microorganism without limitation that can be used as a target of antimicrobial compounds provided in the present invention.
  • the microorganism of the genus Acinetobacter may be specifically Acinetobacter baumannii, but is not limited thereto.
  • the Acinetobacter baumannii is a gram-negative microorganism and it is a multidrug-resistant microorganism having a resistance to fluoroquinolone antibiotics, carbapenem antibiotics, and aminoglycoside antibiotics.
  • the composition can cause the apoptosis of microorganisms that belong to the genus Acinetobacter, the above diseases caused by a microorganism of the genus Acinetobacter can be treated using the composition.
  • a microorganism of the genus Escherichia is a gram-negative microorganism and is a kind of enterobacteria and a pathogen causing food poisoning, etc.
  • a microorganism of the genus Escherichia may include any microorganism without limitation that can be used as a target of antimicrobial compounds provided in the present invention.
  • the microorganism of the genus Escherichia may be specifically Escherichia coli, but is not limited thereto.
  • the composition can cause the apoptosis of microorganisms that belong to the genus Escherichia, the above diseases caused by a microorganism of the genus Escherichia can be treated using the composition.
  • a microorganism of the genus Pseudomonas is a gram-negative microorganism, and the microorganism may be a pathogen or putrefactive bacteria, or may be used for the preparation of amino acids by amino acid fermentation.
  • a microorganism of the genus Pseudomonas may include any microorganism without limitation that can be used as a target of antimicrobial compounds provided in the present invention.
  • Pseudomonas aeruginosa an exemplary microorganism of the genus Pseudomonas, may cause bacteremia, sepsis, etc.
  • the composition can cause the apoptosis of microorganisms that belong to the genus Pseudomonas
  • the above diseases caused by a microorganism of the genus Pseudomonas can be treated using the composition.
  • a microorganism of the genus Klebsiella is a gram-negative microorganism and it is a kind of enterobacteria.
  • the microorganism of the genus Klebsiella can cause pneumonia, endocarditis, peritonitis, cholecystitis, urinary tract infection, sepsis, etc.
  • a microorganism of the genus Klebsiella may include any microorganism without limitation that can be used as a target of antimicrobial compounds provided in the present invention.
  • the microorganism of the genus Klebsiella may be specifically Klebsiella aerogenes, or Klebsiella pneumoniae but is not limited thereto.
  • the composition can cause the apoptosis of microorganisms that belong to the genus Klebsiella, the above diseases caused by a microorganism of the genus Klebsiella can be treated using the composition.
  • the antimicrobial activities of coralmycin A against Staphylococcus aureus, MRSA, QRSA, VRE, VISA, Bacillus subtilis, Bacillus cereus, Streptococcus pneumoniae, Enterococcus faecalis, and Staphylococcus epidermidis, i.e., gram-positive microorganisms, were confirmed (Example 5). Additionally, it was confirmed that coralmycin B has an antimicrobial activity against Staphylococcus aureus, MRSA, Streptococcus pneumoniae, and Enterococcus faecalis, i.e., gram-positive microorganisms.
  • the antimicrobial activities of coralmycin A against Salmonella typhimurium, Acinetobacter calcoaceticus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella aerogenes, i.e., gram-negative microorganisms were confirmed (Example 5). Additionally, it was confirmed that coralmycin B has an antimicrobial activity against E. coli, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae, i.e., gram-negative microorganisms.
  • the antimicrobial composition of the present invention may be a pharmaceutical composition, a quasi-drug composition, a food composition, or a feed composition for livestock or fish, but is not limited thereto.
  • the antimicrobial composition of the present invention may be a pharmaceutical composition for preventing or treating at least one disease selected from the group consisting of (i) to (iii) below:
  • bacteremia bacteremia, sepsis, urinary tract infection, pneumonia, pleural empyema, tympanitis, mastoiditis, meningitis, osteomyelitis, arthritis, peritonitis, pericarditis, cellulitis, typhus, and acute gastroenteritis, but is not limited thereto.
  • coralmycins A and B of the present invention have very strong antimicrobial activities against the microorganisms of the genus Staphylococcus, the genus Bacillus, the genus Streptococcus, the genus Enterococcus, the genus Salmonella, the genus Acinetobacter, the genus Escherichia, the genus Pseudomonas, and the genus Klebsiella, which cause pyogenic infection, food poisoning, bacteremia, sepsis, urinary tract infection, pneumonia, pleural empyema, tympanitis, mastoiditis, meningitis, osteomyelitis, arthritis, peritonitis, pericarditis, cellulitis, typhus, acute gastroenteritis, etc.
  • coralmycins A and B of the present invention can be used for the prevention or treatment of the diseases described above. Additionally, it will be obvious to a person of ordinary skill in the art that the effects of preventing or treating the above diseases may be exhibited not only by coralmycins A and B but also by a microorganism of the genus Corallococcus producing these compounds, spores of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof.
  • pyogenic infection is a symptom caused by bacteria such as Staphylococcus aureus and is divided according to the infected tissues or causative pathogens.
  • pyogenic infection may be one among tympanitis, cystitis, pyogenic acne, furuncle, carbuncle, cellulitis, whitlow, and lymphangitis, but is not limited thereto.
  • the pharmaceutical composition of the present invention may further contain an appropriate carrier, excipient, and diluent which are conventionally used in the preparation of pharmaceutical compositions.
  • each of the pharmaceutical composition of the present invention may be formulated into oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, aerosols, etc.; formulations for external use; suppositories; and sterile injection solutions for use.
  • examples of the carrier, excipient, and diluent to be contained in the pharmaceutical composition may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinyl pyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, mineral oil, etc.
  • solid formulations for oral administration may include tablets, pills, powders, granules, capsules, etc. These solid formulations are prepared, for example, by addition at least one excipient (e.g., starch, calcium carbonate, sucrose, lactose, gelatin, etc) to the extract of red beans and fractions thereof. Additionally, lubricants such as magnesium stearate, talc, etc., may be used in addition to the simple excipients.
  • excipient e.g., starch, calcium carbonate, sucrose, lactose, gelatin, etc
  • lubricants such as magnesium stearate, talc, etc.
  • liquid preparations for oral administration include suspensions, oral solutions, emulsions, syrups, etc., and various kinds of excipients (e.g., humectants, sweeteners, fragrances, preservatives, etc.) may be used in addition to simple diluents such as water and liquid paraffin.
  • Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories.
  • non-aqueous solvents, suspensions may include propylene glycol, polyethylene glycol, a vegetable oil such as olive oil, an injectable ester such as ethylolate, etc.
  • suppository bases include Witepsol, Macrogol, Tween 61, cacao butter, laurinum, glycerogelatin, etc.
  • the pharmaceutical composition may be administered in a pharmaceutically effective amount.
  • a pharmaceutically effective amount refers to an amount sufficient for the treatment of a disease at a reasonable benefit/risk ratio but without any adverse effects, thereby being applicable to medical treatment.
  • the level of the effective dose may be easily determined by the health status of a patient, type of a disease, severity of a disease, drug activities, drug sensitivities, methods of administration, duration of administration, routes of administration and excretion rate, duration of treatment, factors including drugs used at the same time or in combination, and other factors well-known in the medical field.
  • the composition of the present invention may be administered as an individual therapeutic agent or in combination with other therapeutic agent(s).
  • composition of the present invention may be administered sequentially or simultaneously along with the conventional therapeutic agent(s), and may be administered as a single-dose or multi-dose administration. It is important that the administration dose be in a minimal amount to obtain the maximal effect without adverse effects considering the factors described above, and these factors can be easily determined by one of ordinary skill in the art. Specifically, the composition of the present invention may be administered in the amount of 0.1 mg/kg to 50 mg/kg of body weight, and more, preferably 5 mg/kg to 30 mg/kg of body weight.
  • the term “administration” refers to provision of a particular material to a patient using any suitable method and the pharmaceutical composition of the present invention may be administered by any of the conventional routes, as long as it enables the delivery of the composition to the target tissue.
  • the pharmaceutical composition of the present invention may be administered by intraperitoneal, intravenous, intramuscular, subcutaneous, intradermal, oral, local, intranasal, intrapulmonary, or intrarectal administration, but is not limited thereto. Additionally, the pharmaceutical composition of the present invention may be administered using any device that can transport an active material to a target cell.
  • the term “subject” may refer to all animals including humans, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats, rabbits, or guinea pigs, which have or are at the risk of developing the above disease.
  • the above disease can be effectively prevented or treated by administering the pharmaceutical composition of the present invention to a subject.
  • the antimicrobial composition may be a quasi-drug composition, but is not limited thereto.
  • the antimicrobial composition of the present invention has a very strong antimicrobial activity against microorganisms of the genus Staphylococcus, the genus Bacillus, the genus Streptococcus, the genus Enterococcus, the genus Salmonella, the genus Acinetobacter, the genus Escherichia, the genus Pseudomonas, and the genus Klebsiella, and thus it can be used as an antimicrobial quasi-drug composition.
  • the term “quasi-drugs” refers to any of the products corresponding to fiber or rubber products or analogs thereof that are used for the treatment, alleviation, handling, or prevention of diseases in humans or animals; products other than instruments and machines, and analogs thereof which have a weak action in humans or do not directly act in human body; products corresponding to any of the germicides or insecticides, and analogs thereof for the prevention of epidemics, other than instruments, machines, and apparatuses that are used for the diagnosis, treatment, alleviation, handling, or prevention of diseases in humans or animals, and products excluding those other than instruments, machines, and apparatuses that are used for providing pharmacological effects on the structures and functions of humans or animals; and external skin preparations and personal hygiene products are also included therein.
  • the compounds represented by Formula 1 or Formula 2 of the present invention When the compounds represented by Formula 1 or Formula 2 of the present invention are added into a quasi-drug composition for the antimicrobial purpose, the compounds represented by Formula 1 or 2 may be added as they are or used in combination with other quasi-drug ingredients, and may be appropriately used according to the conventional method.
  • the mixed amounts of the active ingredients may be appropriately determined according to their intended purposes.
  • the external skin preparations may be prepared in the form of ointments, lotions, sprays, patches, creams, powders, suspensions, gelling agents, or gels, but are not particularly limited thereto.
  • the personal hygiene products may be soaps, cosmetics, wet tissues, toilet paper rolls, shampoos, skin creams, facial creams, toothpastes, lipsticks, make-ups, foundations, blushers, mascaras, eye shadows, sunscreen lotions, haircare products, air-freshener gels, or facial cleansing gels, but are not particularly limited thereto.
  • other examples of the quasi-drugs of the present invention may include disinfectants, shower foams, mouthwash products, wet tissues, detergents, handwashes, humidifier fillers, masks, ointments, or filter fillers.
  • the antimicrobial composition of the present invention may be a food composition, but is not limited thereto.
  • the coralmycins A and B of the present invention have strong antimicrobial activities against the microorganisms of the genus Staphylococcus, the genus Bacillus, the genus Streptococcus, the genus Enterococcus, the genus Salmonella, the genus Acinetobacter, the genus Escherichia, the genus Pseudomonas, and the genus Klebsiella, and thus it is obvious that these compounds can be used in the antimicrobial food composition.
  • coralmycins A and B but also spores of the microorganism which produce these compounds, a culture broth of the microorganism, an extract of the microorganism, or a fraction of the extract can also exhibit a antimicrobial activity, and thus these can be used in the antimicrobial food composition.
  • the term “food” includes meats, sausages, breads, chocolates, candies, snacks, cookies, pizzas, ramens, other noodles, gums, dairy products including ice creams, various kinds of soups, beverages, teas, drinks, alcoholic beverages, vitamin complexes, etc., and all kinds of foods in the conventional meaning are included.
  • the term “functional food” is the same term as food for special health use (FoSHU), and it refers to a food having high medical and medicinal effects processed to exhibit biological regulation function with efficiency, in addition to nutrition supply.
  • the term “health food” refers to a food which has active effects of maintaining or promoting health
  • the term “health supplement food” refers to a food with a health supplementary purpose.
  • the foods may be prepared in various forms including tablets, capsules, powders, granules, liquids, pills, etc.
  • an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof, a microorganism of the genus Corallococcus producing the same, spores of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof may be contained in an amount of 0.01 wt % to 100 wt % based on the total weight of a food composition, and more specifically, 1 wt % to 80 wt %.
  • the composition may be contained in an amount of 1 g to 30 g, specifically 3 g to 20 g based on 100 mL of the beverage, but is not limited thereto.
  • composition may further contain an ingredient that can be used to improve smell, taste, vision, etc.
  • an ingredient that can be used to improve smell, taste, vision, etc.
  • vitamins A, C, D, E, B1, B2, B6, B12, niacin, biotin, folate, panthotenic acid, etc. may be contained.
  • minerals such as Zn, Fe, Ca, Cr, Mg, Mn, Cu, Cr, etc.
  • amino acids such as lysine, tryptophan, cysteine, valine, etc., may be contained.
  • food additives such as a preservative (potassium sorbate, sodium benzoate, salicylic acid, sodium dehydroacetate, etc.), a germicide (bleaching powder, high-grade bleaching powder, sodium hydrochlorite, etc.), an antioxidant (butylhydroxyanisole (BHA), butylhydroxytoluene (BHT), etc.), a colorant (tar dye, etc.), a color fixing agent (e.g., sodium nitrate, sodium nitrite, etc.), a bleaching agent (sodium sulfite), a seasoning agent (e.g., MSG, sodium glutamate, etc.), a sweetener (e.g., dulcin, cyclamate, sodium saccharine, etc.), a flavoring agent (vanillin, lactone, etc.), a blowing agent (alum, potassium D-bitartrate, etc.), a fortifying agent, an emulsifying agent, a thickener (thicken
  • the antimicrobial composition may be a feed composition for cattle or fish, but is not limited thereto.
  • the amounts of compounds contained in the feed composition for cattle or fish of the present invention represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof, a microorganism of the genus Corallococcus, spores of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof may vary depending on the purposes and conditions of use, for example, may be contained in an amount of 0.01 wt % to 100 wt %, and more specifically, in an amount of 1 wt % to 80 wt % based on the total weight of the feed composition for cattle or fish.
  • the feed composition may be prepared into coarse or granular materials with light viscosity according to the degree of pulverization of its ingredients.
  • the feed composition may be supplied in a mesh or formed into a desired separate shape for further processing or packaging, or may undergo pelletization, expansion, or extrusion processes for storage purposes, and specifically for the easiness of storage, an excess amount of water may be removed by drying.
  • Another aspect of the present invention provides a method for treating at least one disease selected from the group consisting of (i) to (iii) below, including administering the antimicrobial composition to a subject in need thereof:
  • bacteremia sepsis, urinary tract infection, pneumonia, pleural empyema, tympanitis, mastoiditis, meningitis, osteomyelitis, arthritis, peritonitis, pericarditis, cellulitis, typhus, and acute gastroenteritis.
  • the antimicrobial composition has very strong antimicrobial activities against antibiotic-resistant microorganisms and multidrug-resistant microorganisms as well as against gram-positive and gram-negative microorganisms, and thus the composition can be used for the treatment of various microbial infections.
  • Still another aspect of the present invention provides a method for preparing compounds represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof, including:
  • the microorganism may be a microorganism of Corallococcus coralloides, and more specifically, Corallococcus coralloides M23 microorganism with Accession No. of KCTC18279P, but is not limited thereto.
  • the compounds represented by Formula 1 or 2 above, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof having strong antimicrobial activities may be prepared.
  • the microorganism of the genus Corallococcus for producing the compounds of the present invention may be cultured in medium containing nutrient sources that can be utilized by conventional microorganisms.
  • nutrient sources for the microorganism any nutrient source conventionally used in the art may be used without limitation, and specifically, known nutrient sources that are used in the conventional cultivation of fungi may be used.
  • glucose, starch syrup, dextrin, starch, molasses, animal oil, vegetable oil, etc. may be used as carbon sources; and wheat bran, soybean meal, wheat, malt, cottonseed meal, fish scrap, corn steep liquor, meat gravy, yeast extract, ammonium sulfate, sodium nitrate, urea, etc., may be used as nitrogen sources.
  • table salt, potassium, magnesium, cobalt, chloride, phosphoric acid, sulfuric acid, and inorganic salts that promote ion production as necessary will make the cultivation more effective.
  • Possible cultivation methods may include shake culture or stationary culture in an aerobic condition.
  • the cultivation temperature may vary slightly according to conditions when cultured in each of the above conditions, normally it is appropriate to culture at a temperature between 20° C. and 37° C., and specifically at a temperature between 26° C. and 30° C. Additionally, the cultivation may also be performed for a known period of time used in the art and the period may he adjusted as necessary.
  • the compounds of the present invention can be present not only in the culture medium but also within fruiting bodies, the above compounds can be extracted from the medium or fruiting bodies.
  • the extraction and isolation method of the compounds may be performed by the methods conventionally used in the art without limitation, and it is obvious that the amount and efficiency of the compounds as products can be controlled by changing the type of medium, cultivation conditions, extraction/purification methods, etc., as necessary.
  • the amberlite XAD16 (Aldrich XAD16) was recovered in the culture broth of a Corallococcus coralloides M23 microorganism (Example 2); active ingredients were extracted from the amberlite XAD16 by stirring after adding acetone thereto; a solvent extraction was performed with ethyl acetate after evaporating acetone; the ethyl acetate solvent layer including the active ingredients was concentrated under reduced pressure to remove ethyl acetate; and the resultant was subjected to Sephadex LH-20 column chromatography; and thereby the pure materials of the present invention were obtained (Example 3).
  • the inventors have confirmed that the use of the above method enables effective extraction and isolation of coralmycins A and B from the Corallococcus coralloides M23 microorganism.
  • Still another aspect of the present invention provides the uses of the above compounds for preparing a pharmaceutical drug for the treatment of at least one disease selected from the group consisting of (i) to (iii) below, an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof, a microorganism of the genus Corallococcus producing the same, spores of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof:
  • bacteremia sepsis, urinary tract infection, pneumonia, pleural empyema, tympanitis, mastoiditis, meningitis, osteomyelitis, arthritis, peritonitis, pericarditis, cellulitis, typhus, and acute gastroenteritis.
  • the microorganism may be Corallococcus coralloides, and more specifically, a Corallococcus coralloides M23 microorganism with the Accession Number of KCTC18279P, but is not limited thereto,
  • the compounds of the present invention an isomer thereof, a derivative thereof, or a pharmaceutically acceptable salt thereof, a microorganism of the genus Corallococcus producing the same, spores of the microorganism, a culture broth of the microorganism, an extract of the microorganism, a fraction of the extract, or a mixture thereof have very strong antimicrobial activities against antibiotic-resistant microorganisms and multidrug-resistant microorganisms as well as against gram-positive and gram-negative microorganisms, and thus the compounds of the present invention can be used in the preparation of pharmaceutical drugs for treating the above diseases.
  • a Corallococcus coralloides M23 microorganism with Accession No. of KCTC18279P was isolated from a soil sample collected from the brook located at Imhakdong-ro, Incheon, Korea according to the method reported by Park et al. (S. Park, B. Lee, J. Kim, C. Lee, E. Jang and K. Cho, Kor. J. Microbiol. Biotechnol. 32: 218, 2004).
  • the M23 microorganism is a gram-negative Bacillus with a length of about 4 ( FIG. 1 a ), which showed vegetative growth feeding on E. coli, and migrated with gliding motility. Additionally, the microorganism formed its unique fruiting bodies in WC medium (10 mM 3-[N-morpholino]propanesulfonic acid (pH 7.6), 0.1% CaCl 2 .2H 2 O, 1.5% agar) ( Fig. 1 b ).
  • the M23 microorganism was cultured in CY medium and the DNA of the microorganism was extracted.
  • the DNA was amplified by performing PCR for 30 cycles using primers 27F (5′-GAGTTTGATCCTGGCTCAG-3′; SEQ ID NO: 1) and 1544R (5′-AGAAAOGAGOTGATCCAGCC-3′; SEQ ID NO: 2) in conditions of 94° C. for 30 sec, 55° C., for 30 sec, and 72° C. for 2 min), purified, and sequence analysis thereof was requested from Macrogen Inc.
  • the 16S rDNA nucleotide sequence of the Corallococcus coralloides M23 microorganism showed a similarity of 99.86% to the 16S rDNA nucleotide sequence of the Corallococcus coralloides standard microorganism (DSM 2259(T)). Accordingly, the M23 microorganism was identified as a novel microorganism belonging to Corallococcus coralloides based on the physiological and morphological characteristics and analysis of 16S rDNA nucleotide sequence, and the M23 microorganism was deposited to the Korean Collection for Type Culture (KCTC) located at 125 Gwahak-ro, Yuseong-gu, Daejeon, Korea, on Apr.
  • KCTC Korean Collection for Type Culture
  • CYS medium (0.5% casitone, 0.1% yeast extract, 0.3% soluble starch, 0.1% MgSO 4 .7H 2 O, 0.05% CaCl 2 , 50 mM HEPES (pH 7.6)
  • an ST-trace element solution (0.01% MnCl 2 .4H 2 O, 0.004 CoCl 2 .6H 2 O, 0.0016% CuSO 4 .5H 2 O, 0.001% Na 2 MoO 4 .2H 2 O, 0.002% ZnCl 2 , 0.0005% LiCl, 0.0005% SnCl 2 .2H 2 O, 0.001% H 3 BO 3 , 0.002% KBr, 0.002% KI, 0.08% EDTA Na—Fe 3+ salt (trihydrate)) and a vitamin B12 solution (0.05% cyanocobalamine) in an amount of 100 mL, respectively,
  • CYS medium 250 mL was added into a 1 L Erlenmeyer flask, sterilized, and then the ST-trace element solution and vitamin B12 solution in an amount of 250 mL, respectively, and sterilized amberlite XAD16 (Aldrich XAD16) in an amount of 4 mL were added thereto. Then, the culture solution, obtained by culturing for 3 days, was inoculated in an amount of 25 mL, respectively, and cultured at 28° C. at a rate of 150 rpm for 9 days.
  • Example 2 After the cultivation in Example 2, the amberlite XAD16 in the culture solution was recovered. Acetone was added to the amberlite XAD16 and the mixture was stirred to extract active ingredients from the amberlite XAD16. After evaporating acetone, the extract was extracted 3 times by solvent extraction using ethyl acetate. The thus-obtained ethyl acetate solvent layer containing active ingredients was concentrated under reduced pressure to remove ethyl acetate and the resulting residue was subjected to Sephadex LH-20 column chromatography using methanol as a solvent. The thus-obtained active fraction was concentrated under reduced pressure and then subjected to HPLC, in a condition where methanol:water is 50:50, to obtain compounds 1 and 2 of the active fraction.
  • Example 2 The compounds 1 (coralmycin A) and 2 (coralmycin B) obtained in Example 2 were analyzed spectroscopically using 13 C NMR and high resolution ESI-MS (Table 1).
  • a test microorganism was cultured in Mueller Hinton broth (MHB) and the antimicrobial activity was measured by the broth microdilution method.
  • the test microorganism cultured overnight was diluted to a concentration of 2 ⁇ 100,000 cells/mL, aliquoted into a 96-well plate in a concentration of 100 mL per well, and the compound was treated on the well plate in concentrations starting from the highest concentration of 128 ⁇ g/mL to 2-fold gradually-diluted concentrations.
  • the compound was diluted in dimethylsulfoxide (DMSO) and the experiment was performed by adjusting the DMSO concentration to a 1/100 level. After culturing for 20 hours, the OD value was measured at 650 nm and the growth of the microorganism was examined. The minimal concentration of the compound which completely inhibited the growth of the microorganism was determined as MIC.
  • DMSO dimethylsulfoxide
  • the MIC of the coralmycin A compound in S. aureus was in a range of 0.06 ⁇ g/mL to 1 ⁇ g/mL. Additionally, the MICs of the coralmycin A compound in MRSA (CCARM3167, CCARM3506) and QRSA (CCARM 3505, CCARM 3519) were in a range of 0.1 ⁇ g/mL to 1 ⁇ g/mL.
  • the MIC of the coralmycin A compound in Escherichia coli was in a range of 0.5 ⁇ g/mL to 1 ⁇ g/mL; 0.25 ⁇ g/mL in Acinetobacter calcoaceticus; and in a range of 8 ⁇ g/mL to 32 ⁇ g/mL in Klebsiella aerogenes and Pseudomonas aeruginosa.
  • coralmycin A has antimicrobial activities against microorganisms, which have a resistance to methicillin and quinolone antibiotics, and specifically, against methicillin-resistant Staphylococcus aureus (MRSA) and quinolone-resistant Staphylococcus aureus (QRSA).
  • MRSA methicillin-resistant Staphylococcus aureus
  • QRSA quinolone-resistant Staphylococcus aureus
  • coralmycin A has antimicrobial activities against gram-positive microorganisms, and specifically, against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), quinolone-resistant Staphylococcus aureus (QRSA), Bacillus subtilis, Bacillus cereus, Streptococcus pneumoniae, Enterococcus faecalis, or Staphylococcus epidermidis.
  • MRSA methicillin-resistant Staphylococcus aureus
  • QRSA quinolone-resistant Staphylococcus aureus
  • Bacillus subtilis Bacillus cereus
  • Streptococcus pneumoniae Enterococcus faecalis
  • Staphylococcus epidermidis Staphylococcus epidermidis.
  • coralmycin A has antimicrobial activities against gram-negative microorganisms, and specifically, against Salmonella typhimurium, Acinetobacter calcoaceticus, Escherichia coli, Pseudomonas aeruginosa, or Klebsiella aerogenes.
  • the coralmycin A compound showed a lower MIC compared to that of Triclosan, which was used as a control.
  • the coralmycin A compound showed lower MICs, in a range of the minimal 8-fold to the maximal 128-fold, in Streptococcus pneumoniae, Enterococcus faecalis, Acinebacter calcoaceticus, and Pseudomonas aeruginosa compared to those of Triclosan. From these results, it was confirmed that coralmycin A or any microorganism producing coralmycin A has strong antimicrobial activities.
  • the antimicrobial activities of coralmycin B were measured in the same manner as in Example 5. Additionally, the minimal concentration of the coralmycin B compound which completely inhibited the growth of the microorganism was determined as MIC, and Ciprofloxacin was used as a control.
  • coralmycin B has antimicrobial activities against microorganisms, which have a resistance to methicillin antibiotics, specifically, against methicillin-resistant Staphylococcus aureus (MRSA), and multidrug-resistant microorganism, specifically, against Acinetobacter haumannii.
  • MRSA methicillin-resistant Staphylococcus aureus
  • coralmycin B has antimicrobial activities against gram-positive microorganisms, and specifically, against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, Streptococcus pneumoniae, or Enterococcus faecalis.
  • coralmycin B has antimicrobial activities against gram-negative microorganisms, and specifically, against Escherichia coli, Pseudomonas aeruginosa, Acinetobacter baumannii, or Klebsiella aerogenes.
  • coralmycin B has a 2- to 8-fold higher antimicrobial activity compared to that of coralmycin A. It was also confirmed that coralmycin B has an at least about 133-fold higher antimicrobial activity in MRSA compared to that of ciprofloxacin, which is a commercially-available antibiotic; an at least about 16-fold higher antimicrobial activity in microorganisms of the genus Enterococcus faecalis; and an at least about 426-fold higher antimicrobial activity in Escherichia thus confirming that coralmycin B has a very strong antimicrobial activity.
  • genus Corallococcus coralloides which produce coralmycins A and B, has strong antimicrobial activities not only against gram-positive and gram-negative microorganisms but also against antibiotic-resistant and multidrug-resistant microorganisms, and thus genus Corallococcus coralloides can be very useful for prevention, treatment, and alleviation of various microbial infections, thereby enabling its wide applications in the medicine, quasi-drug, food, and feed industries.
  • compositions of the present invention are provided herein below.
  • Tablets were prepared by a conventional method according to the following composition.
  • coralmycin A or coralmycin B compound 10.0 mg lactose 500.0 mg talc 5.0 mg magnesium stearate 1.0 mg
  • Capsules were prepared by a method according to the following composition.
  • a gallamide derivative was sieved, mixed with an excipient, and filled into gelatin capsules to prepare capsules.
  • coralmycin A or coralmycin B compound 10.0 mg starch 1500 10.0 mg magnesium stearate 100.0 mg
  • coralmycin A or coralmycin B compound 10.0 mg sodium bisulfite 10.0 mg methylparaben 6.0 mg propylparaben 4.0 mg monosodium phosphate 12.0 mg disodium phosphate 8.0 mg sodium hydroxide 10.0 mg injection water 10.0 mL
  • coralmycin A or coralmycin B compound 5.00 wt % capric/caprylic triglyceride 10.00 wt % liquid paraffin 10.00 wt % sorbitan sesquioleate 6.00 wt % octyldodeceth-25 9.00 wt % cetyl ethylhexanoate 10.00 wt % squalane 1.00 wt % salicylic acid 1.00 wt % glycerin 15.00 wt % sorbitol 10.00 wt % distilled water the rest quantity wt %
  • the ingredients and contents of the lotions containing coralmycin A or B are shown below.
  • a solution which was prepared by dissolving fatty acids, oily ingredients, emulsifiers, and preservatives, which are in oily state, by heating at 70° C., was added thereto for emulsification.
  • 2% solution of xanthan gum which is a h y drophilic thickener, was added thereto to a final concentration of 0.05 wt %.
  • the solution was cooled to 45° C., and coralmycin A or B compound, fragrance(s), and colorant(s) were added thereto, mixed, and cooled to 30° C.
  • coralmycin A or coralmycin B compound 0.10 wt % glycerin 3.00 wt % carbomer 0.10 wt % xanthan gum 0.05 wt % 1,3-butylene glycol 3.00 wt % polyglyceryl-3 methylglucose distearate 1.50 wt % glyceryl stearate 0.50 wt % cetylaryl alcohol 0.30 wt % jojoba oil 3.00 wt % liquid paraffin 2.00 wt % squalane 3.00 wt % dimethicone 0.50 wt % tocopheryl acetate 0.20 wt % triethanolamine 0.10 wt % preservative(s), fragrance(s), and colorant(s) trace amount distilled water the rest quantity wt %
  • the coralmycin A or coralmycin B compound of the present invention in an amount of 0.5 to 5.0 parts by weight was added to flour and the mixture was used for the preparation of breads, cakes, cookies, crackers, and noodles.
  • Inactive ingredients such as high fructose corn syrup (0.5%), oligosaccharides (2%), sugar (2%), table salt (0.5%), and water (75%), and the coralmycin A or coralmycin B compound of the present invention in an amount of 0.01% to 20% were mixed uniformly, sterilized instantly, and packed into small containers such as glass bottles and pet bottles, for the preparation of beverages.
  • coralmycin A or coralmycin B compound 0.15 wt % corn 42.66 wt % rice 9.99 wt % fermented soybean meal 3.52 wt % soybean 9.99 wt % plasma protein(s) 3.99 wt % fish meal 4.49 wt % whey 5.99 wt % complex dairy product 7.48 wt % soybean oil 2.49 wt % amino acid premix 0.49 wt % feed additive premix 4.22 wt % acidifier premix 2.2 wt % others 2.34 wt %
  • coralmycin A or coralmycin B compound 0.1 wt % white fish meal 52.0 wt % soybean meal 6.0 wt % corn gluten meal 6.0 wt % wheat flour 21.3 wt % squid liver oil 10.00 wt % mineral premix 1.0 wt % vitamin premix 1.0 wt % choline chloride 0.5 wt % alanine 1.1 wt % cellulose 1.0 wt %

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WO2019038405A1 (en) * 2017-08-23 2019-02-28 Helmholtz-Zentrum für Infektionsforschung GmbH NEW CYSTOBACTAMIDE DERIVATIVES
WO2019053265A1 (en) * 2017-09-18 2019-03-21 Sanofi ANTIBACTERIAL COMPOUNDS PRODUCED BY THE CORALLOCOCCUS CORALLOID MICROORGANISM STRAIN ST201330 (DSM 24989)
US10519099B2 (en) 2014-11-26 2019-12-31 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
US10793600B2 (en) 2013-07-12 2020-10-06 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
US11225465B2 (en) 2017-07-18 2022-01-18 Technische Universität Berlin Albicidin derivatives, their use and synthesis
CN116179400A (zh) * 2022-08-17 2023-05-30 山东大学 一株产重排甾体化合物的黏细菌及其应用
WO2023196788A3 (en) * 2022-04-04 2023-11-30 The Rockefeller University Metagenome-guided biosynthesis and compounds and methods of use thereof

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KR101417365B1 (ko) 2012-10-16 2014-07-10 제주대학교 산학협력단 신균주인 리시니바실러스 ｙ-4ｂ 균주 및 이를 포함하는 항균 조성물
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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10793600B2 (en) 2013-07-12 2020-10-06 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
US11225503B2 (en) 2013-07-12 2022-01-18 Helmholtz-Zentrum für Infektionsforschung GmbH Crystobactamides
US10519099B2 (en) 2014-11-26 2019-12-31 Helmholtz-Zentrum für Infektionsforschung GmbH Cystobactamides
US11225465B2 (en) 2017-07-18 2022-01-18 Technische Universität Berlin Albicidin derivatives, their use and synthesis
WO2019038405A1 (en) * 2017-08-23 2019-02-28 Helmholtz-Zentrum für Infektionsforschung GmbH NEW CYSTOBACTAMIDE DERIVATIVES
CN110997627A (zh) * 2017-08-23 2020-04-10 亥姆霍兹感染研究中心有限公司 新型的孢囊菌酰胺衍生物
US11034648B2 (en) 2017-08-23 2021-06-15 Helmholtz-Zentrum Für Cystobactamide derivatives
AU2018321152B2 (en) * 2017-08-23 2023-07-06 Helmholtz-Zentrum für Infektionsforschung GmbH Novel cystobactamide derivatives
WO2019053265A1 (en) * 2017-09-18 2019-03-21 Sanofi ANTIBACTERIAL COMPOUNDS PRODUCED BY THE CORALLOCOCCUS CORALLOID MICROORGANISM STRAIN ST201330 (DSM 24989)
WO2023196788A3 (en) * 2022-04-04 2023-11-30 The Rockefeller University Metagenome-guided biosynthesis and compounds and methods of use thereof
CN116179400A (zh) * 2022-08-17 2023-05-30 山东大学 一株产重排甾体化合物的黏细菌及其应用

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KR101747702B1 (ko) 2017-06-19

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