JP2018058801A - Antibacterial agent - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a safe, natural compound that can be used in the fields of skin care such as skin whitening, acne prevention, anti-inflammation, wrinkle prevention, or skin moisture retention.SOLUTION: An antibacterial agent contains triterpenoid extracted from loquat leaves, specifically, a compound selected from the group consisting of ursolic acid, oleanolic acid, methyl corosolate, maslinic acid, corosolic acid, pomolic acid, tormentic acid, euscaphic acid, 6β,19-dihydroxyurs-12-en-3-oxo-28-oic acid, hyptadienic acid, 3-O-trans-p-coumaroyltormentic acid, 3-O-cis-p-coumaroyltormentic acid.SELECTED DRAWING: None

Description

  The present invention relates to an antibacterial agent.

  Biwa is a subtropical evergreen tree belonging to the family Rosaceae. Biwa leaves have been used in traditional Chinese medicine. In Japan, loquat leaves are used as Biwa tea either alone or mixed with tea leaves. Patent Document 1 shows that loquat leaf extract can be used for the treatment and prevention of osteopenic diseases.

JP-A-2015-178480

  Various cosmetics have been developed in the fields of skin care such as whitening, acne prevention, anti-inflammation, wrinkle prevention, and skin moisturizing.

  Therefore, an object of the present invention is to provide a safe compound of natural origin that can be used in the fields of skin care such as whitening, acne prevention, antiallergy, wrinkle prevention, and skin moisturizing.

  In order to achieve the above object, the present invention is characterized in that an antibacterial agent contains a triterpenoid extracted from loquat leaves as an active ingredient.

  ADVANTAGE OF THE INVENTION According to this invention, the safe compound of the natural origin which can be used in the field | areas of skin care, such as whitening, acne prevention, antiallergy, wrinkle prevention, and skin moisturizing can be provided.

It is a test result of collagen formation stimulation activity value (CP / CV ratio). It is a test result of HA / CV value.

  An embodiment of a melanin inhibitor, an antibacterial agent, an antiallergic agent, a collagen production promoting agent and a moisturizing agent according to the present invention will be described. This embodiment is merely an example, and the present invention is not limited to this.

Loquat, Eriobotrya
It is a flowering plant of the Rosaceae known as japonica. Biwa leaves are known as traditional Chinese medicine. In Japan, Biwa leaves are also drunk as Biwa tea. Biwa has been confirmed to suppress obesity and tumors by numerous chemical pharmacological studies. Therefore, we investigated the utility of loquat leaves for skin care.

[Target]
Eighteen types of triterpenoids that are loquat leaf extracts were evaluated for their effects on skin care. These 18 types of triterpenoids are (1) ursolic acid, (2) oleanolic acid, (3) uvaol, (4) betulinic acid, and (5) muslin. Methyl maslinate, (6) methyl corosolate, (7) maslinc acid, (8) corosolic acid, (9) 3-epicorosolic acid acid), (10) pomolic acid, (11) tormentic acid, (12) euscaphic acid, (13) 3-oxours-12-en-28-oic acid (3) -oxours-12-en-28-oic
acid), (14) 6β, 19-dihydroxyurs-12-en-3-oxo-28-oic acid, (15) 2α , 19α-Dihydroxy-3-oxo-12-ursen-28-oic acid (2α, 19α-dihydroxy-3-oxo-12-ursen-28-oic
acid), (16) hyptadienic acid, (17) 3-O-trans-p-coumaroyltormentic acid, (18) 3-O- Cis-p-coumaroyltormentic acid (3-O-cis-p-coumaroyltormentic
acid).

  Here, the numbers enclosed in parentheses are reference compound (triterpenoid) numbers. For example, when expressed as compound 7 below, maslinic acid is indicated.

  The structure of each compound is as follows.

(1) ursolic acid

(2) oleanolic acid

(3) Uvaol

(4) betulinic acid

(5) Methyl maslinate

(6) Methyl corosolate

(7) Maslinc acid

(8) corosolic acid

(9) 3-epicorosolic acid

(10) pomolic acid

(11) Tormentic acid

(12) Euscaphic acid

(13) 3-oxours-12-en-28-oic acid
acid)

(14) 6β, 19-dihydroxyurs-12-en-3-oxo-28-oic acid (6β, 19-dihydroxyurs-12-en-3-oxo-28-oic
acid)

(15) 2α, 19α-dihydroxy-3-oxo-12-ursen-28-oic acid (2α, 19α-dihydroxy-3-oxo-12-ursen-28-oic
acid)

(16) Hyptadienic acid

(17) 3-O-trans-p-coumaroyltormentic acid

(18) 3-O-cis-p-coumaroyltormentic acid

[Inhibition of melamine production]
In order to evaluate the melanin inhibitory effect of 18 types of triterpenoids extracted from loquat leaves, a test using mouse B16 melanoma cells was performed. Mouse B16 melanoma cells were obtained from the RIKEN BioResource Center cell bank. Cell survival was maintained in Eagle's minimum essential medium supplemented with 0.09 mg / ml theophylline and 10% (v / v) fetal calf serum. Prior to sample processing, B16 melanoma cells were incubated for 24 hours in medium at a cell concentration of 1 × 10 ⁵ (cells / well).

  After 24 hours of incubation, test samples were dissolved in dimethyl sulfoxide (DMSO) with a concentration per well of less than 0.2% and added to each well. The number of samples is 3 (n = 3). Arbutin was used as a control sample.

  B16 melanoma cells were further incubated for 48 hours, after which the medium was again replaced with fresh medium containing each sample. After another 24 hours, melanin content and cell viability were measured using a microplate reader at 405 nm and 570 nm, respectively. Cell viability was measured using the MTT (3- (4,5-dimethylthiazol-2-yl) -2,5 diphenyl bromide) method.

Thus, for various concentrations, the inhibitory effect on melanin synthesis and the cytotoxic effect on cell viability of 16 compounds extracted from loquat leaves were tested. The value of the cytotoxic concentration CC ₅₀ causing death in 50% of viable cells and the concentration IC ₅₀ causing 50% inhibition of melanin synthesis in B16 melanoma cells were calculated from the corresponding dose response curves. The values for CC ₅₀ and IC ₅₀ are shown in Table 1.

The relative efficacy of compounds with respect to the inhibition of melanogenesis against the induction of cell death, ie the value of CC ₅₀ / IC ₅₀ is defined as the selectivity index (SI) and is shown together in Table 1. It was. Situations where melanin synthesis is inhibited include situations where B16 melanoma cells die, in addition to situations where melanin production is simply inhibited. CC ₅₀ indicates that the B16 melanoma cells die, that is, the magnitude of the cytotoxic effect. IC ₅₀ shows the magnitude of the inhibitory effect on melanin synthesis including cytotoxic effects. From the viewpoint of the melanin-suppressing effect, it selectively inhibits melanin production, that is, it does not cause cytotoxicity unless it is at a higher concentration, and inhibits melanin production even at a lower concentration (S. I.> 1).

  According to the evaluation results shown in Table 1, eight types of triterpenoids, that is, compounds 1, 2, 4, 5, 6, 7, 8, and 11 have high melanin production inhibiting properties while having low cytotoxicity ( S.I.> 1) was found. In particular, the maslinic acid of compound 7 is S.I. I. The value of was 1.9, the highest. This value is comparable to that of arbutin known as a whitening component.

Comparison of the chemical structure of the active compound with the inactive compound reveals the following. It can be seen that the activity of compounds 9 and 12 in which the beta-type hydroxyl group is replaced with the alpha-type hydroxyl group, compounds 13 and 14 and 15 in which the ketone is replaced, and compounds 17 and 18 in which the other hydroxyl group is replaced is reduced. Therefore, the beta hydroxyl group at the C-3 position plays an important role in melanin production inhibitory activity. In addition, when a beta-type hydroxyl group is present, the compound (3) loses its activity only by reducing COOH at the C-17 position to CH ₂ OH, so that the carboxyl group partially contributes to the activity. There is a possibility. As seen in compounds 5 and 6, methyl esterification of the carboxyl group slightly reduces the activity.

  Thus, it can be seen that some of the triterpenoids extracted from loquat leaves, that is, compounds 1, 2, 4, 5, 6, 7, 8, and 11 inhibit melanin production. That is, among triterpenoids extracted from loquat leaves, a compound selected from the group consisting of ursolic acid, oleanolic acid, betulinic acid, methyl maslinate, methyl corosolic acid, maslinic acid, corosolic acid, tolmenic acid, or a salt thereof Solvates or hydrates can be used as safe melanin inhibitors of natural origin.

  Melanin and abnormal pigmentation are produced excessively when a person's skin is excessively exposed to ultraviolet light. Some of the triterpenoids extracted from loquat leaves have an effect of suppressing melanin production, and are therefore effective for skin whitening. In addition, some of the triterpenoids extracted from loquat leaves can suppress the excessive generation of reactive species that lead to various skin damages such as reactive inflammation, spots, liver spots, and freckles. Therefore, triterpenoids extracted from loquat leaves, especially ursolic acid, oleanolic acid, betulinic acid, methyl maslinate, methyl corosolic acid, maslinic acid, corosolic acid, and tolmenic acid, are used for skin care with a function of inhibiting melanin production, that is, whitening. It can be used as an agent.

[antibacterial]
Propionibacterium acnes was used as a test bacterium for evaluating the antibacterial properties of 18 types of triterpenoids extracted from loquat leaves. Single colonies of test bacteria were collected, added to the medium, and cultured at 37 ° C. for 30 hours. This was then added to the bacterial suspension and adjusted to a bacterial concentration of 10 ⁵ CFU / ml.

  Each compound was dissolved in DMSO. Sorbic acid was used as a control sample. Furthermore, each compound dissolved in DMSO was incubated at 37 ° C. for 30 hours.

  Thereafter, bacterial growth was measured with a microplate reader at a wavelength of 630 nm. Minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were assessed by standard broth microdilution methods.

  Table 2 shows the antimicrobial activity of 18 triterpenoids against Propionibacterium acne at compound concentrations of 50 μg / ml or 100 μg / ml. All the data showed an average value and a standard deviation (n = 3). Table 2 also shows the minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC) of the active compounds. The antibacterial activity of sorbic acid as a control sample was 104.4 ± 2.5 (%) when the concentration was 400 μg / ml.

  Twelve kinds of compounds, namely compounds 1, 2, 6, 7, 8, 10, 11, 12, 14, 16, 17, and 18, are at their maximum solubility against Propionibacterium acne. Has activity. Compounds 1, 7, 8 and 12 show high activity against Propionibacterium acne at MIC of 50 μg / ml and MBC of 100 μg / ml, 150 μg / ml, 100 μg / ml and 50 μg / ml, respectively. Indicated. Triterpenoids exhibit low hydrophilicity with log P values ranging from 5 to 8. In general, antibacterial activity tends to be low when the hydrophilicity is low, but compounds 1, 2, 6, 7, 8, 10, 11, 12, 14, 16, 17, and 18 have high antibacterial activity. Shows activity.

Thus, some of the triterpenoids extracted from loquat leaves, that is, compounds 1, 2, 6, 7, 8, 10, 11, 12, 14, 16, 17, 18 are propionibacterium acne. It can be seen that it has antibacterial activity against bacteria. In other words, among the triterpenoids extracted from loquat leaves, ursolic acid,
Oleanolic acid, methyl corosolic acid, maslinic acid, corosolic acid, pomolic acid, tolmenic acid, oiscafic acid, 6β, 19-dihydroxyurs-12-en-3-oxo-28-oiic acid, hypotadienic acid, 3-O-trans A compound selected from the group consisting of -p-coumaroyl tormentic acid, 3-O-cis-p-coumaroyl tormentic acid, or a salt, solvate or hydrate thereof is a natural source of safety It can be used as an antibacterial agent.

Propionibacterium acne (P. acne) is an anaerobic gram-positive bacterium mainly located in the hair follicular gland unit and plays an important role in the development of acne. Therefore, some of the triterpenoids extracted from leaf leaves are effective in suppressing the development of acne. Therefore, among the triterpenoids extracted from loquat leaves, ursolic acid,
Oleanolic acid, methyl corosolic acid, maslinic acid, corosolic acid, pomolic acid, tolmenic acid, oiscafic acid, 6β, 19-dihydroxyurs-12-en-3-oxo-28-oiic acid, hypotadienic acid, 3-O-trans -p-Coumaroyl tormentic acid and 3-O-cis-p-coumaroyl tormic acid can be used as a skin care agent having a function as an antibacterial agent that suppresses the development of acne.

[Anti-allergy]
To evaluate the antiallergic effects of 18 triterpenoids extracted from loquat leaves, the release of β-hexosaminidase from IgE-stimulated rat basophilic leukemia (RBL-2H3) cells was checked. RBL-2H3 cells were obtained from the RIKEN BioResource Center cell bank.

RBL-2H3 cells were maintained in EMEM medium containing 10% FBS and 1% antibiotic-antimycotic at 37 ° C. in a humidified air incubator with 5% CO ₂ concentration. The cell concentration was 2 × 10 ⁵ cells / well. After 24 hours of incubation, the medium was supplemented with 1 ml of 0.5 μg / anti-DNP (dinitrophenol) mouse immunoglobulin E (IgE. After further incubation of the culture for 24 hours, the medium was added with 100 μl of thyroid buffer. Replaced with liquid.

  Samples were lysed in 1 μl DMSO at a concentration of less than 0.5% and the cell plate was re-incubated for 30 minutes. The sample containing thyroid buffer was then replaced with 100 μl of thyroid buffer containing 50 μg / ml DNP-BSA. After 1 hour incubation, 50 μl of the supernatant was collected from each well and each was mixed with 50 μl of 2M substrate solution (p-nitrophenyl-N-acetyl-β-glucosaminide).

  At room temperature, the mixture was incubated on a shaker for 3 hours. Finally, 100 μl was added using 100 mM sodium bicarbonate as a stop solution. Thereafter, the absorbance was read at 405 nm. Cell viability was measured by the same MTT test as described above. The compound concentration was 25 μg / ml. Quercetin was used as a control sample.

  The test results of cell viability and antiallergic activity are shown in Table 3. All the data showed an average value and a standard deviation (n = 3). The antiallergic activity of quercetin as a control sample was 72.5 ± 3.0 (%). “*” In Table 3 is a compound in which a significant difference from the control sample was observed with a student t test at a risk factor of 0.05, and “**” was a significant difference from a control sample in a student t test with a risk factor of 0.01. Indicates a compound in which.

  As shown in Table 3, the three triterpenoids, ie, Compounds 1, 9, and 12, significantly inhibited β-hexosaminidase release at non-cytotoxic concentrations. Compound 7 had 66% inhibition although it had slight cytotoxicity.

In addition, for compounds 1, 7, 9, and 12, the concentration IC ₅₀ values that cause hexosaminidase release inhibition are measured and are 39.5 μM, 22.86 μM, 25.6 μM, and 15.8 μM, respectively. I found out.

  Compounds 1, 7, 9, and 12 are inflammatory and TPA inducible in mice caused by 12-O-tetradecanoylphorbol-13-acetate (TPA). It can be seen that it has significant inhibitory activity against Epstein-Barr virus early antigen (EBV-EA) activation.

  Thus, it can be seen that some of the triterpenoids extracted from loquat leaves, that is, compounds 1, 7, 9, and 12 have antiallergic properties. That is, among triterpenoids extracted from loquat leaves, a compound selected from the group consisting of ursolic acid, maslinic acid, 3-epicorosolic acid, oiscafic acid, or a salt, solvate or hydrate thereof, It can be used as a safe antiallergic agent of natural origin.

  Allergies and inflammation appear as an overreaction to environmental substances in various target organs of the body (skin, nose, lungs, gastrointestinal tract, etc.). Since the skin is the main interface between the environment, inappropriate immune activity develops as inflammation, skin rash, itching and eczema. Therefore, some of the triterpenoids extracted from loquat leaves are effective for anti-allergy and anti-inflammation. Thus, among the triterpenoids extracted from loquat leaves, ursolic acid, maslinic acid, 3-epicorosolic acid and oiscafic acid can be used as a skin care agent having anti-allergic and anti-inflammatory functions.

[Collagen production promotion]
In order to evaluate the collagen formation promoting effect of 18 kinds of triterpenoids extracted from loquat leaves, a test using adult normal human skin fibroblasts was performed. Adult normal human dermal fibroblasts (NHDF-AD) were obtained from Lonza.

Adult normal human dermal fibroblasts were maintained in Dulbecco's Modified Eagle Medium (DMEM) containing 10% FBS and 1% antibiotic-antimycotic. The cell density was 5 × 10 ³ / well after the cultured cells grew to a state where the entire adhesion surface was spread (confluence).

  After 24 hours of incubation, the medium was replaced with a 99 microliter mixture of DMEM supplemented with 1 μl of sample solution and 0.5% FBS. The DMSO concentration was 0.5% in the medium. After 72 hours of culture, the amount of type I collagen produced in the medium was measured using an ELISA kit manufactured by ACEL. Collagen production was calculated using a standard curve created by measuring with the same ELISA kit. The remaining cells were used for MTT evaluation. 100 μM ascorbic acid was used as a control sample.

  For each compound, collagen production activity (CP) and cell viability (CV) at three compound concentrations of 1, 5, and 10 μg / ml were determined, respectively. Collagen producing activity (CP) and cell viability (CV) values were determined as a percentage of the control sample. Next, a CP / CV ratio (> 1) representing the average of collagen production activity (%) average per cell viability (%) was determined as an index of the stimulation activity of collagen production per cell.

  The collagen production stimulating activity values (CP / CV ratio) of the test results are shown in Table 4 and FIG.

  As shown in Table 4 and FIG. 1, some triterpenoids significantly increase collagen production of dermal fibroblasts per cell. Of 18 types of triterpenoids extracted from loquat leaves, 10 types of compounds 1, 2, 3, 4, 6, 7, 8, 10, 13, and 14 produced type I collagen at a concentration of 10 μg / ml. . Compounds 6, 8 show particularly strong stimulating activity of 3.4 and 3.6, which is higher than the control sample. Other compounds show a moderate promoting effect.

  Among 18 types of triterpenoids extracted from loquat leaves, 16 types of compounds 1, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17, 18 The compound causes an increase in collagen production at a concentration of 5 μg / ml. Compounds 1 and 4 show higher values of 3.8 and 3.0 than the control sample.

  Of the 18 types of triterpenoids extracted from loquat leaves, 6 types of compounds 4, 8, 9, 10, 13, and 14 have collagen producing activity even at a low concentration of 1 μg / ml. .

  Thus, some of the triterpenoids extracted from loquat leaves, ie, compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 17 , 18 have collagen generation-promoting properties. In other words, among the triterpenoids extracted from loquat leaves, ursolic acid, oleanolic acid, ubaol, betulinic acid, methyl masphosphate, methyl corosolic acid, maslinic acid, corosolic acid, 3-epicorosolic acid, pomolic acid, tolmenic acid, Oiskafic acid, 3-oxourus-12-en-28-oic acid, 6β, 19-dihydroxyurs-12-en-3-oxo-28-oic acid, 2α, 19α-dihydroxy-3-oxo-12-ursen- A compound selected from the group consisting of 28-oic acid, 3-O-trans-p-coumaroyl tormic acid, 3-O-cis-p-coumaroyl tormentic acid, or a salt or solvate thereof The product or hydrate can be used as a safe collagen production promoter of natural origin.

  In aged human skin, the dermal-epidermal junction is flattened and mechanical tension and elasticity are reduced due to a significant decrease in the skin extracellular matrix such as collagen, elastin, hyaluronic acid. Some of the triterpenoids extracted from loquat leaves are effective in producing collagen, and as a result, the generation of wrinkles in the skin can be suppressed. In other words, among the triterpenoids extracted from loquat leaves, ursolic acid, oleanolic acid, ubaol, betulinic acid, methyl masphosphate, methyl corosolic acid, maslinic acid, corosolic acid, 3-epicorosolic acid, pomolic acid, tolmenic acid, Oiskafic acid, 3-oxourus-12-en-28-oic acid, 6β, 19-dihydroxyurs-12-en-3-oxo-28-oic acid, 2α, 19α-dihydroxy-3-oxo-12-ursen- 28-Oic acid, 3-O-trans-p-coumaroyl tormentic acid, 3-O-cis-p-coumaroyl tormentic acid, stimulates collagen production and suppresses skin aging It can be used as a skin care agent having the function of an agent.

[Hyaluronic acid production]
In order to evaluate the hyaluronic acid production promoting effect of 18 kinds of triterpenoids extracted from loquat leaves, a test using adult normal human skin fibroblasts was performed. Adult normal human dermal fibroblasts (NHDF-AD) were obtained from Lonza.

Adult normal human dermal fibroblasts were maintained in Dulbecco's Modified Eagle Medium (DMEM) containing 10% FBS and 1% antibiotic-antimycotic. The cell density was 5 × 10 ³ / well after the cultured cells grew to a state where the entire adhesion surface was spread (confluence).

After 72 hours of culturing, the amount of hyaluronic acid in the medium was measured using a QnE hyaluronic acid ELISA kit manufactured by Bio Trading Partners. Hyaluronic acid production was calculated from a quantitative standard curve. Cell viability was measured by the MTT method. Ascorbic acid was used as a control sample.
For each compound, HA / CV values at three compound concentrations of 1, 5 and 10 μg / ml were determined.

  The HA / CV values of the test results are shown in Table 5 and FIG.

Here, the HA / CV value is a hyaluronic acid production promotion rate, and is an average value of hyaluronic acid concentration (%) / average value of cell viability (%). Hyaluronic acid concentration (HA) and cell viability (CV) values were determined as a percentage of the control sample.

  As shown in Table 5 and FIG. 2, some triterpenoids significantly increase dermal fibroblast hyaluronan production per cell. Of the 18 types of triterpenoids extracted from loquat leaves, 10 types of compounds 1, 2, 3, 4, 6, 7, 8, 10, 13, 16 have a concentration of 10 μg / ml in human skin. It exerted a strong stimulating effect of hyaluronic acid production in fibroblasts. Compounds 8, 10 showed stimulating activity values of 5.9 and 5.8 over the control sample. Compound 6 also shows a high stimulating activity value.

  At a concentration of 5 μg / ml, among the 18 types of triterpenoids extracted from loquat leaves, 6 types of compounds 1, 3, 4, 6, 7, and 8 are capable of producing hyaluronic acid in human skin fibroblasts. It was stimulating. Compound 1 has a stimulating activity value of 4.7 exceeding the comparative example.

  At a low concentration (at 1 μg / ml), one compound of compound 4 out of 18 triterpenoids extracted from loquat leaves showed a hyaluronic acid production promoting effect.

  Thus, it can be seen that some of the triterpenoids extracted from loquat leaves, that is, compounds 1, 2, 3, 4, 6, 7, 8, 10, 13, 18 have hyaluronic acid production promoting properties. . That is, among the triterpenoids extracted from loquat leaves, ursolic acid, oleanolic acid, ubaol, betulinic acid, methyl corosolic acid, maslinic acid, corosolic acid, pomolic acid, 3-oxours-12-en-28-oic acid, A compound selected from the group consisting of 3-O-cis-p-coumaroyl tormentic acid, or a salt, solvate or hydrate thereof, should be used as a safe hyaluronic acid production accelerator of natural origin. Can do.

  Youthful skin is rich in moisture and maintains turgor, elasticity and flexibility. Hyaluronic acid has a high ability to retain moisture and greatly affects the amount of moisture in the skin. Some of the triterpenoids extracted from loquat leaves are effective in producing collagen and, as a result, are effective in maintaining youthful skin. That is, among the triterpenoids extracted from loquat leaves, ursolic acid, oleanolic acid, ubaol, betulinic acid, methyl corosolic acid, maslinic acid, corosolic acid, pomolic acid, 3-oxours-12-en-28-oic acid, 3-O-cis-p-coumaroyl tormentic acid can be used as a skin care agent having a function as a moisturizing agent for increasing the moisture content of the skin.

Claims (2)

  An antibacterial agent containing triterpenoids extracted from loquat leaves as an active ingredient.   Triterpenoids extracted from the leaves of the loquat are ursolic acid, oleanolic acid, methyl corosolic acid, maslinic acid, corosolic acid, pomolic acid, tolmenic acid, oiscafic acid, 6β, 19-dihydroxyurs-12-en-3-oxo -28-Oic acid, Hiptadienic acid, 3-O-trans-p-coumaroyl tormic acid, compound selected from the group consisting of 3-O-cis-p-coumaroyl tormentic acid, or a salt thereof The antibacterial agent according to claim 1, comprising a solvate or a hydrate.

Images