JPH0873362A - Anti-mrsa agent - Google Patents

Abstract

PURPOSE: To obtain a new anti-MRSA(methicillia resistant staphylococcus aureus) agent capable of suppressing the growth of MRSA and enhancing antibacterial activity of an antibiotic against it. CONSTITUTION: This anti-MRSA agent contains heteropolytungstic acid ion expressed by the general formula, (XW12 O40 )<(8-n)-> , (XW11 O39 )<(12-n)-> , (YW9 O34 )<(14-n)-> or (ZW9 O33 )<(12-n)-> (W is a tungsten atom; O is an oxygen atom; n is an ionic valence of the element X, Y or Z; X is one kind of atom capable of becoming a cation having mono- to penta-valence selected from a group consisting of Cu, Ni, Al, B, Bi, Sb, Ge, Si, P and V; Y is one kind of atom selected from a group consisting of Si, Ge, P and As; Z is one kind of atom selected from a group consisting of Bi, B and Sb) and has a so called Keggin- type or defective Keggin-type hetero-polytungstic acid ion as main effective component.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an anti-MRSA drug which suppresses the growth of methicillin-resistant Staphylococcus aureus (MRSA).

[0002]

BACKGROUND OF THE INVENTION Staphylococcus aureus belongs to Gram-positive cocci and is a major causative agent of purulent diseases. Although the evidence of infection was temporarily overcome by the practical use of penicillin and the subsequent penicillin G, resistant staphylococci which produced the penicillin dispersal enzyme penicillinase appeared. New drug substances such as tetracycline and chloramphenicol appeared in the 1950s, but multidrug-resistant bacteria appeared within a few years. afterwards,
In the 1960s, after passing through a semi-synthetic penicillin such as methicillin and oxacillin, which are stable to penicillinase,
First-generation cephem agents were developed in the 70's and showed excellent antibacterial activity. However, within a few years MRSA, a new type of staphylococcus, has emerged. In the 1980s, the third-generation cephem agent, which has a weak antibacterial activity against Staphylococcus, was widely applied to bacterial treatment, and the resistance of MRSA was further improved and the frequency of appearance was increased. Although MRSA is a weakly virulent bacterium, it proliferates in patients with predominantly reduced body resistance, premature infants, and immunocompromised patients, causing serious infections. In many cases, since the bacteria are produced in hospitals, nosocomial infections suddenly occur, and countermeasures against them are urgently needed. Patient isolation, disinfection, and preventive measures are gradually being taken, but it is the current situation that an effective treatment for MRSA infection cannot be established.

That is, carriers are only disinfected, and infected persons are given a necessary and sufficient amount of a specific antibiotic for a short period of time (5 days at the longest). Antibiotics suitable for cloxacillin-infected strains include minocycline for light to moderately resistant strains, a combination of fosfomycin and cephem drugs, netilmycin, etc. Is being administered.

[0004]

The MRSA infection is intractable, and since it develops in patients whose resistance to pathogenic bacteria has decreased in the hospital as in the previous period, the infected person may fall seriously in a short period of time. Many. Since MRSA is a multidrug-resistant bacterium, it is often difficult to cure even in the case of deep infection even if the above antibiotics are administered. Further, it is said that if the dose is suppressed in consideration of the physical strength of the patient, resistance will occur in any strain, resulting in a loss of healing opportunity. So M
It is desired to develop a concomitant drug that amplifies the effect of an antibiotic agent effective against RSA infection and causes strong damage to resistant bacteria, or that can give a sufficient therapeutic effect even when a small amount of antibiotic agent is administered. The present invention aims to provide a new anti-MRSA agent capable of enhancing the antibacterial action of an antibiotic agent.

[0005]

In the present invention, the general formulas are (XW ₁₂ O ₄₀ ) ^(8-n)- , (XW ₁₁ O ₃₉ ) ^(12-n)- , (Y
W ₉ O ₃₄ ) ^(14-n) -or (ZW ₉ O ₃₃ ) ^(12-n)- , where W is a tungsten atom, O is an oxygen atom, and n is an element X or Y.
Alternatively, Cu, Ni, Co, A1, B, Bi, Sb, and G, which are ionic valences of Z and X are cations having 1 to 5 valences.
A so-called Keggin type or defective Kegg represented by one kind of atom selected from the group consisting of e, Si, P and V
Disclosed is an anti-MRSA agent containing an in-type heteropolytungstate ion as a main active ingredient.

In the heteropolytungstate ion, a part of 12 tungsten atoms, 1 to 6 are replaced with at least one atom selected from the group consisting of V, Mo, Ti, Co, Nb and Fe. can do. In addition, a structure in which one or two hydrogen atoms are bonded to oxygen atoms forming the heteropolytungstate ion can also be used.

[0007]

The effectiveness of anti-MRSA drugs is often judged with oxacillin as the standard. That is, MRS
The growth inhibition rate of the oxacillin when the oxacillin was administered alone or in combination with the strain A was determined.

The above-mentioned heteropolytungstate ion having a Keggin structure exerts an excellent antibacterial action and an antibacterial effect. In other words, M is ²⁵ times higher than that of oxacillin administered alone at a dose much lower than the "toxic concentration" at which MRSA proliferation can be completely suppressed only by its toxicity.
The RSA growth inhibition rate is shown.

Heteropolytungstate ions having a Keggin structure have already been known to exhibit an excellent antiviral action (eg, Japanese Patent Publication No. 6-29191, Y.Ta).
keetal.; Antiviral Res. 15: 113-114, 19
1991). It is considered that what is effective also for MRSA is derived from a special molecular capsule structure in which the heteroatom ion X (Y or Z) occupies the center of the tungstate cluster sphere. It is considered that the catalytic action of heteropolytungstic acid containing an electron transfer system is involved in the pharmacological effect.

[0010]

EXAMPLES The present invention will now be described in more detail based on examples. (1) Several kinds of Keggin-type and defective Keggin-type heteropolytungstic acid alkali salts were synthesized and subjected to an antibacterial test against ATCC43300 (Inducible MRSA), which is a kind of MRSA strain.

The test is conducted by Kirby-Baue according to the WHO recommendation.
According to the oxacillin disc susceptibility test method based on the r (KB) method. That is, oxacillin 1 μg / ml
Is a method in which a mixed solution of MRSA and a drug is applied to a disc containing the above, and the diameter of the growth-inhibiting circle is measured after culturing at 34 ° C. for 18 hours. Based on the case of oxacillin alone, the concentration of coexisting polyacid showing a ^25- fold inhibition rate was E (μM;
Micromol). On the other hand, in order to examine the toxicity of polyacid, the polyacid concentration T (μM) at which MRSA is growth-inhibited only by polyacid was determined. T is a factor relating to cytotoxicity, and E is a factor supporting the healing effect of oxacillin. Therefore, it can be said that the larger T / E is, the better the anti-MRSA drug is.

[0012]

[Table 1]

Table 1 shows a part of the obtained data. The drug containing the heteropolytungstate ion was extracted in the form of a hydrated alkali salt and tested using its aqueous solution. For comparison, sodium tungstate and non-Kegg were used.
The data when the in-type heteropolytungstate is used are also shown in Table 1.

Table 1 shows that T / E of sodium tungstate is N.V. D. , Ie bad and totally anti-MRSA
It shows no activity and that the anti-MRSA activity of the non-Keggin type heteropolytungstate ion is low. On the other hand, it can be seen that Keggin-type and defective Keggin-type heteropolytungstate ions exhibit excellent anti-MRSA action. In particular, (SiW ₁₂ O ₄₀ ) ^4- , α-type (PW ₁₁ O ₃₉ ) ^7- , A-β-type (HSiW ₉ O
₃₄ ) ^9- shows the 3-digit T / E value and is noted.

(2) In the same method as the previous embodiment, another MRS is used.
A heteropolytungstate antibacterial test was performed on SR3605 (Consti-tutive MRSA), which is a strain of A. In this case, the same test was performed using sodium tungstate and non-Keggin type heteropolytungstate for comparison. A part of the obtained results is shown in Table 2 for each item of T, E and T / E as in the previous example.

[0016]

[Table 2]

Table 2 shows the clear superiority of the Keggin-type heteropolytungstate ion, but not as much as the previous example. In comparison with the results shown in Table 1, among the Keggin-type heteropolytungstate ions, there are a type that exerts a particularly strong effect on a certain strain and a type that exerts an effect on many strains relatively slowly. Recognize. A representative of the latter is the mixed type heteropolyacid ion (PTi ₂ W ₁₀
O ₄₀ ) ^7- . This alkaline salt (PM-19) was used as the strain ATCC43300 of the previous example and the strain SR of this example.
In addition to 3605, it shows excellent antibacterial action against many MRSA. This is shown in FIG.

FIG. 1 shows the dose of PM-19 and the degree of enhancement of oxacillin antibacterial activity against each strain of MRSA (MIC).
Indicates. MIC on the vertical axis of the figure means the minimum inhibitory concentration for MRSA. PM- for any strain
The inhibitory concentration decreased sharply as the dose of 19 increased. That is, it can be seen that the growth inhibitory effect of oxacillin against MRSA is increased. PM-19 is
It was confirmed that an excellent antibacterial action was exhibited against many MRSA strains not shown.

(3) It was confirmed that the Keggin-type heterotungstate ion of the present invention enhances the anti-MRSA action of many anti-drugs other than oxacillin, which is the anti-drug used in the previous examples. As a typical example, PM used in the previous example
-19, ie, (PTi ₂ W ₁₀ O ₄₀ ) · 6H ₂ O, was investigated for its antidoteering effect. Table 3 shows a part of the result. Table 3 shows the anti-MRSA activity enhancing effect of the anti-drugs when PM-19 was administered at 100 μM as an index of factorial of 2.

[0020]

[Table 3]

Table 3 shows that the penicillin-based and cephem-based anti-drugs have remarkable enhancement effects.

The acute toxicity value LD ₅₀ of these Keggin type heteropolytungstates was investigated as follows. 8
Three SD male rats a week are included in one group, and 2 per 3 groups
After fasting for 4 hours, the drug is administered, and 6 hours after that, feeding is started. For oral administration, it was dissolved in distilled water (100 mg / 5
(ml / kg), for intravenous injection, a solution dissolved in physiological saline was administered. As a result, the LD ₅₀ value is (PTi ₂ W
₁₀ O ₄₀ ) ^7- was 1.28 g / kg by oral administration and 390 mg / kg by intravenous administration. Also, (SiW ₁₂ O ₄₀ )
^4- is 1.51 g / kg by oral administration and 435 by intravenous administration
_{mg / kg, (BVW 11 O} 40) 7- it is orally administered 1.21
g / kg, 365 mg / kg by intravenous administration, (PW ₁₁ O
₃₉ ) ^7- was 2.2 g / kg by oral administration and 51 by intravenous administration.
5 mg / kg, β- (HSiW ₉ O ₃₄ ) ^9- was 2.4 g / kg by oral administration and 520 mg / kg or more by intravenous administration.

In addition to the examples described above, the general formula of Keggin type heteropolytungstate ion is (XW ₁₂ O ₄₀ ).
^(8-n)- , (XW ₁₁ O ₃₉ ) ^(12-n)- , (YW ₉ O ₃₄ )
^{When expressed as (14-n)-} , (ZW ₉ O ₃₃ ) ^(12-n)- , X is 1
To Cu, Zn, Ni, Co, A, which become positive cations
One atom selected from the group consisting of 1, Bi, Ge and V, Y is one atom selected from the group consisting of Ge, P and As, and Z is one selected from Bi, B and Sb. Anti-MRSA effects are seen with heteropolyacids represented by different types of atoms. Also in the mixed type heteropolyacid, V and M other than Ti described in the above embodiment are used as atoms mixed with W.
The anti-MRSA effect was observed when at least one atom selected from the group consisting of o, Co, Nb and Fe was used. Further, in the hydrogen-bonding type heteropolyacid, the anti-MRSA effect was observed not only in the case where one hydrogen atom was bonded but also in the type where two hydrogen atoms were bonded. The LD ₅₀ of acute toxicity of these heteropolytungstic acids was almost the same level as in the above-mentioned Examples.

In the above embodiments, only the case where the heteropolytungstate is an alkali metal salt has been described. However, the present invention is not limited to this. In addition to these, alkaline earth metal salts and polymer salts are possible. Generally, alkali metal salts and alkaline earth metal salts are water-soluble and are mainly suitable for oral administration, infusion and inhalation.
On the other hand, polymeric ammonium salts are insoluble in water,
Suitable for transdermal administration such as application and sticking.

[0025]

As described above, according to the present invention, the MR
By appropriately selecting Keggin-type or defective Keggin-type heteropolytungstate ion depending on the SA strain and the type of antibiotic and administering the same at the same time as the antibiotic, it is possible to impart excellent antibacterial activity to the antibiotic. As a result, it is considered to be effective in treating MRSA infection. Also,
As shown in the partial data in Tables 1 and 2, even if heteropolytungstate ion alone was administered without antibiotics, anti-M
Since the RSA action is obtained, it is considered possible to administer the drug of the present invention as a new inorganic antibiotic alone or in combination with other drugs.

[Brief description of drawings]

FIG. 1 is a diagram showing the heteropolyacid concentration dependence of the antibacterial effect enhancement of the antibiotic oxacillin according to the example.

Claims (3)

[Claims] 1. The general formula is (XW ₁₂ O ₄₀ ) ^(8-n)- , (XW
₁₁ O ₃₉ ) ^(12-n)- , (YW ₉ O ₃₄ ) ^(14-n) -or (ZW ₉
O ₃₃ ) ^(12-n)- , where W is a tungsten atom, O is an oxygen atom, n is the ionic valence of the element X, Y or Z, and X is
Is Cu, Zn, Ni, C which is a monovalent to pentavalent cation
one kind of atom selected from the group consisting of o, A1, B, Bi, Sb, Ge, Si, P and V, and Y is Si, Ge,
One kind of atom selected from the group consisting of P and As, Z
Is an anti-MRSA drug containing a so-called Keggin-type or defective Keggin-type heteropolytungstate ion represented by one kind of atom selected from the group consisting of Bi, B, and Sb as a main active ingredient. 2. The general formula is (XM _a W _12-a O ₄₀ ) ^(8-m)- ,
(XM _a W _11-a O ₃₉ ) ^(12-m)- , (YM _a W _9-a O ₃₄ )
^(14-m) -or (ZM _a W ₉ O ₃₃ ) ^(12-m)- , where W is a tungsten atom, O is an oxygen atom, m is an element X (Y or Z) and the ionic valences of M and W. A constant determined, a is a mixed atomic ratio represented by any of 1 to 6, M is V, M
at least one kind of atom selected from the group consisting of o, Ti, Co, Nb and Fe, X and Y and Z are atoms according to claim 1, represented by the so-called mixed type Keggin type or defective Keggin type An anti-MRSA agent containing the heteropolytungstate ion as a main active ingredient. 3. The general formula is (H _b XW ₁₂ O ₄₀ ) ^(8-nb)- ,
_{(H b XW 11 O 39)} (12-nb) -, (H b YW 9 O 34)
^{(14-nb) -} or _{(H b ZW 9 O 33)} (12-nb) -, provided that H
The anti-MRSA drug according to claim 1, wherein is represented by a hydrogen atom and b is represented by 1 or 2.