Use of sitagliptin and related compounds for resisting microbial infections

Abstract

The invention provides application of sitagliptin and related compounds thereof to preparation of a medicament for resisting microbial infection. The inventor of the invention finds that sitagliptin has a remarkable inhibition effect on microbial infection, especially infection caused by staphylococcus aureus, MRSA, enterococcus faecalis, MRSE and escherichia coli. Under the same dosage, the antibacterial effect of sitagliptin on staphylococcus aureus and MRSA exceeds that of a positive control drug linezolid. The biofilm inhibition effect of sitagliptin on MRSA is higher than that of linezolid under the same dosage. In addition, the sitagliptin sodium also has the effects of resisting staphylococcus aureus and MRSA (Methicillin Resistant Staphylococcus Aureus). Oral administration of the sitagliptin sodium can significantly reduce the level of MRSA in the heart, liver, spleen, lung, kidney and abdominal cavity of MRSA systemically infected mice. In addition, administration of sitagliptin at wounds promotes healing of MRSA infectious wounds. And a new thought is provided for the preparation of antibacterial drugs.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of medicine, and relates to a new use of Chiglitazar, in particular, the use of Chiglitazar and related compounds for resisting microbial infection. BACKGROUND

[0002] The extensive use of current antibacterial drugs (such as β-lactams, quinolones, and glycopeptides) has led to an explosive increase in multi-drug resistant bacteria (MDR), especially antibiotic-resistant pathogens such as Staphylococcus aureus, which poses a serious threat to clinical treatment. The World Health Organization has warned that drug-resistant infections may cause 10 million deaths worldwide per year by 2050. The current first-line drug is linezolid, but there are still problems such as insufficient efficacy and large side effects, and the development of new antibacterial drugs faces bottlenecks such as long cycle, high cost, and rapid evolution of drug resistance.

[0003] Chiglitazar Sodium is a PPAR alpha / gamma / delta full agonist that has been marketed, and the current approved indications are limited to type 2 diabetes (such as Dualogin® approved by NMPA in China). Its mechanism of action focuses on regulating glucose homeostasis, improving insulin resistance, and abnormal blood lipids. Currently, there is no report on the inhibitory effect of Chiglitazar and Chiglitazar Sodium on bacteria, fungi, and other microorganisms, as well as the direct or indirect inhibitory effect on infections caused by microorganisms. SUMMARY

[0004] The purpose of the present application is to provide a new drug for treating microbial infection. The inventors of the present application found that Chiglitazar has a significant inhibitory effect on microbial infection, especially on infections caused by Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE, and Escherichia coli. At the same dose, Chiglitazar has a better antibacterial effect on Staphylococcus aureus and MRSA than the positive control drug linezolid. Chiglitazar has a higher inhibitory effect on the biofilm of MRSA than linezolid at the same dose. In addition, Chiglitazar Sodium also has an effect on Staphylococcus aureus and MRSA. Oral administration of Chiglitazar Sodium significantly reduces the level of MRSA in the heart, liver, spleen, lung, kidney, and abdominal cavity of MRSA-infected mice. In addition, administration of Chiglitazar at the wound site promotes the healing of MRSA-infected wounds. This provides a new idea for the preparation of antibacterial drugs.

[0005] To achieve the above-mentioned purpose, the present application provides the following technical solutions:

[0006] In a first aspect, the present application provides the use of Chiglitazar and derivatives thereof for the preparation of a drug for resisting microbial infection, wherein Chiglitazar has the structure shown in the following formula:

[0007] .

[0008] In the above scheme, the related compounds of seglitide refer to pharmaceutically acceptable salts, stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystal forms, amorphous isomers, solvates or metabolites of seglitide.

[0009] Preferably, the microbial infection includes systemic infection or local infection caused by bacteria or fungi.

[0010] Further, the systemic infection or local infection caused by bacteria or fungi includes respiratory tract infection, digestive tract infection, urogenital system infection, central nervous system infection and blood infection caused by bacteria or fungi, and infection caused by difficult-to-heal wounds of diabetic patients, physical damage and chemical damage of skin.

[0011] More preferably, the bacteria or fungi include Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli.

[0012] In a second aspect, the present application provides a medicine for resisting microbial infection, which comprises seglitide or a derivative thereof, and a pharmaceutically acceptable carrier or excipient.

[0013] Preferably, the medicine is prepared in a dosage form.

[0014] Further, the dosage form includes oral dosage, external dosage, injection dosage, suppository, inhalation dosage or implant dosage.

[0015] More preferably, the dosage form is any one selected from tablet, capsule, granule, oral solution, injection solution, ointment, cream, gel, spray, emulsion, patch, powder or film.

[0016] Compared with the prior art, the present application has the following beneficial effects: the inventors of the present application have found that the effect of seglitide in inhibiting MRSA is better than that of linezolid with the same concentration. Oral administration of seglitide sodium can reduce the bacterial load in heart, liver, spleen, lung, kidney and abdominal cavity of mice with systemic MRSA infection. Topical administration of seglitide can significantly promote the healing of MRSA infected wounds in mice. Seglitide has the effect of resisting Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli. Seglitide sodium has the effect of inhibiting Staphylococcus aureus and MRSA in vitro, and can be used for preparing antibacterial medicine. The present application develops the new function of seglitide and its related compounds, expands the application range of seglitide, and provides a new technical scheme for the development of anti-infection medicine. BRIEF DESCRIPTION OF DRAWINGS

[0017] Figure 1 It is shown that seglitide has better inhibitory effect on the proliferation of Staphylococcus aureus than positive control linezolid with the same concentration;

[0018] Figure 2 The better inhibitory effect of siglitinib on the proliferation of methicillin-resistant Staphylococcus aureus (MRSA) is shown compared with the positive control linezolid at the same concentration;

[0019] Figure 3 The comparison of the inhibitory effect of siglitinib and the positive control linezolid on the proliferation of Enterococcus faecalis at the same concentration is shown;

[0020] Figure 4 The comparison of the inhibitory effect of siglitinib and the positive control linezolid on the proliferation of methicillin-resistant Staphylococcus epidermidis (MRSE) at the same concentration is shown;

[0021] Figure 5 The comparison of the inhibitory effect of siglitinib and the positive control linezolid on the proliferation of Escherichia coli at the same concentration is shown;

[0022] Figure 6 The effect characteristics of siglitinib against Staphylococcus aureus are shown;

[0023] Figure 7 The experimental result photos of siglitinib on the minimum bactericidal concentration (MBC) of Staphylococcus aureus and MRSA are shown;

[0024] Figure 8 The experimental result photos of siglitinib on the inhibition of MRSA biofilm level are shown;

[0025] Figure 9 The comparison of the inhibitory effect of siglitinib and linezolid on Staphylococcus aureus and MRSA at the same concentration is shown;

[0026] Figure 10 The experimental result of siglitinib on the inhibition of MRSA-induced systemic infection in mice is shown;

[0027] Figure 11 The experimental result of siglitinib on the promotion of MRSA-infected wound healing in mice is shown;

[0028] Figure 12 and Figure 13 The experimental result of verifying the antibacterial effect of other marketed PPAR agonists is shown, and according to the result, it can be seen that the selected PPAR agonists do not have antibacterial effect. DETAILED DESCRIPTION

[0029] The application discloses application of Chiglitazar and related compounds thereof in preparation of antibacterial drugs and anti-infection drugs. The inventor of the application finds through research that Chiglitazar has effects of resisting Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli. Chiglitazar sodium has inhibiting effects on Staphylococcus aureus and MRSA. The inhibiting effect of Chiglitazar on MRSA is better than that of the same dose of Linezolid. In addition, Chiglitazar can inhibit the biofilm level of MRSA. Oral administration of Chiglitazar sodium can inhibit systemic infection caused by MRSA. Administration of Chiglitazar at a wound can significantly promote healing of a MRSA infectious wound.

[0030] Therefore, Chiglitazar and related compounds thereof have wide application prospects in prevention and treatment of microbial infectious diseases, especially in prevention and treatment of systemic infection or local infection caused by conditional pathogenic bacteria such as Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli, especially bacterial and fungal infection at a difficult-to-heal wound caused by a diabetic wound, physical damage or chemical damage of skin.

[0031] On the basis of the above research, the application proposes application of Chiglitazar and related compounds thereof in preparation of anti-microbial infection drugs. Structures of Chiglitazar, commonly used Chiglitazar derivatives Chiglitazar sodium and Chiglitazar potassium are as follows:

[0032] .

[0033] In the exemplary embodiments, the infection caused by the microorganism includes systemic infection or local infection caused by Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli, or secondary infection of a normal or diabetic wound, respiratory tract infection, digestive tract infection, urogenital system infection, central nervous system infection and blood infection.

[0034] The Chiglitazar and related compounds thereof have effects of killing Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli, and have an effect of inhibiting the biofilm level of the bacteria.

[0035] The application also discloses a drug for treating microbial infection, wherein the drug further comprises a pharmaceutically acceptable carrier or excipient.

[0036] Preferably, the carrier or excipient is one or more selected from the following: water, a solvent, an emulsifier, a dispersant, a wetting agent, a thickening agent, an antifoaming agent, a stabilizer, a binder, a disintegrant, an anti-freezing agent, an anti-caking agent, a suspending agent, a film-forming agent, a preservative, a coloring agent, a high molecular capsule wall material, a pH regulator or a filler.

[0037] Carriers or excipients can improve the stability, effectiveness, safety, compliance, and convenience of a drug. Here are some common carriers or excipients and their functions:

[0038] 1. Solvent

[0039] The function of a solvent is to dissolve the active ingredient and help it disperse uniformly. Commonly used substances include, for example, water (most commonly used), ethanol, isopropyl alcohol (organic solvent), acetone, xylene (used in oil-based formulations), etc.

[0040] 2. Emulsifier

[0041] The function of an emulsifier is to mix the water phase and the oil phase to form a stable emulsion. Commonly used substances include, for example, polyoxyethylene fatty acid esters (such as the Tween series), alkyl benzene sulfonate (such as sodium dodecyl benzene sulfonate), sorbitan monooleate (such as the Span series), etc.

[0042] 3. Stabilizer

[0043] The function of a stabilizer is to prevent the degradation of the active ingredient and extend the shelf life. Commonly used substances include, for example, antioxidants (such as BHT, BHA), UV absorbers (such as benzotriazole), chelating agents (such as EDTA), etc.

[0044] 4. Thickening agent

[0045] The function of a thickening agent is to adjust the viscosity and improve the sprayability. Commonly used substances include, for example, xanthan gum, carboxymethyl cellulose (CMC), magnesium aluminum silicate, etc.

[0046] 5. Dispersant

[0047] The function of a dispersant is to prevent particle aggregation and ensure uniform distribution. Commonly used substances include, for example, lignin sulfonate, polycarboxylate, naphthalene sulfonate formaldehyde condensate, etc.

[0048] 6. Wetting agent

[0049] The function of a wetting agent is to reduce surface tension and enhance the adhesion and penetration of the drug solution on the target surface. Commonly used substances include, for example, alkyl sulfate (such as sodium dodecyl sulfate), alkyl phenol polyoxyethylene ether (such as Triton X-100), etc.

[0050] 7. Antifreeze

[0051] The function of an antifreeze is to prevent the freezing of the drug solution at low temperatures. Commonly used substances include, for example, ethylene glycol, propylene glycol, etc.

[0052] 8. Preservative

[0053] The function of a preservative is to prevent microbial contamination. Commonly used substances include, for example, sodium benzoate, potassium sorbate, formaldehyde donor (such as DMDM hydantoin), etc.

[0054] 9. Synergist

[0055] The synergist serves to enhance the effect of the active ingredient. Commonly used substances include, for example, piperonyl butoxide (PBO), octachlorodipropyl ether (S-421), etc.

[0056] 10. Colorant

[0057] The colorant serves to identify the liquid medicine, avoiding misuse. Commonly used substances include, for example, food-grade pigments (such as brilliant blue, carmine), etc.

[0058] 11. Flavoring agent

[0059] The flavoring agent serves to mask odors and improve user experience. Commonly used substances include, for example, natural flavoring agents (such as lemon oil, peppermint oil), synthetic flavoring agents (such as vanillin), etc.

[0060] 12. Defoaming agent

[0061] The defoaming agent serves to reduce foam during production and use. Commonly used substances include, for example, silicone oil, polydimethylsiloxane, etc.

[0062] 13. pH adjuster

[0063] The pH adjuster serves to adjust the acidity or alkalinity of the liquid medicine, ensuring stability. Commonly used substances include, for example, citric acid (to lower pH), sodium hydroxide (to raise pH), etc.

[0064] 14. Filler

[0065] The filler serves to increase volume and reduce cost. Commonly used substances include, for example, talc, kaolin, diatomaceous earth, etc.

[0066] Preferably, the medicine is prepared as a dosage form. The dosage form includes oral, topical, injectable, suppository, inhalable, or implantable, etc., such as oral, sublingual, or injectable preparations, and external application products, etc.

[0067] Preferably, the dosage form of the medicine of the present application is any one selected from tablets, capsules, granules, oral solutions, injection solutions, ointments, creams, gels, sprays, emulsions, patches, powders, or films.

[0068] The technical solutions in the embodiments of the present application will be described clearly and completely below in combination with specific embodiments of the present application and the accompanying drawings. Obviously, the described embodiments are only a part of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative labor fall within the scope of protection of the present application.

[0069] In the description of the present application, it should be noted that the terms "upper", "lower", "inner", "outer", "front end", "rear end", "both ends", "one end", "the other end" and the like are only for the convenience of describing the present application and simplifying the description, and do not indicate or imply that the devices or elements referred to must have a particular orientation, be constructed and operated in a particular orientation, and therefore cannot be understood as a limitation on the present application. In addition, the terms "first", "second" are only for the purpose of description, and cannot be understood as indicating or implying relative importance.

[0070] In the description of the present application, it should be noted that unless otherwise explicitly specified and limited, the terms "mounting", "provided with", "connection" and the like should be broadly understood, for example, "connection" can be fixed connection, can also be detachable connection, or integral connection; can be mechanical connection, can also be electrical connection; can be directly connected, can also be indirectly connected through an intermediate medium, can be internal communication of two elements. For those skilled in the art, the specific meaning of the above terms in the present application can be understood according to the specific circumstances.

[0071] The present inventors found that sitagliptin has an effect of resisting Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli. Sitagliptin sodium has an inhibitory effect on Staphylococcus aureus and MRSA. The inhibitory effect of sitagliptin on MRSA is better than that of linezolid of the same dose. In addition, sitagliptin can inhibit the biofilm level of MRSA. Oral administration of sitagliptin sodium can inhibit systemic infection caused by MRSA. Administration of sitagliptin at a wound site can significantly promote the healing of a MRSA infected wound.

[0072] Therefore, sitagliptin and sitagliptin sodium have broad application prospects in preventing and treating bacterial and fungal infectious diseases, especially in preventing and treating systemic infection or local infection caused by conditional pathogenic bacteria such as Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli, especially bacterial and fungal infection at a difficult-to-heal wound caused by physical damage, chemical damage of the skin of a diabetic wound.

[0073] Example 1 Sitagliptin has an anti-Staphylococcus aureus proliferation effect

[0074] Staphylococcus aureus (ATCC 6538), Staphylococcus aureus (ATCC 29213), Staphylococcus aureus (ATCC 25923) were added with siglitin at final concentrations of 1 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM and 4 μM and the same concentration of positive control linezolid, and incubated at 37 °C, constant humidity, and rotation speed of 180 rpm for 24 hours. The absorbance OD value was detected at 600 nm wavelength by using a microplate reader. The results showed that siglitin at concentrations of 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM and 4 μM had significant inhibitory effect on Staphylococcus aureus (ATCC 6538), and the effect was equivalent to that of linezolid at the same concentration. The minimum inhibitory concentration (MIC) of siglitin on Staphylococcus aureus (ATCC 6538) was 2 μM. Figure 1 A).

[0075] Siglitin at concentrations of 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM and 4 μM had significant inhibitory effect on Staphylococcus aureus (ATCC 25923), and the inhibitory effect was better than that of linezolid at the same concentration. The minimum inhibitory concentration (MIC) of siglitin on Staphylococcus aureus (ATCC 25923) was 2.25 μM. Figure 1 B).

[0076] Siglitin at concentrations of 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM and 4 μM had significant inhibitory effect on Staphylococcus aureus (ATCC 29213), and the inhibitory effect was better than that of linezolid at the same concentration. The minimum inhibitory concentration (MIC) of siglitin on Staphylococcus aureus (ATCC 29213) was 2 μM. Figure 1 C). This indicates that siglitin has the effect of inhibiting the proliferation of Staphylococcus aureus.

[0077] Example 2 Siglitin has anti-MRSA proliferation effect

[0078] Siglitinib was added in MRSA (ATCC 43300 and USA300) at final concentration of 1 μΜ, 2 μΜ, 2.25 μΜ, 2.5 μΜ, 2.75 μΜ, 3 μΜ and 4 μΜ respectively and same concentration of positive control Linezolid and incubated for 24 hours at 37 °C, constant humidity, at 180 rpm. The absorbance OD value was measured at 600 nm wavelength using a microplate reader. The results showed that siglitinib had significant inhibitory effect on MRSA (ATCC 43300) at 2 μΜ, 2.25 μΜ, 2.5 μΜ, 2.75 μΜ, 3 μΜ and 4 μΜ concentrations. And at 2.5 μΜ, 2.75 μΜ, 3 μΜ and 4 μΜ concentrations, the inhibitory effect of siglitinib on MRSA (ATCC 43300) was higher than that of Linezolid at the same concentration. The minimum inhibitory concentration (MIC) of siglitinib on MRSA (ATCC 43300) was 2.75 μΜ. Figure 2 A).

[0079] Siglitinib had significant inhibitory effect on MRSA (USA300) at 1 μΜ, 2 μΜ, 2.25 μΜ, 2.5 μΜ, 2.75 μΜ, 3 μΜ and 4 μΜ concentrations. And at 2 μΜ, 2.5 μΜ, 2.75 μΜ, 3 μΜ and 4 μΜ concentrations, the inhibitory effect of siglitinib on MRSA (USA300) was significantly higher than that of Linezolid at the same concentration. The minimum inhibitory concentration (MIC) of siglitinib on MRSA (USA300) was 2.75 μΜ. Figure 2 B).

[0080] Example 3: Siglitinib has anti-proliferative effect on Enterococcus faecalis

[0081] Siglitinib was added in Enterococcus faecalis (ATCC 29212) at final concentration of 2 μΜ, 3 μΜ, 4 μΜ, 5 μΜ, 10 μΜ, 20 μΜ, 30 μΜ, 40 μΜ and 50 μΜ respectively and same concentration of positive control Linezolid and incubated for 24 hours at 37 °C, constant humidity, at 180 rpm. The absorbance OD value was measured at 600 nm wavelength using a microplate reader. The results showed that siglitinib had significant inhibitory effect on Enterococcus faecalis (ATCC 29212) at 2 μΜ, 3 μΜ, 4 μΜ, 5 μΜ, 10 μΜ, 20 μΜ, 30 μΜ, 40 μΜ and 50 μΜ concentrations. The minimum inhibitory concentration (MIC) of siglitinib on Enterococcus faecalis (ATCC 29212) was 20 μΜ. Figure 3 .

[0082] Example 4: Siglitinib has anti-proliferative effect on oxacillin-resistant Staphylococcus epidermidis

[0083] The final concentration of 1 μM, 2 μM, 2.25 μM, 2.5 μM, 2.75 μM, 3 μM, 4 μM, 5 μM, 6 μM, 8 μM, 10 μM, 15 μM, 20 μM, 30 μM, 40 μM of siglitin and the same concentration of positive control linezolid were added to the MRSE, and incubated at 37°C, constant humidity, and 180 rpm for 24 hours. The absorbance OD value was detected at 600 nm wavelength by using a microplate reader. The results showed that siglitin had a significant inhibitory effect on MRSE at 30 μM and 40 μM concentrations. The MIC of siglitin on MRSE was 40 μM. Figure 4 ).

[0084] Example 5 Siglitin has an anti-proliferative effect on E. coli

[0085] The final concentration of 1 μM, 2 μM, 2.25 μM, 2.5 μM, 3 μM, 4 μM, 5 μM, 8 μM, 10 μM, 12 μM, 20 μM, 24 μM, 30 μM, 36 μM, 40 μM, 48 μM, 60 μM and 100 μM of siglitin and the same concentration of positive control linezolid were added to the E. coli (ATCC43895), and incubated at 37°C, constant humidity, and 180 rpm for 24 hours. The absorbance OD value was detected at 600 nm wavelength by using a microplate reader. The results showed that siglitin had a significant inhibitory effect on E. coli (ATCC43895) at 12 μM, 20 μM, 24 μM, 30 μM, 36 μM, 40 μM, 48 μM, 60 μM and 100 μM concentrations. The MIC of siglitin on E. coli (ATCC43895) was 20 μM. Figure 5 ).

[0086] Example 6 The effect of siglitin on S. aureus

[0087] We used the micro-broth dilution method to determine the time-concentration dependent curve of siglitin at a concentration of 2.25 μM on S. aureus (ATCC 6538) within 0-24 hours. The experimental results showed that siglitin began to have an inhibitory effect on S. aureus (ATCC 6538) 2 hours after treatment, and the effect lasted for 24 hours. Figure 6 A).

[0088] We used microbroth dilution method to determine the time-concentration dependent curve of sitagliptin at 3 mM concentration on the action of methicillin-resistant Staphylococcus aureus (ATCC 43300) within 0-24 hours. The experimental results showed that, compared with the control group, sitagliptin began to have bacteriostatic effect on methicillin-resistant Staphylococcus aureus (ATCC 43300) 2 hours after treatment, and the effect lasted for 24 hours. And from the 8th hour to the 24th hour, the inhibition of methicillin-resistant Staphylococcus aureus (ATCC 43300) was more than that of linezolid (3 mM) Figure 6 B}.

[0089] We used microbroth dilution method to determine the time-concentration dependent curve of sitagliptin at 3 mM concentration on the action of methicillin-resistant Staphylococcus aureus (USA300) within 0-24 hours. The experimental results showed that, compared with the control group, sitagliptin began to have bacteriostatic effect on methicillin-resistant Staphylococcus aureus (USA300) 4 hours after treatment, and the effect lasted for 24 hours. And from the 8th hour to the 24th hour, the inhibition of methicillin-resistant Staphylococcus aureus (ATCC USA300) was more than that of linezolid (3 mM) Figure 6 C}.

[0090] Example 7 Minimum bactericidal concentration (MBC) of sitagliptin on Staphylococcus aureus

[0091] We used LB solid medium plate coating method to explore the bactericidal effect and minimum bactericidal concentration of sitagliptin on Staphylococcus aureus (ATCC 6538, ATCC 29213) and methicillin-resistant Staphylococcus aureus (USA300, ATCC 43300). The experimental results showed that, compared with the control group, the inhibition rate of sitagliptin on the formation of Staphylococcus aureus (ATCC 6538, ATCC 29213) colonies on LB solid medium was greater than 99.99% when the concentration was 2.25 mM and above Figure 7 A). The inhibition rate of sitagliptin on the formation of methicillin-resistant Staphylococcus aureus (USA300, ATCC 43300) colonies on LB solid medium was greater than 99.99% when the concentration was 4 mM and above Figure 7 B). This result showed that sitagliptin had bactericidal effect on Staphylococcus aureus, and the MBC of sitagliptin on Staphylococcus aureus (ATCC 6538, ATCC 29213) was 2.25 mM, and the MBC of sitagliptin on methicillin-resistant Staphylococcus aureus (USA300, ATCC 43300) was 4 mM.

[0092] Example 8 Sitagliptin inhibits the biofilm content of MRSA

[0093] The effect of sitagliptin on the level of MRSA (USA300) biofilm was detected by using crystal violet staining experiment. The experimental results showed that, compared with the control group, sitagliptin at the concentrations of 1.5 μM, 3 μM and 6 μM significantly reduced the biofilm content of methicillin-resistant Staphylococcus aureus (USA300), and its inhibitory effect was better than that of linezolid at the same concentration. Figure 8 The results of this example showed that sitagliptin had the effect of inhibiting microbial biofilm. It is known that biofilm is an important reason for microbial resistance to antibiotics. Because of the existence of biofilm, it is difficult for drugs to reach the deep place, and at the same time, the biofilm produces a microbial synergistic organization, thus creating a microenvironment conducive to the growth of microorganisms. Sitagliptin destroys the microenvironment created by microorganisms by destroying the biofilm, breaking the synergistic effect of microbial organization, and at the same time, destroying the biofilm is conducive to the deepening of the drug, so that sitagliptin can play a better antibacterial effect. Especially in the case of drug-resistant bacteria and fungi, a large part of the drug resistance of drug-resistant bacteria is derived from biofilm, and an important reason for the difficulty in treating fungal infections is that fungi are more likely to form biofilms. Therefore, sitagliptin can play a better anti-infective effect on these more difficult to treat infections by inhibiting microbial biofilm formation.

[0094] Example 9 Inhibitory effect of sitagliptin sodium on Staphylococcus aureus and MRSA

[0095] In Staphylococcus aureus (ATCC29213) and MRSA (USA300, ATCC43300), 10 μg / mL, 20 μg / mL, 30 μg / mL, 40 μg / mL, 60 μg / mL, 80 μg / mL and 100 μg / mL of compound sitagliptin sodium were added respectively, and the absorbance OD value was detected by using an enzyme-labeled instrument at 600 nm wavelength under the condition of 37°C, constant humidity and rotation speed of 180 rpm for 24 hours. The results showed that sitagliptin sodium had a significant inhibitory effect on Staphylococcus aureus (ATCC29213) at the concentrations of 40 μg / mL, 60 μg / mL, 80 μg / mL and 100 μg / mL. The minimum inhibitory concentration (MIC) of sitagliptin sodium on Staphylococcus aureus (ATCC29213) was 40 μg / mL. Figure 9 A).

[0096] Siglitinat had significant inhibitory effect on MRSA (USA300) at concentrations of 10 μg / mL, 20 μg / mL, 30 μg / mL, 40 μg / mL, 60 μg / mL, 80 μg / mL and 100 μg / mL, and the inhibitory effect of siglitinat on MRSA (USA300) was higher than that of linezolid at the same concentration. The minimum inhibitory concentration (MIC) of siglitinat on MRSA (USA300) was 60 μg / mL. Figure 9 B}.

[0097] Siglitinat had significant inhibitory effect on MRSA (ATCC43300) at concentrations of 20 μg / mL, 30 μg / mL, 40 μg / mL, 60 μg / mL, 80 μg / mL and 100 μg / mL, and the inhibitory effect of siglitinat on MRSA (ATCC43300) was higher than that of linezolid at the same concentration. The minimum inhibitory concentration (MIC) of siglitinat on MRSA (ATCC43300) was 20 μg / mL. Figure 9 C}.

[0098] Example 10 Siglitinat inhibits systemic infection induced by MRSA

[0099] To investigate whether siglitinat has therapeutic effect on systemic infection induced by MRSA. We injected MRSA into the abdominal cavity of normal mice at a dose of 750 μL, 10 8 CFU / mL to construct a mouse model of systemic infection induced by MRSA. The mice in the infection group were given siglitinat and linezolid by gavage at a dose of 20 mg / kg, and after 5 days of gavage treatment, the heart, liver, spleen, lung, kidney and abdominal effusion were taken in a clean environment, the organs were homogenized, and the MRSA content in the heart, liver, spleen, lung, kidney and abdominal effusion was detected by LB solid medium plate coating method. As shown in Figure 10 compared with the infection group, siglitinat significantly reduced the bacterial load of MRSA in the heart, liver, spleen, lung, kidney and abdominal effusion.

[0100] Example 11 Siglitinat promotes the healing of MRSA infected wounds

[0101] To investigate whether siglitin can promote the healing of MRSA infected wounds, we constructed MRSA infected wounds in mice, during which siglitin (4 μmol / L) was used for treatment Figure 11 A). The results showed that compared with the MRSA wound infection group, the wound area of mice in the siglitin (4 μmol / L) treatment group was significantly reduced on the 2nd, 6th, 10th and 14th day Figure 11 ). The above results show that siglitin can promote the healing of MRSA infected wounds.

[0102] Example 12 Other marketed PPAR agonists do not have antibacterial effect

[0103] To investigate whether other marketed PPAR agonists have antibacterial activity, we detected the effects of different concentrations of fenofibrate (PPARα agonist), Pemafibrate (PPARα modulator), saroglitazar (PPARα / γ dual agonist), rosiglitazone (PPARγ selective agonist), gemfibrozil (PPARα selective agonist) on S. aureus (ATCC6538) and drug-resistant S. aureus (USA300). The results are shown in Figure 12-13 Other PPAR agonists including fenofibrate, Pemafibrate, saroglitazar, rosiglitazone, gemfibrozil do not have antibacterial effect on S. aureus and MRSA.

[0104] Example 13 Inhibitory effect of siglitin on Candida albicans

[0105] We detected the effect of siglitin on fungi. We added different concentrations of siglitin to Candida albicans (ATCC14053) and incubated at 35 degrees Celsius for 48 hours. The results showed that siglitin also has good inhibitory activity on Candida albicans (ATCC14053), and the MIC is less than 50 μmol / L.

[0106] Although only siglitin itself and its sodium salt are used as examples in the above examples, it should be understood that other siglitin derivatives with the same core structure will be easily thought of by those skilled in the art according to the principles disclosed in the present application, including pharmaceutically acceptable salts, stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystal forms, amorphous isomers, solvates or metabolites other than sodium salt also have the same effect and effect, the use of these siglitin derivatives as anti-infective drugs should also be included in the protection scope of the present application. The protection scope of the present application should not be limited by the specific examples, but should be subject to the claims.

[0107] The details of the present application not described are well known to those skilled in the art.

[0108] Finally, it should be noted that the above detailed description is merely illustrative of the technical solutions of the present application and is not limiting. Although the present application is described in detail with reference to the embodiments, those skilled in the art should understand that the technical solutions of the present application can be modified and replaced by equivalents without departing from the spirit and scope of the technical solutions of the present application, and all such modifications and replacements should be encompassed in the scope of the claims of the present application.

Claims

1. Use of sitagliptin and related compounds thereof for the preparation of a medicament against microbial infections, characterized in that, The seglitide has a structure shown in the following formula: 。 2. Use according to claim 1, characterized in that, The seglitide and related compounds thereof include pharmaceutically acceptable salts, stereoisomers, geometric isomers, tautomers, solvates, metabolites, crystalline forms, amorphous isomers, solvates or metabolites.

3. Use according to claim 1, characterized in that, The microbial infection includes systemic infection or local infection caused by bacteria or fungi.

4. Use according to claim 3, characterized in that, The systemic infection or local infection caused by bacteria or fungi includes respiratory tract infection, digestive tract infection, urogenital system infection, central nervous system infection and blood infection caused by bacteria or fungi, and infection caused by difficult-to-heal wounds of diabetic patients, physical damage, chemical damage of skin.

5. The use according to claim 3, characterized in that, The bacteria or fungi include Staphylococcus aureus, MRSA, Enterococcus faecalis, MRSE and Escherichia coli.

6. A medicament for the treatment of a microbial infection, characterized in that, The medicine contains seglitide or related compounds thereof, and pharmaceutically acceptable carriers or excipients.

7. The medicament according to claim 6, wherein The medicine is prepared as a dosage form.

8. The medicament according to claim 7, wherein The dosage form includes oral dosage, external dosage, injection dosage, suppository, inhalation or implantation.

9. The medicament according to claim 7, wherein The dosage form is any one selected from tablets, capsules, granules, oral solutions, injection solutions, ointments, creams, gels, sprays, emulsions, patches, powders or films.

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