Use of Pomalidomide in the Preparation of Anti-Bacterial Infection Drugs

Abstract

The present invention discloses the use of pomalidomide in the preparation of antibacterial infection drugs. The present invention for the first time studies and discovers that pomalidomide can significantly improve the survival rate of mice after pulmonary and abdominal bacterial infections, suggesting that pomalidomide can be used to treat bacterial infections and provides a new approach for the treatment of bacterial infections.

Description

Technical Field

[0001] The present invention belongs to the technical field of biomedicine, and particularly relates to the application of pomalidomide in the preparation of antibacterial drugs. Background Art

[0002] Pomalidomide (Pomalid, Pomalidomide), chemically named 4-amino-2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione. Pomalidomide can inhibit the proliferation of tumor cells and induce apoptosis. Therefore, in 2013, it was approved by the US Food and Drug Administration (FDA) for the treatment of relapsed and refractory multiple myeloma (MM), and in May 2020, it was approved for the treatment of AIDS-related Kaposi sarcoma (KS). In November 2020, pomalidomide was also approved for marketing in China. However, the approved indication of pomalidomide in China is only relapsed and refractory MM, that is, patients who have received at least two previous treatments including lenalidomide and bortezomib and have no response to the treatment (failed to work) and progress (relapsed and refractory) within 60 days after the last treatment.

[0003] As is well known, tumor patients (including the above-mentioned multiple myeloma, Kaposi sarcoma, etc.) have low immunity and are prone to repeated infections; and the immunomodulatory effect of pomalidomide during treatment, while killing tumor cells, also causes adverse reactions such as damage to the blood and lymphatic systems, making those skilled in the art believe that the infections after using pomalidomide to treat patients with multiple myeloma and Kaposi sarcoma are common side effects of this drug, including pneumonia, urinary tract infection, sepsis, septic shock, etc., and are more common in patients with myelosuppression. This cognitive obstacle has led to no reports on the use of pomalidomide for the treatment of bacterial infections. Summary of the Invention

[0004] The invention purpose of the present invention is to provide the application of pomalidomide in the preparation of antibacterial drugs, which provides a new use for pomalidomide and a new treatment approach for bacterial infections.

[0005] To achieve the above invention purpose, the technical solution of the present invention is:

[0006] The application of pomalidomide in the preparation of antibacterial drugs.

[0007] Preferably, the bacterial infection is located in the lungs or abdomen.

[0008] Preferably, the bacteria include at least one of Acinetobacter baumannii, Streptococcus pneumoniae, Escherichia coli, and Enterococcus faecalis.

[0009] The present invention for the first time discovers that pomalidomide can significantly improve the survival rate of mice after pulmonary and abdominal bacterial infections, suggesting that pomalidomide can be used to treat bacterial infections and provides a new approach for the treatment of bacterial infections.

[0010] The present invention also discovers that pomalidomide can significantly reduce the bacterial load at the site of bacterial infection and significantly improve the organ damage caused by bacterial infection. Therefore, the present invention also provides the use of pomalidomide in the preparation of therapeutic drugs for organ damage caused by bacterial infection.

[0011] Preferably, the organ damage includes at least one of liver damage, lung damage, and kidney damage.

[0012] Preferably, the bacteria include at least one of Acinetobacter baumannii, Streptococcus pneumoniae, Escherichia coli, and Enterococcus faecalis.

[0013] The present invention also discovers that pomalidomide can significantly increase the level of collagen in the lungs after bacterial infection. Based on this, the present invention also provides the use of pomalidomide in the preparation of a collagen expression promoter; and the use of pomalidomide in the preparation of a drug for promoting tissue repair after bacterial infection.

[0014] Among them, the collagen includes at least one of type I collagen and type III collagen; the tissue repair drug is a lung tissue repair drug; the bacterial infection includes at least one of Acinetobacter baumannii infection and Streptococcus pneumoniae infection.

[0015] Compared with the prior art, the beneficial effects of the present invention are reflected in:

[0016] The present invention for the first time discovers through research that pomalidomide can significantly improve the survival rate of mice after pulmonary and abdominal bacterial infections, significantly reduce the bacterial load at the site of bacterial infection, and significantly increase the level of collagen in the lungs after bacterial infection; suggesting that pomalidomide can be used to treat bacterial infections, improve organ damage caused by bacterial infections, promote tissue repair after bacterial infections, and provide a new approach for the treatment of bacterial infections. Description of the Drawings

[0017] Figure 1 Effect of pomalidomide on improving the survival rate of a mouse model infected with Acinetobacter baumannii in the lungs;

[0018] Wherein, Time (h) after A.baumannii injection represents the time (hours) of Acinetobacter baumannii infection, Survival (%) represents the survival rate (percentage), Vehicle represents the group injected with an equal volume of solvent into healthy mice, A.b represents the Acinetobacter baumannii infection group, Pomalid represents the group injected with 50 mg / kg pomalidomide into healthy mice, A.b + P 5 mg / kg represents the group injected with 5 mg / kg pomalidomide after Acinetobacter baumannii infection, A.b + P 20 mg / kg represents the group injected with 20 mg / kg pomalidomide after Acinetobacter baumannii infection, A.b + P 50 mg / kg represents the group injected with 50 mg / kg pomalidomide after Acinetobacter baumannii infection, * represents P < 0.05, *** represents P < 0.001, **** represents P < 0.0001, the same below;

[0019] Figure 2 Effect of pomalidomide on improving the bacterial load in bronchoalveolar lavage fluid (BALF) of a mouse model infected with Acinetobacter baumannii in the lungs;

[0020] Wherein, Bacterial burden in BALF (lg CFU / mL) represents the bacterial load (lg CFU / mL) in bronchoalveolar lavage fluid (BALF);

[0021] Figure 3 Effect of pomalidomide on improving the lung pathological injury of a mouse model infected with Acinetobacter baumannii in the lungs;

[0022] Wherein, Lung injury score represents the lung pathological injury score, the same below;

[0023] Figure 4 Effect of pomalidomide on promoting the expression level of type I collagen in the lung tissue of a mouse model infected with Acinetobacter baumannii in the lungs;

[0024] Among them, TypeⅠCollagen expression represents the expression level of type I collagen, ** indicates P < 0.01, the same below;

[0025] Figure 5 It is the promoting effect of pomalidomide on the expression level of type III collagen in the lung tissue of a mouse model of Acinetobacter baumannii pulmonary infection;

[0026] Among them, TypeⅢCollagen expression represents the expression level of type III collagen;

[0027] Figure 6 It is the improvement effect of pomalidomide on the survival rate of a mouse model of Streptococcus pneumoniae pulmonary infection;

[0028] Among them, Time(h)after S.pneumoniae injection represents the infection time of Streptococcus pneumoniae (hours), S.P represents the Streptococcus pneumoniae infection group, and S.P+50mg / kg represents the group injected with 50mg / kg pomalidomide after Streptococcus pneumoniae infection;

[0029] Figure 7 It is the improvement effect of pomalidomide on the survival rate of a mouse model of Escherichia coli abdominal infection;

[0030] Among them, Time(h)after E.coliinjection represents the infection time of Escherichia coli (hours), E.coli represents the Escherichia coli infection group, and E.coli+50mg / kg represents the group injected with 50mg / kg pomalidomide after Escherichia coli infection;

[0031] Figure 8 It is the improvement effect of pomalidomide on the survival rate of a mouse model of Enterococcus faecalis abdominal infection;

[0032] Among them, Time(h)after E.faecalis injection represents the infection time of Enterococcus faecalis (hours), E.f represents the Enterococcus faecalis infection group, and E.f+50mg / kg represents the group injected with 50mg / kg pomalidomide after Enterococcus faecalis infection;

[0033] Figure 9 It is the improvement effect of pomalidomide on the lung pathological injury of a mouse model of Enterococcus faecalis abdominal infection;

[0034] Among them, E.faecalis represents Enterococcus faecalis, the same below;

[0035] Figure 10 It is the improvement effect of pomalidomide on the liver pathological injury of a mouse model of Enterococcus faecalis abdominal infection;

[0036] Among them, bleeding represents the bleeding condition score, infiltration represents the inflammatory infiltration condition score, and Total represents the total score of the combination of the former two; Liver injury score represents the liver pathological injury score, and the same applies hereinafter.

[0037] Figure 11 It is the improvement effect of pomalidomide on the renal pathological injury in a mouse model of intra-abdominal infection with Enterococcus faecalis.

[0038] Among them, Hemmorrage represents the bleeding condition score, brush border represents the brush border condition score, Cast represents the cast condition score, and Total represents the total score of the combination of the former three; Kidney injury score represents the renal pathological injury score. Specific implementation manners

[0039] The technical solutions of the present invention will be further described in detail below in conjunction with the accompanying drawings and specific implementation manners.

[0040] Example 1: Improvement of the survival rate of a mouse model with Acinetobacter baumannii pulmonary infection by pomalidomide

[0041] Mice were infected with a lethal dose of Acinetobacter baumannii (ATCC17978) in the lungs. One hour after infection, the mice were divided into four groups, and pomalidomide or an equal volume of solvent was injected into the mice by intraperitoneal administration. Specifically, group A was not given any drug, group B was given 5 mg / kg of pomalidomide, group C was given 20 mg / kg of pomalidomide, and group D was given 50 mg / kg of pomalidomide; at the same time, another group of healthy mice was divided into two groups. Among them, group E was given an equal volume of solvent, and group F was given 50 mg / kg of pomalidomide; the survival rate was observed for 120 h after administration, and the results are shown in Figure 1 .

[0042] As can be seen from Figure 1 that no death occurred in the mice of group E and group F, indicating that the solvent and pomalidomide had no effect on the survival rate of healthy mice. Compared with group A (the 24-h survival rate was 0%), after administration of pomalidomide, the survival rates of the mice in groups B, C, and D were significantly increased and showed a dose-dependence; among them, the 120-h survival rate of the mice in group B was 25%, the 120-h survival rate of the mice in group C was 58.3%, and the 120-h survival rate of the mice in group D was 75%; indicating that pomalidomide can significantly improve the survival rate of mice after Acinetobacter baumannii pulmonary infection and can be used to treat pulmonary infection caused by Acinetobacter baumannii.

[0043] Example 2: Improvement of the bacterial load in the bronchoalveolar lavage fluid (BALF) of a mouse model with Acinetobacter baumannii pulmonary infection by pomalidomide

[0044] Mice were infected with a lethal dose of Acinetobacter baumannii in the lungs. One hour after infection, the mice were divided into two groups. Group A was not given any drug, and Group B was given 50 mg / kg of pomalidomide. At the same time, healthy mice were taken and divided into two groups. Among them, Group C was given an equal volume of solvent, and Group D was given 50 mg / kg of pomalidomide. After 12 hours of infection, the bacterial load in the bronchoalveolar lavage fluid (BALF) of each group of mice was detected. The detection results are shown in Figure 2 .

[0045] As can be seen from Figure 2 , there was basically no bacterial load in the bronchoalveolar lavage fluid of healthy mice in Group C and Group D; while there was bacterial load in the bronchoalveolar lavage fluid of mice in Group A and Group B. Compared with Group A, the bacterial load in the bronchoalveolar lavage fluid of mice in Group B was significantly decreased (P < 0.001) due to the injection of pomalidomide.

[0046] Example 3 Pomalidomide improves the lung pathological damage of a mouse model with Acinetobacter baumannii pulmonary infection

[0047] Mice were infected with a lethal dose of Acinetobacter baumannii in the lungs. One hour after infection, the mice were divided into two groups. Group A was not given any drug, and Group B was given 50 mg / kg of pomalidomide. At the same time, healthy mice were taken and divided into two groups. Among them, Group C was given an equal volume of solvent, and Group D was given 50 mg / kg of pomalidomide. After 12 hours of infection, lung tissue sections were made for each group of mice, and the organ damage of each group of mice was scored histopathologically (evaluated on a scale of 0 - 5 points, with 5 points indicating the most severe damage and 0 points indicating no damage). The scoring results are shown in Figure 3 .

[0048] As can be seen from Figure 3 , there was no damage to the lung tissue of healthy mice in Group C and Group D; while due to the infection with Acinetobacter baumannii, the lungs of mice in Group A and Group B were damaged. However, due to the injection of pomalidomide in Group B mice, the lung pathological damage score of Group B mice was significantly decreased compared with that of Group A (P < 0.001).

[0049] Example 4 Pomalidomide improves the collagen expression in the lung tissue of a mouse model with Acinetobacter baumannii pulmonary infection

[0050] Mice were infected with a lethal dose of Acinetobacter baumannii in the lungs. One hour after infection, the mice were divided into two groups. Group A was not given any drug, and Group B was given 50 mg / kg of pomalidomide. At the same time, healthy mice were taken and divided into two groups. Among them, Group C was given an equal volume of solvent, and Group D was given 50 mg / kg of pomalidomide. After 12 hours of infection, the lung tissues of each group of mice were taken to detect the expression levels of type I collagen and type III collagen. The detection results are shown in Figure 4 and Figure 5 .

[0051] As can be seen from Figure 4 andFigure 5 It can be seen that in the lung tissues of healthy mice in Group C and Group D and infected mice in Group A, the expressions of type I collagen and type III collagen both remained at relatively low levels. However, in Group B mice, due to the injection of pomalidomide, the expression levels of type I collagen and type III collagen were both significantly increased (P < 0.01), indicating that after pomalidomide treatment, the repair ability of lung tissues was enhanced.

[0052] Example 5. Survival rate of mice model with pneumococcal pneumonia improved by pomalidomide

[0053] The lungs of mice were infected with a lethal dose of Streptococcus pneumoniae (ATCC6303). One hour after infection, the mice were divided into two groups. Group A was not given any drug, and Group B was given 50 mg / kg of pomalidomide. At the same time, another group of healthy mice was divided into two groups. Among them, Group C was given an equal volume of solvent, and Group D was given 50 mg / kg of pomalidomide. The survival rate was observed for 120 h after drug administration, and the results are shown in Figure 6 .

[0054] As Figure 6 It can be seen that the mice in Group C and Group D did not die, indicating that the solvent and pomalidomide had no effect on the survival rate of healthy mice. Compared with Group A (the 30-h survival rate was 0%), after pomalidomide was given, the survival rate of Group B mice was significantly increased, reaching 60%. This indicates that pomalidomide can significantly increase the survival rate of mice after pneumococcal pneumonia and can be used to treat lung infections caused by Streptococcus pneumoniae.

[0055] Example 6. Survival rate of mice model with Escherichia coli abdominal infection improved by pomalidomide

[0056] The abdominal cavities of mice were infected with Escherichia coli (ATCC25922). One hour after infection, the mice were divided into two groups. Group A was not given any drug, and Group B was given 50 mg / kg of pomalidomide. At the same time, another group of healthy mice was divided into two groups. Among them, Group C was given an equal volume of solvent, and Group D was given 50 mg / kg of pomalidomide. The survival rate was observed for 120 h after drug administration, and the results are shown in Figure 7 .

[0057] As Figure 7 It can be seen that the mice in Group C and Group D did not die, indicating that the solvent and pomalidomide had no effect on the survival rate of healthy mice. Compared with Group A (the 24-h survival rate was 0%), after pomalidomide was given, the survival rate of Group B mice was significantly increased, reaching 55.5%. This indicates that pomalidomide can significantly increase the survival rate of mice after abdominal Escherichia coli infection and can be used to treat infections caused by Escherichia coli.

[0058] Example 7. Survival rate of mice model with Enterococcus faecalis abdominal infection improved by pomalidomide

[0059] The abdominal cavity of mice was infected with Enterococcus faecalis (ATCC29212). One hour after infection, the mice were divided into two groups. Group A was not given any drug, and Group B was given 50 mg / kg pomalidomide. At the same time, another group of healthy mice was divided into two groups. Among them, Group C was given an equal volume of solvent, and Group D was given 50 mg / kg pomalidomide. The survival rate of the mice was observed 120 hours after drug administration. The results are shown in Figure 7 .

[0060] As Figure 7 can be seen, the mice in Group C and Group D did not die, indicating that the solvent and pomalidomide had no effect on the survival rate of healthy mice. Compared with Group A (the 24-hour survival rate was 0%), after administration of pomalidomide, the survival rate of the mice in Group B was significantly increased, reaching 55.5%. It shows that pomalidomide can significantly improve the survival rate of mice after abdominal cavity infection with Enterococcus faecalis and can be used to treat infections caused by Enterococcus faecalis.

[0061] Example 8 Pomalidomide improves the pathological damage of the lungs, livers and kidneys in a mouse model of abdominal Enterococcus faecalis infection

[0062] The abdominal cavity of mice was infected with Enterococcus faecalis (ATCC29212). One hour after infection, the mice were divided into two groups. Group A was not given any drug, and Group B was given 50 mg / kg pomalidomide. At the same time, another group of healthy mice was divided into two groups. Among them, Group C was given an equal volume of solvent, and Group D was given 50 mg / kg pomalidomide;

[0063] After 12 hours of infection, lung tissue, liver tissue and kidney tissue sections of the mice in each group were obtained, and the organ damage of the mice in each group was scored by histopathology. The scoring results are shown in Figure 8 , Figure 9 and Figure 10 .

[0064] As Figure 9 can be seen, there was no damage to the lung tissue of the healthy mice in Group C and Group D. However, due to the infection with Enterococcus faecalis, the lungs of the mice in Group A and Group B were damaged. However, since the mice in Group B were injected with pomalidomide, the lung pathological damage score of the mice in Group B was significantly decreased compared with that in Group A (P < 0.001).

[0065] As Figure 10 can be seen, there was no damage to the liver tissue of the healthy mice in Group C and Group D. However, compared with Group A, since the mice in Group B were injected with pomalidomide, the pathological score of the liver of the mice in Group B was significantly decreased (P < 0.0001).

[0066] As Figure 11 can be seen, there was no damage to the kidney tissue of the healthy mice in Group C and Group D. However, compared with Group A, since the mice in Group B were injected with pomalidomide, the pathological score of the kidney of the mice in Group B was significantly decreased (P < 0.0001).

Claims

1. Use of pomalidomide in the preparation of antibacterial drugs, characterized in that, The bacterium described above is Acinetobacter baumannii Acinetobacter baumannii , Escherichia coli Escherichia coli and Enterococcus faecalis Enterococcus faecalis and at least one of them 2. The application according to claim 1, characterized in that, Bacterial infection in the lungs or abdomen.

3. Use of pomalidomide in the preparation of a therapeutic drug for organ injury caused by bacterial infection, characterized in that, The bacteria described above are Acinetobacter baumannii Acinetobacter baumannii , Escherichia coli Escherichia coli and Enterococcus faecalis Enterococcus faecalis and at least one of them.

4. The application according to claim 3, wherein The organ damage includes at least one of liver damage, lung damage and kidney damage.

5. Use of pomalidomide in the preparation of a drug for promoting tissue repair after bacterial infection, characterized in that, The tissue repair drug described above is a lung tissue repair drug; the bacterial infection is Acinetobacter baumannii Acinetobacter baumannii infection.

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