CN119235831A - Application of Pentamidine in the treatment of Mycobacterium abscessus infection - Google Patents
Application of Pentamidine in the treatment of Mycobacterium abscessus infection Download PDFInfo
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- CN119235831A CN119235831A CN202411621991.5A CN202411621991A CN119235831A CN 119235831 A CN119235831 A CN 119235831A CN 202411621991 A CN202411621991 A CN 202411621991A CN 119235831 A CN119235831 A CN 119235831A
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- mycobacterium abscessus
- mycobacterium
- pentamidine
- infection
- abscessus
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Abstract
本发明属于生物医药技术领域，具体涉及一种芳香双脒类药物在抗脓肿分枝杆菌感染中的应用。本发明中的喷他脒对脓肿分枝杆菌标准菌株和临床分离株均具有较好的抑菌效果；对脓肿分枝杆菌标准菌株MIC可达8μg/mL，对脓肿分枝杆菌临床分离株MIC最好可达2μg/mL，拓宽了喷他脒的应用领域，为脓肿分枝杆菌感染治疗提供了新方法。The present invention belongs to the field of biomedicine technology, and specifically relates to an application of an aromatic biguanide drug in anti-abscess mycobacterium infection. The pentamidine in the present invention has a good antibacterial effect on both the standard strain and clinical isolate of mycobacterium abscess; the MIC of the standard strain of mycobacterium abscess can reach 8 μg/mL, and the MIC of the clinical isolate of mycobacterium abscess can reach 2 μg/mL at best, which broadens the application field of pentamidine and provides a new method for the treatment of mycobacterium abscess infection.
Description
Technical Field
The invention belongs to the technical field of biological medicines, and particularly relates to application of an aromatic diamidine medicine in resisting infection of mycobacterium abscessus.
Background
Nontuberculous mycobacteria (nontuberculous mycobacteria, NTM) refers to the collective term for all mycobacteria except for the Mycobacterium tuberculosis complex and Mycobacterium leprae. The incidence of NTM pulmonary infections and related mortality continue to increase worldwide (Non-tuberculous mycobacterial pulmonary disease [ J ]. Eur Respir J,2019,54 (1): 1900250.). NTM is divided into fast-growing mycobacteria and slow-growing mycobacteria, with mycobacterium abscessus (Mycobacterium abscessum, MAB) being the most common human pathogenic fast-growing mycobacteria. MAB is one of the most difficult non-tuberculosis mycobacteria to treat, natural drug resistance exists for most antibiotics, the recommended therapeutic drugs of American thoracic society, chinese medical society tuberculosis meeting, chinese anti-tuberculosis society and the like are only a limited few antibiotics, most of patients still fail to treat the patients though long treatment course and high cost are achieved by adopting the injection drugs (Prevalence and speciation of non-tuberculous mycobacteria among pulmonary and extrapulmonary tuberculosis suspects in South India[J].J Infect Public Health,2021,14(3):320-323.)., the cure rate is less than 30%, the recurrence rate is high (tidrug-resistant Mycobacterium abscessus threatens patients with cystic fibrosis[J].Lancet Respir Med,2017,5(1):15.)., and the problems of natural drug resistance of MAB to most antibiotics, high occurrence rate of the existing effective drug adverse reaction and poor patient compliance are related to long treatment course and most of intravenous drug administration. There is an urgent need to develop a therapeutically effective, low incidence of adverse reactions and good compliance drug for the treatment of MAB. The mycobacterium abscessus has a special drug-resistant mechanism, so that the drug-resistant spectrum of the mycobacterium abscessus is wider than that of other microorganisms. Resistance can be divided into two categories, natural resistance and acquired resistance, where acquired resistance is mostly caused by genetic mutations due to exposure to the antibiotic environment. Fully digs the anti-abscess mycobacteria activity of the existing compound or antibiotics, and is also a high-efficiency way for developing anti-abscess mycobacteria medicines.
Pentamidine (PENTAMIDINE) is an antiparasitic drug, which is an aromatic diamidine chemical synthetic drug with a half-life of 0.5-1h. The isethionate (isethionate pentamidine) is commonly used in clinic, and the isethionate pentamidine has a direct killing effect on leishmania, is an effective medicament for treating kaleidosis, and can also be used for the early treatment of African trypanosomiasis and the treatment of pulmonary inflammation caused by pneumocystis carinii (Zhao, yang Yihong, zhang Hang, and the like). In addition, it was found that pentamidine has an antitumor effect, and that pentamidine can inhibit the proliferation of various tumor cells including malignant melanoma, prostate cancer, rectal cancer, breast cancer, etc. in vitro (Wu Yanyin, zhang Mingyue, ding Hong, etc. the inhibition of pentamidine on human ovarian cancer CAOV3 cells was studied [ J ]. Southeast national defense medicine, 2012,14 (1): 27-28.). At present, related reports of the pentamidine inhibiting mycobacterium abscessus are not available.
Disclosure of Invention
The present invention has been completed based on the finding that pentamidine has an effect of inhibiting the activity of mycobacterium abscessus.
In a first aspect, the invention provides the use of pentamidine for the preparation of a product for inhibiting mycobacterium abscessus.
Further, the mycobacterium abscessus includes a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus, or a mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
Further, the mycobacteria-inhibiting products include medical products or non-medical products.
Further, the medical product refers to a medical drug, and the non-medical product refers to an experimental reagent or a bacteriostatic agent.
Further, one or more pharmaceutically acceptable carriers or excipients may be added to the product.
Still further, the carrier material includes, but is not limited to, one or more of a water-soluble carrier material, a poorly soluble carrier material, and/or an enteric carrier material.
Further, the water-soluble carrier material includes, but is not limited to, one or more of polyethylene glycol, polyvinylpyrrolidone, and/or an organic acid.
Further, the poorly soluble carrier materials include, but are not limited to, one or more of ethylcellulose and/or cholesterol stearate.
Further, the enteric carrier material includes, but is not limited to, one or more of cellulose acetate phthalate and/or carboxymethyl ethyl cellulose.
Further, the product may be formulated into a variety of dosage forms including, but not limited to, one or more of tablets, capsules, drops, aerosols, pills, powders, solutions, suspensions, granules, liposomes, transdermal agents, buccal tablets, suppositories, and/or lyophilized powder for injection.
In a second aspect, the present invention provides the use of pentamidine for the manufacture of a medicament for the prophylaxis and/or treatment of a disease caused by infection with mycobacterium abscessus, said pentamidine acting by inhibiting the activity of mycobacterium abscessus.
Further, the mycobacterium abscessus comprises a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus or mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
Further, one or more pharmaceutically acceptable carriers or excipients can be added into the medicine for preventing and/or treating diseases caused by the infection of the mycobacterium abscessus.
Still further, the carrier material includes, but is not limited to, one or more of a water-soluble carrier material, a poorly soluble carrier material, and/or an enteric carrier material.
Further, the medicament for preventing and/or treating diseases caused by mycobacterium tuberculosis infection can be prepared into various dosage forms, including but not limited to one or more of tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, granules, liposomes, transdermal agents, buccal tablets, suppositories and/or freeze-dried powder injection.
Still further, the formulation may be one or more of a general formulation, a slow release formulation, a controlled release formulation, and/or various microparticle delivery systems.
Further, the various formulations may also incorporate colorants, preservatives, flavors, flavoring agents, sweeteners, or other materials into the pharmaceutical formulation as desired.
Further, the agent for preventing and/or treating a disease caused by infection with mycobacterium abscess may be administered by injection, by luminal administration, by respiratory administration or by mucosal administration.
Still further, the administration of injections includes subcutaneous injections, intravenous injections, intramuscular injections, and intra-luminal injections.
In a third aspect, the present invention provides a pharmaceutical composition comprising pentamidine and another drug against mycobacterial infection, said pharmaceutical composition having at least one of the following efficacy:
a) Inhibiting mycobacteria abscesses activity;
b) Anti-mycobacterial abscess infections;
c) Preventing and/or treating diseases caused by mycobacterium abscessus.
Further, the mycobacterium abscessus comprises a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus or mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
Further, the other anti-mycobacterial infection agent includes one or more of an antibiotic and other agents that can facilitate inhibiting or killing mycobacteria abscess or enhancing patient resistance.
Still further, the antibiotic comprises one or more of clofazimine, bedaquiline, fusidic acid, clarithromycin, azithromycin, cefoxitin, amikacin, tigecycline, phenelzine and fidaxomycin, and the other drug comprises one or more of vitamins, amino acids, proteins or minerals.
Further, one or more pharmaceutically acceptable carriers may be added to the pharmaceutical composition.
Furthermore, the pharmaceutical composition can be prepared into various forms such as injection, tablet, powder, granule, capsule, oral liquid or pharmaceutical excipients, and the medicaments of the various forms can be prepared according to the conventional method in the pharmaceutical field.
Further, the pharmaceutical composition may be introduced into the body by injection, permeation, absorption, physical or chemical mediated methods, such as intramuscular, intradermal, subcutaneous, intravenous or mucosal tissue, or may be introduced into the body after being mixed or encapsulated with other substances.
Advantageous effects
The pentamidine has good antibacterial effect on standard strains and clinical isolates of the mycobacterium abscessus, the MIC of the standard strains of the mycobacterium abscessus can reach 8 mug/mL, and the MIC of the clinical isolates of the mycobacterium abscessus can reach 2 mug/mL.
The invention widens the application field of the pentamidine and provides a new method for treating the infection of the mycobacterium abscessus.
Detailed Description
The following describes the invention in more detail. The description of these embodiments is provided to assist understanding of the present invention, but is not intended to limit the present invention. In addition, the technical features of the embodiments described below may be combined with each other as long as they do not collide with each other.
The experimental methods in the following examples, unless otherwise specified, are conventional, and the experimental materials used in the following examples, unless otherwise specified, are commercially available.
Description of materials
1. Ma's turbidimetric tube
The McFarland turbidimeter tube is a standard turbidimeter tube for different turbidimeters of microorganisms, and is prepared according to the proportion of sulfuric acid and barium chloride, and specifically comprises the following steps:
2. Test strains and drugs
The standard strain of Mycobacterium abscessum ATCC 19977.
The molecular formula of the pentamidine is C 19H24N4O2, and the structural formula is as follows:
The molecular formula of the pentamidine isethionate (PENTAMIDINE ISETHIONATE) is C 23H36N4O10S2, and the structural formula is as follows:
3. test drug conversion
Pentamidine isethionate having a molecular weight of 592.68g/mol, wherein the molecular weight of isethionic acid is 125.12g/mol, the potency of pentamidine in pentamidine isethionate is calculated to be 79.06%, and according to the calculated potency, 16.19mg of pentamidine isethionate (pentamidine content 12.8 mg) is weighed and 1ml of DMSO is added to prepare a pentamidine drug stock solution having a final concentration of 12.8 mg/ml. The mixture was diluted to a working solution having a concentration of 256. Mu.g/ml at a ratio of 1:50.
Example 1 detection of bacteriostatic Activity of pentamidine against Mycobacterium abscessum Standard Strain
1.1 Preparation of Mycobacterium abscessum Standard Strain suspension
Inoculating a standard strain of mycobacterium abscess (ATCC 19977) to a culture medium, scraping a colony, placing the colony into a fungus grinding bottle, and diluting the colony to the turbidity of 0.5 Mitsubishi tube by 1:200 for later use.
1.2 Minimum Inhibitory Concentration (MIC)
(1) 100 Mu LMueller Hinton (MH) medium was added to 96-well plates;
(2) Adding sequentially gradient diluted medicines into 1-11 rows;
(3) Adding diluted standard bacterial suspension of Mycobacterium abscessum into 1-11 columns to obtain bacterial solution with final concentration of 4× 5 CFU/mL, and culturing with final drug concentration in each well shown in Table 1;
(4) Adding 30 mu L of resazurin chromogenic liquid, and observing the color change of the pore plate after culturing;
(5) The lowest inhibitory concentration (Minimal inhibitory concentration, MIC) was read.
TABLE 1 drug concentration of pentamidine
| Column number | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 |
| Drug concentration (μg/mL) | 64 | 32 | 16 | 8 | 4 | 2 | 1 | 0.5 | 0.25 | 0.125 | 0.0625 | 0 |
MIC is the concentration of drug that inhibits 90% of colony growth. The blue wells were sterile grown and the pink wells were bacterial grown, and the lowest drug concentration that prevented the color from changing from blue to pink was noted as MIC that inhibited bacterial growth.
The positive control is a fungus-containing culture medium without medicine, namely column 12, and the other 96-well plate is taken, and the culture medium without medicine and fungus liquid is added, namely the negative control. MIC data for this batch was valid when the positive control was pink and the negative control was blue.
1.3 Test results
The MIC of pentamidine for the standard strain of Mycobacterium abscessum was 8. Mu.g/mL.
Example 2 detection of bacteriostatic Activity of pentamidine on clinically isolated Mycobacterium abscessum Strain
2.1 Test samples and methods
Clinical isolation of strains 34 strains isolated and cultured from sputum specimens of patients infected with Mycobacterium abscessum were identified as Mycobacterium abscessum by sequencing of 16SrRNA, hsp65, rpoB and 16-23S rRNA interarea.
In vitro bacteriostatic activity of pentamidine on 34 clinical isolates of mycobacterium abscessus was examined as in example 1.
2.2 Test results
MIC results of pentamidine on clinical isolates of Mycobacterium abscessum are shown in Table 2, and MIC concentration profile statistics are shown in Table 3.
TABLE 2 MIC of pentamidine for clinical isolates of Mycobacterium abscessum
TABLE 3 statistical results of MIC concentration distribution
| Drug concentration (μg/mL) | 0.0625 | 0.125 | 0.25 | 0.5 | 1 | 2 | 4 | 8 | 16 | 32 |
| Number of bacterial plants (strain) | 0 | 0 | 0 | 0 | 0 | 2 | 0 | 8 | 24 | 0 |
The result shows that the pentamidine has better antibacterial activity on clinical isolates of mycobacterium abscessus, and the MIC distribution range is 2-16 mug/mL, and can reach 2 mug/mL best.
Claims (10)
1. The application of the pentamidine in preparing a mycobacterium abscessus inhibiting product is characterized in that the molecular formula of the pentamidine is C 19H24N4O2, and the structural formula is as follows:
2. The use of claim 1, wherein the mycobacterium abscessus comprises a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus, or a mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
3. The use according to any one of claims 1 or 2, wherein the mycobacteria inhibiting product comprises a medical product or a non-medical product, wherein the medical product is a medical drug and the non-medical product is an experimental agent or a bacteriostatic agent.
4. Use of pentamidine for the manufacture of a medicament for the prevention and/or treatment of a disease caused by infection with mycobacterium abscessus, said pentamidine acting by inhibiting the activity of mycobacterium abscessus.
5. The use of claim 4, wherein the mycobacterium abscessus comprises a standard strain of mycobacterium abscessus, a clinical isolate of mycobacterium abscessus, or a mycobacterium abscessus carried by a patient infected with mycobacterium abscessus.
6. The use according to any one of claims 4 or 5, wherein the medicament for preventing and/or treating diseases caused by mycobacterium tuberculosis infection can be prepared into various dosage forms, including but not limited to one or more of tablets, capsules, dripping pills, aerosols, pills, powders, solutions, suspensions, granules, liposomes, transdermal agents, buccal tablets, suppositories and/or freeze-dried powder injection.
7. The use according to any one of claims 4 to 6, wherein the medicament for preventing and/or treating a disease caused by infection with mycobacterium abscessus is administered by injection, by luminal, respiratory or mucosal administration.
8. A pharmaceutical composition comprising pentamidine and another drug against mycobacterial abscess infection, said pharmaceutical composition having at least one of the following efficacy:
a) Inhibiting mycobacteria abscesses activity;
b) Anti-mycobacterial abscess infections;
c) Preventing and/or treating diseases caused by mycobacterium abscessus.
9. The pharmaceutical composition of claim 8, wherein the additional anti-mycobacterial infection agent comprises one or more of an antibiotic and other agents that can facilitate inhibition or killing of mycobacteria abscess or increase patient resistance.
10. The pharmaceutical composition of claim 9, wherein the antibiotic comprises one or more of clofazimine, bedaquiline, fusidic acid, clarithromycin, azithromycin, cefoxitin, amikacin, tigecycline, phenelzine, and fidaxomycin, and wherein the other drug comprises one or more of vitamins, amino acids, proteins, or minerals.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180243333A1 (en) * | 2017-02-02 | 2018-08-30 | Mcmaster University | Bicarbonate as a potentiator for antimicrobial agents |
| CN114845708A (en) * | 2019-12-19 | 2022-08-02 | 乔治亚州大学研究基金会 | Compounds for treating bacterial infections and enhancing antibiotics |
| WO2023077235A1 (en) * | 2021-11-05 | 2023-05-11 | Mcmaster University | Pentamidine analogs |
| US20230391727A1 (en) * | 2020-10-22 | 2023-12-07 | Auransa Inc. | Analogues of pentamidine and methods for treating infections |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20180243333A1 (en) * | 2017-02-02 | 2018-08-30 | Mcmaster University | Bicarbonate as a potentiator for antimicrobial agents |
| CN114845708A (en) * | 2019-12-19 | 2022-08-02 | 乔治亚州大学研究基金会 | Compounds for treating bacterial infections and enhancing antibiotics |
| US20230391727A1 (en) * | 2020-10-22 | 2023-12-07 | Auransa Inc. | Analogues of pentamidine and methods for treating infections |
| WO2023077235A1 (en) * | 2021-11-05 | 2023-05-11 | Mcmaster University | Pentamidine analogs |
Non-Patent Citations (2)
| Title |
|---|
| HU, J. 等: "Encephalomyelitis Caused by Balamuthia mandrillaris in a Woman With Breast Cancer: A Case Report and Review of the Literature", FRONTIERS IN IMMUNOLOGY, vol. 12, 5 January 2022 (2022-01-05), pages 1 - 7 * |
| KOTTHAUS, J. 等: "New Prodrugs of the Antiprotozoal Drug Pentamidine", CHEMMEDCHEM, vol. 6, 31 December 2011 (2011-12-31), pages 2233 - 2242, XP055631557, DOI: 10.1002/cmdc.201100422 * |
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