Use of sanguinarine in the preparation of a drug for preventing and treating clinical rare fungal-related infectious diseases

Abstract

The present application relates to the application of sanguinarine in the preparation of drugs for preventing and treating rare clinical fungal infection diseases. Apiotrichum mycotoxinivorans has been confirmed to have the ability to infect humans, and current research confirms that the fungus is at least associated with postoperative pulmonary infection and blood infection diseases. Since the above fungus is still a rare clinical pathogenic bacterium, there is no clear and feasible treatment drug at present. Based on the advantages of low toxicity and side effects of natural drugs and mild efficacy, the present application screens natural drugs with bacteriostatic effect, and provides the application of sanguinarine as a fungus inhibitor, which has good clinical application prospect.

Description

Technical Field

[0001] This invention belongs to the field of antifungal drug technology, specifically relating to the application of sanguinarine in the preparation of drugs for the prevention and treatment of Apiotrichummycotoxinivorans, a rare clinical fungal-associated infectious disease. Background Technology

[0002] The information disclosed in this background section is intended only to enhance understanding of the overall background of the invention and is not necessarily to be construed as an admission or in any way implying that such information constitutes prior art known to those skilled in the art.

[0003] Sanguinarine, mainly found in the whole plant of Celandine, the tuberous root of Corydalis, the whole plant of Bok Choy, and the aerial parts of Bloodwort, is a bensulfanilidine isoquinoline alkaloid with various pharmacological activities such as antibacterial, anti-inflammatory, antioxidant, liver function improvement, immunity enhancement, and antitumor effects.

[0004] Apiotrichum mycotoxinivorans, formerly known as Trichosporon mycotoxinivorans, is commonly used to degrade mycotoxins in livestock feed. In 2009, Apiotrichum mycotoxinivorans was isolated from the sputum of a cystic fibrosis (CF) patient in the United States who developed chronic pneumonia after an acute exacerbation, marking the first reported case of human infection with Apiotrichum mycotoxinivorans. Current research has confirmed that Apiotrichum mycotoxinivorans can infect humans and cause various diseases with a high mortality rate. However, this fungus remains clinically rare, and there are currently no effective drug treatments to inhibit infections caused by it. Summary of the Invention

[0005] In light of the current state of research, this invention argues that natural compounds, as antibacterial agents, possess advantages such as low toxicity and side effects, mild therapeutic effects, and low likelihood of drug resistance, making them an important method for antibacterial agent screening. Therefore, this invention designs and provides an inhibitor of *Apiotrichum mycotoxinivorans*, screening for feasible antibacterial active ingredients from natural compounds. Based on this approach, research in this invention demonstrates that sanguinarine exhibits good inhibitory activity against various *Apiotrichum mycotoxinivorans* strains, and holds promise for application in the preparation of related antifungal drugs, achieving inhibitory effects against this clinically rare fungus, *Apiotrichummycotoxinivorans*.

[0006] Specifically, the present invention provides the following technical solution:

[0007] Firstly, it provides the application of sanguinarine in the preparation of drugs for the prevention and treatment of infectious diseases related to Apiotrichum mycotoxinivorans.

[0008] The sanguinarine mentioned in the above scheme includes the alkaloid compound with CAS number 2447-54-3, as well as related derivatives of sanguinarine, such as ethoxysanguinarine (CAS: 28342-31-6), sanguinarine hydrochloride (CAS: 5578-73-4), sanguinarine citrate (CAS: 132210-34-5), and dihydrosanguinarine (CAS: 3606-45-9).

[0009] The infectious diseases associated with Apiotrichum mycotoxinivorans include, but are not limited to, one or more of the following: lung infection, pulmonary fibrosis, bacteremia, and sepsis.

[0010] Preferably, the specific forms of the above applications include, but are not limited to, any one of the following;

[0011] (1) Applying sanguinarine to the lesion site can prevent, alleviate or cure diseases caused by Apiotrichummycotoxinivorans infection;

[0012] (2) Use sanguinarine to prepare related drugs against Apiotrichum mycotoxinivorans.

[0013] In aspect (1) above, the method of “application” includes, but is not limited to, oral administration, inhalation, intravenous injection or surgical procedures such as intervention, and the dosage of the application is subject to adjustment according to the target of application and the purpose of application.

[0014] In aspect (2) above, the drug includes therapeutic drugs and model drugs; wherein, the purpose of the application of therapeutic drugs is mainly to prevent, alleviate or cure the related symptoms caused by Apiotrichum mycotoxinivorans infection; the model drugs are used to prepare Apiotrichum mycotoxinivorans activity inhibition models, and the feasible application purposes of the models are such as screening of active antibacterial components, research on fungal infection mechanisms, etc.

[0015] In a second aspect, a pharmaceutical composition is provided, characterized in that the pharmaceutical composition comprises an active dose of sanguinarine and a pharmaceutically necessary carrier.

[0016] The feasible dosage forms of the pharmaceutical composition include solid dosage forms, liquid dosage forms, and aerosols; wherein, specific examples of solid dosage forms include tablets, capsules, granules, powders, ointments, emulsions, or patches; and specific examples of liquid dosage forms include solutions and suspensions.

[0017] In the case of solid dosage forms, feasible carriers include excipients, lubricants, binders, disintegrants, etc., and preservatives, antioxidants, colorants, sweeteners or additives may also be added as needed.

[0018] In the case of liquid formulations, feasible carriers include solvents, solubilizers, suspending agents, tensioning agents, buffers, soothing agents, preservatives, or antioxidants.

[0019] Thirdly, a medicament for treating Apiotrichum mycotoxinivorans infection is provided, the medicament comprising the pharmaceutical composition described in the second aspect.

[0020] In the pharmaceutical composition described in the second aspect and the pharmaceutical product described in the third aspect, the content of sanguinarine should be an effective dose, and its dose range may be 1%-99% of the total mass of the pharmaceutical product, further 10%-80%, even further 20%-70%, and more preferably, such as 30%-50% or 40%-60%.

[0021] In the verified embodiments of the present invention, the MIC of sanguinarine inhibiting Apiotrichum mycotoxinivorans is 4-16 μg / mL. Correspondingly, the dosage of sanguinarine in the drug is a technical content that can be routinely adjusted by those skilled in the art based on factors such as the purpose of application, method of application, and target of application.

[0022] The beneficial effects of one or more of the above technical solutions are:

[0023] Apiotrichum mycotoxinivorans is a clinically rare pathogenic fungus associated with diseases such as lung infections, bacteremia, and sepsis. To provide feasible clinical treatments for these fungi, this invention screened natural compounds and determined that sanguinarine exhibits inhibitory effects on multiple strains of Apiotrichum mycotoxinivorans, showing promise for application in antifungal drug development and providing a viable treatment option for rare fungal infections. Attached Figure Description

[0024] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. Exemplary embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0025] Figure 1 The antibacterial activity of the five natural products against AM1 was determined as described in the examples;

[0026] Figure 2 The antibacterial activity of the five natural products against AM2 was determined as described in the examples. Detailed Implementation

[0027] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0028] It should be noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to limit the scope of exemplary embodiments according to the invention. As used herein, the singular form is intended to include the plural form as well, unless the context clearly indicates otherwise. Furthermore, it should be understood that when the terms "comprising" and / or "including" are used in this specification, they indicate the presence of features, steps, operations, devices, components, and / or combinations thereof.

[0029] To enable those skilled in the art to better understand the technical solution of the present invention, the technical solution of the present invention will be described in detail below with reference to specific embodiments.

[0030] 1. Materials and Methods

[0031] 1.1 Main strains and reagents

[0032] Two experimental strains, *Apiotrichum mycotoxinivorans* (AM1 and AM2), were isolated from clinical patients (the strains were donated by Professor Wang Shifu of the Children's Hospital Affiliated to Shandong University). All strains were identified by mass spectrometry and 18S assay. *Candida albicans* ATCC10231 was used as the quality control strain for quality control throughout the entire experimental process.

[0033] Sanguisorbine (CAS No.: 2447-54-3), chelidonine (CAS No.: 3895-92-9), cinnamon chloride (CAS No.: 13063-04-2), epigallocatechin gallate (CAS No.: 989-51-5), mangiferin (CAS No.: 4773-96-0), Sabouraud dextrose peptone agar plates, RPIM 1640 medium.

[0034] 1.2 Drug susceptibility testing and judgment criteria

[0035] Using the microdilution method recommended by the Clinical and Laboratory Standards Institute (CLSI) M27-A3, the suspensions of the fungi to be tested (AM1, AM2) were diluted (2 × 10⁻⁶). 3 The concentrations of the test compound (CFU / mL) were transferred to 96-well plates, and different concentrations of the test compound were added. The 96-well plates were incubated in a fungal incubator at 35°C for 24 hours. After incubation, the minimum inhibitory concentration (MIC) of the compound against fungi was determined by a combination of visual interpretation and microplate reader analysis. The MIC is the lowest concentration of the compound that inhibits fungal growth by more than 80% compared to the growth control. Visual interpretation was performed by two experienced researchers under natural light. The standard strain *Candida albicans* ATCC10231 was used as the quality control strain.

[0036] 2. Experimental Results

[0037] The MICs for anti-AM1 effects of sanguisorbin, chelidonine, zeaxanthin chloride, epigallocatechin gallate, and mangiferin were 4 μg / mL, 4 μg / mL, 4 μg / mL, 16 μg / mL, and >128 μg / mL, respectively. Figure 1 (Table 1)

[0038] like Figure 1 As shown in the red box, the natural compounds in the wells significantly inhibited fungal growth. Among them, sanguisorbin, celandine, zeaxanthin chloride, and epigallocatechin gallate all showed certain inhibitory effects on strain AM1; in particular, sanguisorbin, celandine, and zeaxanthin chloride at 4 μg / mL showed high antibacterial activity.

[0039] Table 1. MIC of five natural compounds against AM1

[0040]

[0041]

[0042] The MICs for anti-AM2 effects of sanguisorbin, chelidonine, zeaxanthin chloride, epigallocatechin gallate, and mangiferin were 16 μg / mL, >128 μg / mL, >128 μg / mL, >128 μg / mL, and >128 μg / mL, respectively. Figure 2 (Table 2). For example... Figure 2 As shown in the red box, the natural compounds significantly inhibited fungal growth in the wells. In the inhibition experiment against strain AM2, only sanguinarine showed significant antibacterial activity, with 16 μg / mL of sanguinarine inhibiting fungal growth by more than 80%.

[0043] Table 2. MICs of five natural compounds against AM2

[0044]

[0045] 3. Experimental Conclusions

[0046] Sanguinarine can significantly inhibit Apiotrichum mycotoxinivorans, a clinically rare fungus, with a MIC of 4-16 μg / mL.

[0047] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. Sanguisorbin in the preparation of preventive and therapeutic drugs Apiotrichum mycotoxinivorans The use of sanguinarine in drugs for infectious diseases, wherein sanguinarine is an alkaloid compound with CAS number 2447-54-3.

2. The sanguinarine as described in claim 1 in the preparation of preventive and therapeutic drugs Apiotrichum mycotoxinivorans Its application in drugs for infectious diseases is characterized by, The Apiotrichum mycotoxinivorans Infectious diseases are selected from one or more of the following: lung infection, pulmonary fibrosis, bacteremia, and sepsis.

3. The sanguinarine as described in claim 1 in the preparation of preventive and therapeutic drugs Apiotrichum mycotoxinivorans Its application in drugs for infectious diseases is characterized by, The drug can be administered orally, by inhalation, or by intravenous injection.

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