Use of sodium sulphanthine in the preparation of a medicament for the treatment and / or prevention of a multi-drug resistant bacterial infection

Abstract

The application discloses application of sodium sulamyd in preparation of a medicine for treating and / or preventing multiple drug-resistant bacteria infection. It is found that sodium sulamyd can be combined with a conservative ligand binding interface of a bacterial dCACHE type chemotactic receptor protein family with high affinity, effectively blocks the chemotactic movement of bacteria to host macrophages, reduces the pathogenicity of bacteria, and significantly inhibits multiple drug-resistant bacteria infection in and out of the body. The broad-spectrum anti-drug-resistant bacteria activity of sodium sulamyd is verified by taking carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli and carbapenem-resistant Pseudomonas aeruginosa as representatives, and based on the high conservation of the target, sodium sulamyd has broad-spectrum antibacterial potential for multiple drug-resistant bacteria carrying the target. And it is proved by long-term drug pressure screening experiment that sodium sulamyd is not easy to induce bacteria to produce acquired drug resistance, and has long-term treatment potential. The application provides a new treatment strategy for fighting multiple drug-resistant bacteria infection, and has very high clinical conversion value and commercial development potential.

Description

Technical Field

[0001] This invention relates to novel pharmaceutical uses of suramin sodium, and more particularly to its application in the preparation of drugs for inhibiting multidrug-resistant bacterial infections, reducing bacterial pathogenicity, and improving the survival rate of infected hosts. This invention belongs to the field of biomedical technology. Background Technology

[0002] Multidrug-resistant bacterial infections pose a significant and serious challenge to global public health. Commonly seen drug-resistant bacteria in clinical practice, such as carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa, are prone to causing severe infections due to their strong resistance and widespread transmission, leading to significantly increased patient mortality and posing a major challenge to clinical treatment. Currently used antimicrobial drugs primarily target classic targets such as bacterial cell wall synthesis, nucleic acid replication, and protein synthesis. Long-term and widespread use of these drugs easily induces bacterial resistance, and the development of novel antimicrobial drugs lags far behind the evolutionary rate of drug-resistant bacteria. Therefore, discovering novel anti-infective drug targets and developing new therapeutic agents is crucial to solving the antimicrobial resistance crisis.

[0003] Suramin sodium (molecular formula C) 51 H 34 N6Na6O 23 S6 (molecular weight approximately 1429 Da) is a polysulfated naphthaleneurea compound that has long been used clinically to treat African trypanosomiasis and onchocerciasis. Recent studies have discovered that sulamine sodium also possesses various biological activities, including antitumor and antiviral activity. However, the novel use of sulamine sodium to combat multidrug-resistant bacterial infections by inhibiting the function of the bacterial dCACHE-type chemokine receptor protein family has not yet been reported.

[0004] In previous research, the inventors first revealed that the bacterial dCACHE-type chemotactic receptor protein family (Yersinia pseudotuberculosis YcrA and its homologous proteins) is a key receptor mediating bacterial chemotaxis towards macrophages. Its conserved ligand-binding interface (containing a conserved motif as shown in SEQ ID NO:1 and five key amino acid residues R120, W122, Y138, D140, and D167) can serve as a drug target against multidrug-resistant bacteria (see Chinese patent application CN122277682A). Based on this, the inventors further screened and found that suramin sodium can bind to this conserved interface with high affinity, effectively blocking bacterial chemotactic movement, reducing bacterial pathogenicity, and demonstrating significant therapeutic effects in various drug-resistant bacterial infection models. Summary of the Invention

[0005] The present invention aims to provide new pharmaceutical uses of suramin sodium or its pharmaceutically acceptable salts, hydrates or solvates, particularly in the preparation of medicaments for inhibiting multidrug-resistant bacterial infections, reducing bacterial pathogenicity and improving the survival rate of infected hosts.

[0006] Another objective of this invention is to provide a novel pharmaceutical use for sulamine sodium in treating multidrug-resistant bacterial infections without inducing drug resistance. Sulamine sodium targets the conserved chemokine receptor protein interface of bacteria without affecting bacterial growth, fundamentally reducing the risk of drug resistance. Experimental verification has shown that various multidrug-resistant bacteria have not developed detectable drug resistance even after being passaged for more than 200 generations under drug pressure.

[0007] To achieve the above objectives, the present invention employs the following technical means:

[0008] This invention first proposes the use of suramin sodium or its pharmaceutically acceptable salts, hydrates or solvates in the preparation of medicaments for the treatment and / or prevention of multidrug-resistant bacterial infections.

[0009] Preferably, the drug does not induce detectable acquired resistance in the multidrug-resistant bacteria; preferably, the acquired resistance is acquired resistance against its antiviral activity; more preferably, after the multidrug-resistant bacteria have been continuously passaged for more than 200 generations in an environment containing the drug, treatment with the drug can still significantly improve the survival rate of the infected host.

[0010] Preferably, the treatment includes administration at an early stage of infection (e.g., 2 hours after infection) or delayed until 8 hours after infection, both of which can significantly improve the survival rate of hosts infected with multidrug-resistant bacteria.

[0011] Preferably, the multidrug-resistant bacteria are bacteria carrying dCACHE-type chemokine receptor proteins.

[0012] Preferably, the dCACHE-type chemokine receptor protein satisfies at least one of the following conditions:

[0013] (a) Contains an amino acid sequence that has at least 70% sequence identity with the conserved motif shown in SEQ ID NO:1;

[0014] (b) Contains a conserved ligand-binding interface, wherein the conserved ligand-binding interface comprises at least a positively charged amino acid residue at the entrance of the binding pocket, an aromatic amino acid residue at the hydrophobic core, and a negatively charged amino acid residue at the bottom of the binding interface; wherein the positively charged amino acid residue is structurally and functionally equivalent to arginine at position 120 (R120) of the dCACHE-type chemokine receptor protein YcrA of *Yersinia pseudotuberculosis* bacterial membrane, wherein the aromatic amino acid residue is structurally and functionally equivalent to tryptophan at position 122 (W122) and tyrosine at position 138 (Y138), and wherein the negatively charged amino acid residue is structurally and functionally equivalent to aspartic acid at position 140 (D140) and aspartic acid at position 167 (D167); wherein “functional equivalence” means that the residue can form the same type of interaction with the host ligand, and that mutating it to the specific residue does not significantly reduce the ligand-binding affinity by more than 10-fold.

[0015] Preferably, the multidrug-resistant bacteria are selected from one or more of the following bacteria: carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, carbapenem-resistant Pseudomonas aeruginosa, and Yersinia pseudotuberculosis.

[0016] Preferably, the sulamine sodium reduces the pathogenicity of multidrug-resistant bacteria by inhibiting the function of the bacterial dCACHE-type chemotactic receptor protein family, thereby blocking the chemotactic movement of bacteria to host macrophages, reducing the bacterial load of multidrug-resistant bacteria in the infected host, and inhibiting the spread and colonization of multidrug-resistant bacteria.

[0017] Preferably, the dosage form of the drug is a parenteral dosage form, and more preferably, the parenteral dosage form is an injection.

[0018] Preferably, the drug may further contain at least one other active agent; preferably, the other active agent is an antibiotic.

[0019] Compared with the prior art, the beneficial effects of the present invention are:

[0020] 1. This invention reveals for the first time a novel mechanism of action of sulamine sodium, namely, by targeting the conserved interface of bacterial dCACHE chemotactic receptors, blocking bacterial chemotactic movement, thereby inhibiting multidrug-resistant bacterial infections, providing a new direction for the repurposing of existing drugs.

[0021] 2. Based on the high conservation of the target protein-ligand binding interface in various clinically resistant bacteria, sulamine sodium has broad-spectrum antibacterial potential against multidrug-resistant bacteria carrying this target. This invention has verified that sulamine sodium has significant inhibitory effects on various high-risk clinically resistant bacteria, including carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa.

[0022] 3. Traditional antibiotics exert their effects by inhibiting key bacterial growth pathways, easily inducing drug resistance mutations. Supramin, however, targets the highly conserved dCACHE chemokine interface, which is not essential for growth but is crucial for pathogenicity, thus exhibiting minimal pressure for drug resistance mutations. After 200 generations of continuous culture testing, bacteria did not develop acquired resistance to its antiviral activity, demonstrating excellent long-term efficacy potential and commercial lifespan.

[0023] 4. This invention is the first to demonstrate that sulamine sodium, administered up to 8 hours after infection, can still significantly improve the survival rate of hosts infected with multidrug-resistant bacteria. This characteristic indicates that the drug of this invention is not limited to immediate prevention or treatment of infection, but can still effectively intervene after the infection has occurred and progressed for some time, thus gaining a valuable time window for clinical diagnosis and treatment, and greatly improving the feasibility and application value of clinical translation. Attached Figure Description

[0024] Figure 1 Growth curves of multidrug-resistant bacteria after adding different concentrations of sulamine sodium;

[0025] Figure 2 The Transwell assay results show the inhibition of macrophage chemotaxis by sulamine sodium;

[0026] Figure 3 The diagram shows the ITC results of suramin sodium binding to dCACHE chemokine receptor protein;

[0027] Figure 4 Figure showing the results of an experiment demonstrating the effect of sulamine sodium on reducing the cytotoxicity of macrophages infected with multidrug-resistant bacteria;

[0028] Figure 5A and Figure 5B Survival curves of mice infected with multidrug-resistant bacteria treated with sulamine sodium at 2 hours and 8 hours post-infection;

[0029] Figure 6 A statistical graph showing the bacterial load (CFU) in mice infected with multidrug-resistant bacteria treated with sulamine sodium.

[0030] Figure 7 This is a graph showing the survival rates of mice infected with drug-induced sodium resistance after drug stress passage versus those infected with unpassaged strains in a sulamine sodium resistance induction experiment. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to embodiments. It should be understood that the specific embodiments described herein are merely illustrative and not intended to limit the invention.

[0032] The carbapenem-resistant Acinetobacter baumannii used in the following examples were clinical isolates (NCBI accession number: Ab-C17, serotype: ST457), carbapenem-resistant Escherichia coli were clinical isolates (NCBI accession number: EC155), and carbapenem-resistant Pseudomonas aeruginosa were clinical isolates (accession number: ATCC BAA-2108).

[0033] Example 1: Supramin sodium does not affect the growth of multidrug-resistant bacteria.

[0034] Carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa were diluted 1:100 in LB broth, and 200 μL of each solution was added to 96-well plates. Supramin sodium was added to each culture to achieve final concentrations of 0 (solvent control group), 5, 10, 50, 100, and 200 μg / mL, respectively. Each group was configured with three replicates. The plates were placed in a microplate reader and continuously shaken for incubation, with OD measured every 2 hours. 600 Value. With time as the x-axis, OD 600 The values ​​are plotted on the ordinate to generate growth curves for bacteria in each treatment group.

[0035] Experimental results are as follows Figure 1 As shown, within the concentration range of 0 to 200 μg / mL, suramin sodium did not exhibit significant inhibitory or bactericidal activity against the growth of carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa. The growth curves of each concentration treatment group largely overlapped with the solvent control group, and the bacteria were able to normally enter the logarithmic growth phase and reach the plateau phase. Even at the highest tested concentration of 200 μg / mL (far exceeding the effective chemotactic inhibition concentration of 5 μg / mL used in this invention), the growth of the three drug-resistant bacteria was not significantly affected. This indicates that suramin sodium has no direct bactericidal or bacteriostatic activity against carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa.

[0036] Example 2: Effect of sulamine sodium on the chemotaxis of multidrug-resistant bacteria

[0037] RAW 264.7 macrophages were seeded in 12-well plates at a density of 2.0 × 10⁶ cells per well. 5Cells were co-cultured for 48 hours to form a confluent monolayer. Overnight cultured carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa were diluted 1:100 in LB broth. Experimental group: Supramin sodium at a final concentration of 5 µg / mL was added simultaneously to the upper chamber of a Transwell apparatus containing a 5.0 μm pore size polyethylene terephthalate (PET) membrane with the diluted bacterial suspension (total volume 0.8 mL). Control group: An equal volume of PBS and diluted bacterial suspension was added to the upper chamber; the lower chamber contained only sterile cell culture medium (cell-free control) to assess baseline bacterial migration. After incubation at 37°C and 5% CO2 for 2 h, the contents of the lower chamber were collected and plated onto YLB agar plates. After incubation at 30°C for 24 h, colony counts were performed. The final colony count was corrected by subtracting the number of bacteria that migrated to the cell-free control.

[0038] Experimental results are as follows Figure 2 As shown, the number of bacteria migrating to macrophages was significantly reduced after the addition of sulamine sodium, proving that sulamine sodium can effectively interfere with the bacterial chemotaxis system and cause bacteria to lose their ability to directionally chemotactically attract macrophages.

[0039] Example 3: Detection of the binding affinity of suramin sodium to dCACHE chemokine receptor protein

[0040] 1. Protein expression and purification

[0041] The dCACHE chemokine receptor homologous protein genes of carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa, respectively, are encoded by amino acid sequences as shown in SEQ ID NO:2-4 (each satisfying at least one of the following conditions: a) containing the amino acid sequence of SEQ ID NO:2-4. NO:1 shows a conserved motif with an amino acid sequence having at least 70% sequence identity; b) it contains a conserved ligand-binding interface, which includes at least a positively charged amino acid residue at the entrance of the binding pocket, an aromatic amino acid residue at the hydrophobic core, and a negatively charged amino acid residue at the bottom of the binding interface; the positively charged amino acid residue is structurally and functionally equivalent to arginine at position 120 (R120) of the dCACHE-type chemokine receptor protein YcrA of *Yersinia pseudotuberculosis* bacterial membrane, the aromatic amino acid residue is structurally and functionally equivalent to tryptophan at position 122 (W122) and tyrosine at position 138 (Y138), and the negatively charged amino acid residue is structurally and functionally equivalent to aspartic acid at position 140 (D140) and aspartic acid at position 167 (D167); the term "functional equivalence" means that the residue can form the same type of interaction with the host ligand, and that mutating it to the specific residue does not significantly reduce the ligand-binding affinity by more than 10-fold. The protein was cloned into the pET28a vector, transformed into E. coli BL21(DE3), induced to express by IPTG, purified by Ni-NTA affinity chromatography, and obtained a chemokine receptor protein sample with a purity >95% after dialysis.

[0042] 2. ITC Experiment

[0043] Both sulamine sodium and purified chemokine receptor protein were diluted in ITC buffer (50 mM Tris, 150 mM NaCl, 10% glycerol, pH 8.0), with sulamine sodium diluted to 100 μM and chemokine receptor protein diluted to 10 μM. Samples were degassed for 15 min before titration. After degassing, 250 μL of sulamine sodium was pipetted into the titration syringe, and 1 mL of chemokine receptor protein was added to the reaction chamber. Each reaction was titrated 25 times at 25°C and 200 rpm with stirring. Each sample underwent three independent experiments. Protein dialysis buffer was used as a control. Results were analyzed using Nano Analyze software, and the affinity constant K was calculated. d .

[0044] Experimental results are as follows Figure 3 As shown, the binding constant (K) of sulamine sodium with the dCACHE chemotactic receptor homolog of carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa is... dThe effective molecular weights (NM) were 9 nM, 15 nM, and 27 nM, respectively. The results showed that sulamine sodium bound to the dCACHE chemokine receptor protein of all bacterial species with high affinity and a highly consistent binding pattern, further confirming the mechanism of action of sulamine sodium targeting this conserved interface. This binding mainly depends on the chemical properties and spatial arrangement of highly conserved key amino acid residues in this interface, rather than other sequence regions that differ between bacterial species.

[0045] Example 4: Detection of the effect of sulamine sodium on reducing cytotoxicity in multidrug-resistant bacterial infections

[0046] Macrophages were digested with Raw264.7 trypsin and then... 6 Cells were seeded in 6-well plates at a density of [number] cells per well. Experimental group: After cell adhesion, cells were infected with carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa at an MOI of 100:1. Supramin sodium was added simultaneously with the bacteria to a final concentration of 5 µg / mL. Control group: Cells were infected with the above pathogens at an MOI of 100:1. An equal volume of PBS (sulamine sodium) was added simultaneously with the bacteria. Blank group: Only supramin sodium was added to a final concentration of 5 µg / mL to test the cytotoxicity of the drug. Cells were collected 2 h after infection, washed with PBS, resuspended in 195 μL binding buffer, and stained with Annexin V-FITC and PI at room temperature in the dark for 10 min. Samples were immediately analyzed on a CytoFLEX flow cytometer, and data were processed using CytExpert software.

[0047] Experimental results are as follows Figure 4 As shown, regardless of the pathogenic bacteria, the apoptosis rate in the experimental group where both bacteria and suramin sodium were added was significantly lower than that in the control group, indicating that suramin sodium, which targets the bacterial membrane chemotactic receptor protein family, can effectively reduce the toxicity of pathogenic bacteria to host cells. Meanwhile, the apoptosis rate in the blank group (containing only suramin sodium) was not significantly different from that in the untreated group, demonstrating that suramin sodium has good biosafety to host cells at working concentrations.

[0048] Example 5: Survival rate experiment of mice infected with multidrug-resistant bacteria treated with suramin sodium.

[0049] (1) All mice were maintained and treated in accordance with the animal welfare guarantee policy promulgated by Northwest A&F University. The mice were 6-week-old SPF-grade female BALB / c mice, which were kept for 2-3 days after purchase before infection.

[0050] (2) Carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa were cultured in LB medium at 37°C. After reaching the initial stable stage, the strains were washed twice in sterile PBS and diluted to prepare bacterial suspensions. The injection counts of carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa were 1×10⁻⁶. 6 1, 2×10 7 5×10 6 Each mouse was injected with 100 μL.

[0051] (3) Different groups were set up, with 10 mice in each group. Treatment intervention: 2 hours or 8 hours after intraperitoneal injection of bacteria, mice were subcutaneously injected with sulamine sodium (10 mg / kg body weight). Sulamine sodium was injected once every 12 hours for the first three days, and once every 24 hours thereafter. The control group included: (i) treated with PBS instead of sulamine sodium; (ii) injected with sulamine sodium alone without bacterial infection; (iii) injected with PBS alone as a blank control. The infected mice were observed, and the survival status of each infection group was statistically compared. The observation lasted for 6 days, and survival curves were plotted.

[0052] Experimental results are as follows Figure 5A and 5B As shown, regardless of the pathogen causing the infection, mice treated with sulamine sodium 2 hours after infection showed a significant survival advantage compared to mice not treated with sulamine sodium. Figure 5A No mice in the control group who received only sulamine sodium without bacterial infection died, demonstrating that sulamine sodium has good biocompatibility at working concentrations. Furthermore, treatment administered 8 hours after infection also showed excellent efficacy. Figure 5B This indicates that sulamine sodium can still be effective in intervening even after the infection has occurred and progressed for some time.

[0053] Example 6: Determination of bacterial load in mice infected with multidrug-resistant bacteria after treatment with suramin sodium

[0054] (1) All mice were maintained and treated in accordance with the animal welfare guarantee policy promulgated by Northwest A&F University. The mice were 6-week-old SPF-grade female BALB / c mice, which were kept for 2-3 days after purchase before infection.

[0055] (2) Carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa were cultured in LB medium at 37°C. After reaching the initial stable stage, the strains were washed twice in sterile PBS and diluted to prepare bacterial suspensions. The injection counts of carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa were 1×10⁻⁶. 6 1, 2×10 7 5×106 Each mouse was injected with 100 μL.

[0056] (3) Different groups were set up, with 6 mice in each group. Treatment intervention: Two hours after intraperitoneal injection of bacteria, mice were subcutaneously injected with sulamine sodium (10 mg / kg body weight). The control group was treated with PBS instead of sulamine sodium. Twelve hours after treatment, the infected mice were euthanized, and blood, peritoneal lavage fluid, liver and spleen were collected. Then, dilution gradient plate counts were performed (the liver and spleen were homogenized), and the bacterial load (CFU) of each tissue was counted.

[0057] Experimental results are as follows Figure 6 As shown, regardless of whether it is carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, or carbapenem-resistant Pseudomonas aeruginosa, the bacterial load in the blood, peritoneal lavage fluid, liver, and spleen of mice treated with sulamine sodium two hours after intraperitoneal infection was significantly reduced compared to the untreated group. This indicates that sulamine sodium can effectively reduce the bacterial load of multidrug-resistant bacteria in the infected host and inhibit the spread and colonization of multidrug-resistant bacteria.

[0058] Example 7: Detection of Supramin Sodium Resistance Induction

[0059] (1) All mice were maintained and treated in accordance with the animal welfare guarantee policy promulgated by Northwest A&F University. The mice were 6-week-old SPF-grade female BALB / c mice, which were kept for 2-3 days after purchase before infection.

[0060] (2) Carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa were cultured in LB medium at 37°C. Each bacterium was divided into three groups: (i) continuous subculture in the absence of suramin sodium (continuous subculture group); (ii) continuous subculture in the presence of 10 μg / mL suramin sodium (drug-stress continuous subculture group); and (iii) no continuous subculture as a control. Escherichia coli, Pseudomonas aeruginosa, and Acinetobacter baumannii were continuously subcultured for more than 200 generations.

[0061] (3) After the strains reached the initial stable stage, they were washed twice in sterile PBS and diluted to prepare a bacterial suspension. The injection counts of carbapenem-resistant Acinetobacter baumannii, carbapenem-resistant Escherichia coli, and carbapenem-resistant Pseudomonas aeruginosa were 1×10⁻⁶. 6 1, 2×10 7 5×10 6 Each mouse was injected with 100 μL.

[0062] (4) Different groups were set up, with 10 mice in each group. Treatment intervention: Two hours after intraperitoneal injection of bacteria, mice were subcutaneously injected with sulamine sodium (10 mg / kg body weight). Sulamine sodium was injected once every 12 hours for the first three days, and then once every 24 hours thereafter. The control group included: (i) treated with PBS instead of sulamine sodium; (ii) injected with sulamine sodium alone without bacterial infection; (iii) injected with PBS alone as a blank control. The infected mice were observed, and the survival status of each infection group was statistically compared. The observation lasted for 6 days, and survival curves were plotted.

[0063] Experimental results are as follows Figure 7 As shown, regardless of whether drug stress was applied, bacteria passaged for more than 200 generations showed no significant difference in virulence in mice compared to the unpassaged control group, indicating that long-term passage itself does not affect bacterial pathogenicity. Even bacteria passaged for more than 200 generations under the continuous presence of 10 μg / mL supramin sodium showed that treatment with supramin sodium after infection significantly improved mouse survival, with no significant difference in treatment effect compared to the unpassaged group. This indicates that under long-term drug stress, the multidrug-resistant bacteria did not develop acquired resistance to their antiviral activity, and the therapeutic effect of supramin sodium remained stable.

[0064] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them. Based on the present invention, some modifications or substitutions can be made, but these modifications or substitutions do not cause the essence of the corresponding technical solutions to depart from the scope of protection claimed by the present invention.

Claims

1. Use of suramin sodium or a pharmaceutically acceptable salt, hydrate or solvate thereof in the preparation of medicaments for the treatment and / or prevention of multidrug-resistant bacterial infections.

2. The application according to claim 1, characterized in that, The drug does not induce detectable acquired resistance in the multidrug-resistant bacteria, nor does it induce acquired resistance against its antiviral activity in the multidrug-resistant bacteria.

3. The application according to claim 3, characterized in that, Even after the multidrug-resistant bacteria have been continuously passaged for more than 200 generations in an environment containing the drug, treatment with the drug can still significantly improve the survival rate of the infected host.

4. The application according to claim 1, characterized in that, The treatment, including administration either early in the infection or delayed until 8 hours after infection, significantly improves the survival rate of hosts infected with multidrug-resistant bacteria.

5. The application according to claim 1, characterized in that, The multidrug-resistant bacteria mentioned above are bacteria carrying dCACHE-type chemokine receptor proteins.

6. The application according to claim 5, characterized in that, The dCACHE-type chemokine receptor protein described herein satisfies at least one of the following conditions: (a) Contains an amino acid sequence that has at least 70% sequence identity with the conserved motif shown in SEQ ID NO:1; (b) Contains a conserved ligand-binding interface, wherein the conserved ligand-binding interface comprises at least a positively charged amino acid residue at the entrance of the binding pocket, an aromatic amino acid residue at the hydrophobic core, and a negatively charged amino acid residue at the bottom of the binding interface; wherein the positively charged amino acid residue is structurally and functionally equivalent to arginine at position 120 (R120) of the dCACHE-type chemokine receptor protein YcrA of *Yersinia pseudotuberculosis* bacterial membrane, wherein the aromatic amino acid residue is structurally and functionally equivalent to tryptophan at position 122 (W122) and tyrosine at position 138 (Y138), and wherein the negatively charged amino acid residue is structurally and functionally equivalent to aspartic acid at position 140 (D140) and aspartic acid at position 167 (D167); wherein "functional equivalence" means that the residue can form the same type of interaction with the host ligand, and that mutating it to the specific residue does not significantly reduce the ligand-binding affinity by more than 10-fold.

7. The application according to claim 5 or 6, characterized in that, The multidrug-resistant bacteria are selected from one or more of the following bacteria: Carbapenem-resistant Acinetobacter baumannii. Acinetobacter baumannii CRAB), Carbapenem-resistant Escherichia coli Escherichiacoli CREC), Carbapenem-resistant Pseudomonas aeruginosa Pseudomonas aeruginosa CRPA), Yersinia pseudotuberculosis ( Yersinia pseudotuberculosis ).

8. The application according to claim 5 or 6, characterized in that, The sulamine sodium inhibits the function of the bacterial dCACHE-type chemotactic receptor protein family, blocking the chemotactic movement of bacteria to host macrophages, thereby reducing the pathogenicity of multidrug-resistant bacteria, reducing the bacterial load of multidrug-resistant bacteria in the infected host, inhibiting the spread and colonization of multidrug-resistant bacteria, and improving the survival rate of multidrug-resistant bacteria infecting the host.

9. The application according to claim 1, characterized in that, The drug is in the form of a parenteral administration formulation, preferably an injection.

10. The application according to any one of claims 1-9, characterized in that, The drug may further contain at least one other active agent; preferably, the other active agent is an antibiotic.

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