Enhance the Antimycobacterial Activity of Streptomycin with Ebselen as an Antibiotic Adjuvant Through Disrupting Redox Homeostasis.

IF 4.7 2区医学 Q1 CHEMISTRY, MEDICINAL Drug Design, Development and Therapy Pub Date : 2024-08-27 eCollection Date: 2024-01-01 DOI:10.2147/DDDT.S475535

Chuanjiang Dong, Yueqing Wang, Yi Cai, Yuhuang Wu, Wei Chen, Lu Wang, Xiaowen Liu, Lili Zou, Jun Wang

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Abstract

Purpose: Tuberculosis (TB) remains a major health threat worldwide, and the spread of drug-resistant (DR) TB impedes the reduction of the global disease burden. Ebselen (EbSe) targets bacterial thioredoxin reductase (bTrxR) and causes an imbalance in the redox status of bacteria. Previous work has shown that the synergistic action of bTrxR and sensitization to common antibiotics by EbSe is a promising strategy for the treatment of DR pathogens. Thus, we aimed to evaluate whether EbSe could enhance anti-TB drugs against Mycobacterium marinum (M. marinum) which is genetically related to Mycobacterium tuberculosis (Mtb) and resistant to many antituberculosis drugs.

Methods: Minimum inhibitory concentrations (MIC) of isoniazid (INH), rifampicin (RFP), and streptomycin (SM) against M. marinum were determined by microdilution. The Bliss Independence Model was used to determine the adjuvant effects of EbSe over the anti-TB drugs. Thioredoxin reductase activity was measured using the DTNB assay, and its effects on bacterial redox homeostasis were verified by the elevation of intracellular ROS levels and intracellular GSH levels. The adjuvant efficacy of EbSe as an anti-TB drug was further evaluated in a mouse model of M. marinum infection. Cytotoxicity was observed in the macrophage cells Raw264.7 and mice model.

Results: The results reveal that EbSe acts as an antibiotic adjuvant over SM on M. marinum. EbSe + SM disrupted the intracellular redox microenvironment of M. marinum by inhibiting bTrxR activity, which could rescue mice from the high bacterial load, and accelerated recovery from tail injury with low mammalian toxicity.

Conclusion: The above studies suggest that EbSe significantly enhanced the anti-Mtb effect of SM, and its synergistic combination showed low mammalian toxicity in vitro and in vivo. Further efforts are required to study the underlying mechanisms of EbSe as an antibiotic adjuvant in combination with anti-TB drug MS.

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用依布硒作为抗生素辅助剂，通过破坏氧化还原平衡增强链霉素的抗霉菌活性

目的：结核病（TB）仍然是全球主要的健康威胁，耐药性结核病（DR）的传播阻碍了全球疾病负担的减轻。依布色林（EbSe）以细菌硫氧还原酶（bTrxR）为靶标，导致细菌氧化还原状态失衡。先前的工作表明，EbSe 对 bTrxR 的协同作用和对普通抗生素的增敏作用是治疗 DR 病原体的一种很有前景的策略。因此，我们旨在评估 EbSe 是否能增强抗结核药物对马林分枝杆菌（M. marinum）的作用：方法：通过微量稀释法测定异烟肼（INH）、利福平（RFP）和链霉素（SM）对马林桿菌的最小抑菌浓度（MIC）。Bliss Independence 模型用于确定 EbSe 对抗结核药物的辅助作用。使用 DTNB 试验测定了硫代氧化还原酶的活性，并通过细胞内 ROS 水平和细胞内 GSH 水平的升高验证了 EbSe 对细菌氧化还原平衡的影响。EbSe 作为抗结核药物的辅助疗效在小鼠 M. marinum 感染模型中得到了进一步评估。在巨噬细胞 Raw264.7 和小鼠模型中观察到了细胞毒性：结果表明，EbSe 比 SM 对 M. marinum 起着抗生素辅助作用。EbSe+SM通过抑制bTrxR的活性，破坏了M. marinum细胞内的氧化还原微环境，可将小鼠从高细菌负荷中解救出来，并加速尾部损伤的恢复，且对哺乳动物的毒性较低：上述研究表明，EbSe 能显著增强 SM 的抗 Mtb 作用，其协同组合在体外和体内均表现出较低的哺乳动物毒性。需要进一步研究 EbSe 作为抗生素辅助剂与抗结核药物 MS 联用的内在机制。

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来源期刊

Drug Design, Development and Therapy CHEMISTRY, MEDICINAL-PHARMACOLOGY & PHARMACY

CiteScore

9.00

自引率

0.00%

发文量

382

审稿时长

>12 weeks

期刊介绍： Drug Design, Development and Therapy is an international, peer-reviewed, open access journal that spans the spectrum of drug design, discovery and development through to clinical applications. The journal is characterized by the rapid reporting of high-quality original research, reviews, expert opinions, commentary and clinical studies in all therapeutic areas. Specific topics covered by the journal include: Drug target identification and validation Phenotypic screening and target deconvolution Biochemical analyses of drug targets and their pathways New methods or relevant applications in molecular/drug design and computer-aided drug discovery* Design, synthesis, and biological evaluation of novel biologically active compounds (including diagnostics or chemical probes) Structural or molecular biological studies elucidating molecular recognition processes Fragment-based drug discovery Pharmaceutical/red biotechnology Isolation, structural characterization, (bio)synthesis, bioengineering and pharmacological evaluation of natural products** Distribution, pharmacokinetics and metabolic transformations of drugs or biologically active compounds in drug development Drug delivery and formulation (design and characterization of dosage forms, release mechanisms and in vivo testing) Preclinical development studies Translational animal models Mechanisms of action and signalling pathways Toxicology Gene therapy, cell therapy and immunotherapy Personalized medicine and pharmacogenomics Clinical drug evaluation Patient safety and sustained use of medicines.