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

Autor:	Dong C; Department of Urology, The First Dongguan Affiliated Hospital, Guangdong Medical University, Dongguan, Guangdong province, 523718, People's Republic of China., Wang Y; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China.; Yichang Key Laboratory of Infection and Inflammation, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China., Cai Y; Department of Laboratory Medicine, Xiaogan Central Hospital, Xiaogan, Hubei Province, 432099, People's Republic of China., Wu Y; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China.; Yichang Key Laboratory of Infection and Inflammation, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China., Chen W; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China.; Yichang Key Laboratory of Infection and Inflammation, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China., Wang L; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China.; Yichang Key Laboratory of Infection and Inflammation, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China., Liu X; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China., Zou L; Hubei Key Laboratory of Tumor Microenvironment and Immunotherapy, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China.; Yichang Key Laboratory of Infection and Inflammation, College of Basic Medical Science, China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China., Wang J; The Second People's Hospital of China Three Gorges University, Yichang, Hubei Province, 443002, People's Republic of China.
Jazyk:	angličtina
Zdroj:	Drug design, development and therapy [Drug Des Devel Ther] 2024 Aug 27; Vol. 18, pp. 3811-3824. Date of Electronic Publication: 2024 Aug 27 (Print Publication: 2024).
DOI:	10.2147/DDDT.S475535
Abstrakt:	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. Competing Interests: The authors declare no conflicts of interest in this work. (© 2024 Dong et al.)
Databáze:	MEDLINE
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