2. Academic Validation
  3. Cisatracurium besylate rescues Mycobacterium Tuberculosis-infected macrophages from necroptosis and enhances the bactericidal effect of isoniazid

Cisatracurium besylate rescues Mycobacterium Tuberculosis-infected macrophages from necroptosis and enhances the bactericidal effect of isoniazid

  • Int Immunopharmacol. 2023 May 12;120:110291. doi: 10.1016/j.intimp.2023.110291.
Qian Wen 1,  Jing Zhang 1,  Zhanqing Zhang 1,  Liru Chen 1,  Honglin Liu 1,  Zhenyu Han 1,  Yaoxin Chen 1,  Ke Wang 1,  Jieyu Liu 1,  Na Sai 1,  Xinying Zhou 1,  Chaoying Zhou 1,  Shengfeng Hu 1,  Li Ma 2
Affiliations

Affiliations

  • 1 Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China.
  • 2 Institute of Molecular Immunology, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China. Electronic address: [email protected].
PMID: 37182451 DOI: 10.1016/j.intimp.2023.110291
Abstract

Objective: Tuberculosis is the leading killer among the chronic single-source infectious diseases. Mycobacterium tuberculosis can induce necrotic-dominant multiple modes of cell death in macrophages, which accelerates bacterium dissemination and expands tissue injury in host lungs. Mining drugs to counteract Mycobacterium tuberculosis-induced cell death would be beneficial to tuberculosis patients.

Methods: In this study, the protective drug was screened out from the FDA-approved drug library in Mycobacterium tuberculosis-infected macrophages with CCK-8 assay. The death mode regulated by the drug was identified using transcriptomic sequencing, cytomorphological observation, and in the experimental mouse Mycobacterium tuberculosis-infection model. The functional mechanism was explored using western blot, co-immunoprecipitation, and DARTS assay. The intracellular Bacterial survival was detected using colony forming unit assays.

Results: Cisatracurium besylate was identified to be highly protective for the viability of macrophages during Mycobacterium tuberculosis Infection via inhibiting Necroptosis. Cisatracurium besylate prevented RIPK3 to be associated with the executive molecule MLKL for forming the necroptotic complex, resulting in the inhibition of MLKL phosphorylation and pore formation on cell membrane. However, Cisatracurium besylate did not interfere with the association between RIPK3 with its upstream kinase RIPK1 or ZBP1 but regulated RIPK3 autophosphorylation. Moreover, Cisatracurium besylate significantly inhibited the expansion of intracellular Mycobacterium tuberculosis both in vitro and in vivo, which also displayed a strong auxiliary bacteriostatic effect to support the therapeutic efficacy of isoniazid and rifampicin, the first-line anti-tubercular drugs.

Conclusion: Cisatracurium besylate performs anti-Mycobacterium tuberculosis and anti-necroptotic roles, which potentiates its application to be an adjuvant drug for antituberculosis therapy to assist the battle against drug-resistant tuberculosis.

Keywords

Cisatracurium besylate; MLKL; Mycobacterium tuberculosis; Necroptosis; RIPK3.

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