2. Academic Validation
  3. Flunarizine suppresses Mycobacterium tuberculosis growth via calmodulin-dependent phagosome maturation

Flunarizine suppresses Mycobacterium tuberculosis growth via calmodulin-dependent phagosome maturation

  • J Leukoc Biol. 2022 May;111(5):1021-1029. doi: 10.1002/JLB.4A0221-119RR.
Siwei Mo 1,  Xiaoqian Liu 2 3,  Kehong Zhang 1 4,  Wenfei Wang 1 4,  Yi Cai 1,  Qi Ouyang 1,  Chuanzhi Zhu 5,  Dachuan Lin 1,  Haoqiang Wan 2,  Dechang Li 6,  Zhihua Wen 6,  Xinchun Chen 1
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Regional Immunity and Diseases, Department of Pathogen Biology, School of Medicine, Shenzhen University, Shenzhen, China.
  • 2 Department of Infectious Disease, Shenzhen People's Hospital, Second Clinical Medical College of Jinan University, Shenzhen, Guangdong Province, China.
  • 3 Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, Guangdong Province, China.
  • 4 Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich-Schiller-University, Jena, Germany.
  • 5 Laboratory of Molecular Biology, Beijing Key Laboratory for Drug Resistance Tuberculosis Research, Beijing Chest Hospital, Capital Medical University, Beijing Tuberculosis and Thoracic Tumor Research Institute, Beijing, China.
  • 6 Yuebei Second People's Hospital, Shaoguan, Guangdong, China.
PMID: 34533236 DOI: 10.1002/JLB.4A0221-119RR
Abstract

Tuberculosis (TB), an infectious Bacterial disease caused by Mycobacterium tuberculosis (Mtb), is a major cause of death worldwide. Multidrug-resistant TB remains a public health crisis and thus novel effective treatments, such as host-directed therapies (HDTs), are urgently required to overcome the challenges of TB Infection. In this study, we evaluated 4 calcium modulators for their effects on Mtb growth in macrophages. Only flunarizine enhanced the bactericidal ability of macrophages against Mtb, which was induced by an increase in phosphorylated calcium/Calmodulin (CaM)-dependent protein kinase II (pCaMKII) levels. We further discovered that the expression of CaM was decreased in Mtb-infected macrophages and restored following flunarizine treatment; this was associated with phagolysosome maturation and acidification. Consistent with these findings, the anti-TB ability of macrophages was reduced following the silencing of CaM or inhibition of CAMKII activity. In conclusion, our results demonstrated that flunarizine enhanced the bactericidal ability of macrophages and clarified its CaM-pCAMKII-dependent mechanism. Therefore, our findings strongly support further studies of this currently approved drug as an HDT candidate for TB therapy.

Keywords

HDT; calcium modulators; pCAMKII.

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