Human Kinase IGF1R/IR Inhibitor Linsitinib Controls the In Vitro and Intracellular Growth of Mycobacterium tuberculosis

• Published in: ACS infectious diseases 2022-10, Vol.8 (10), p.2019-2027
• Main Authors: Wang, Heng, Bi, Jing, Zhang, Yuan, Pan, Miaomiao, Guo, Qinglong, Xiao, Genhui, Cui, Yumeng, Hu, Song, Chan, Chi Kin, Yuan, Ying, Kaneko, Takushi, Zhang, Guoliang, Chen, Shawn
• Format: Article
• Language: English
• Subjects: Adenosine Triphosphate - metabolism; Anti-Bacterial Agents - metabolism; Glutamine - metabolism; Humans; Imidazoles; Isoniazid; Lipids; Mycobacterium tuberculosis - metabolism; Protein Kinase Inhibitors; Pyrazines; Receptor, IGF Type 1 - metabolism; TOR Serine-Threonine Kinases - metabolism; Tuberculosis - drug therapy; Tuberculosis - microbiology
• ISSN: 2373-8227; 2373-8227
• DOI: 10.1021/acsinfecdis.2c00278

ATP provides energy in the biosynthesis of cellular metabolites as well as regulates protein functions through phosphorylation. Many ATP-dependent enzymes are antibacterial and anticancer targets including human kinases acted on by most of the successful drugs. In search of new chemotherapeutics for tuberculosis (TB), we screened repurposing compounds against the essential glutamine synthase (GlnA1) of Mycobacterium tuberculosis (Mtb) and identified linsitinib, a clinical-stage drug originally targeting kinase IGF1R/IR as a potent GlnA1 inhibitor. Linsitinib has direct antimycobacterial activity. Biochemical, molecular modeling, and target engagement analyses revealed the inhibition is ATP-competitive and specific in Mtb. Linsitinib also improves autophagy flux in both Mtb-infected and uninfected THP1 macrophages, as demonstrated by the decreased p-mTOR and p62 and the increased lipid-bound LC3B-II and autophagosome forming puncta. Linsitinib-mediated autophagy reduces intracellular growth of wild-type and isoniazid-resistant Mtb alone or in combination with bedaquiline. We have demonstrated that an IGF-IR/IR inhibitor can potentially be used to treat TB. Our study reinforces the concept of targeting ATP-dependent enzymes for novel anti-TB therapy.