Co-treatment with Clofazimine and Rapamycin eliminates drug-resistant tuberculosis by inducing polyfunctional central memory T cell responses.

Abstract

Mycobacterium tuberculosis (M.tb), the causative agent of tuberculosis (TB), is acquiring drug resistance at a faster rate than the discovery of new antibiotics. Therefore, alternate therapies that can limit the drug resistance and disease recurrence are urgently needed. Emerging evidences indicate that combined treatment with antibiotics and an immunomodulator provides superior treatment efficacy. Clofazimine (CFZ) enhances the generation of T central memory (TCM) cells by blocking the Kv1.3+ potassium channels. Rapamycin (Rapa) facilitates M.tb clearance by inducing autophagy. In this study, we observed that the co-treatment with CFZ and Rapa potently eliminates both multiple and extensively drug-resistant (MDR and XDR) clinical isolates of M.tb in a mouse model by inducing robust T cell memory and polyfunctional TCM responses. Furthermore, co-treatment reduces the expression of latency-associated genes of M.tb in human macrophages. Therefore, CFZ and Rapa co-therapy holds promise for treating patients infected with MDR and XDR strains of M.tb.