Cotreatment With Clofazimine and Rapamycin Eliminates Drug-Resistant Tuberculosis by Inducing Polyfunctional Central Memory T-Cell Responses

Mycobacterium tuberculosis, the causative agent of tuberculosis, 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 evidence indicates that combined treatment with antibiotics and an immunomodulator provides superior treatment efficacy. Clofazimine (CFZ) enhances the generation of T central memory (T-CM) cells by blocking the Kv1.3(+) potassium channels. Rapamycin (RAPA) facilitates M. tuberculosis clearance by inducing autophagy. In this study, we observed that cotreatment with CFZ and RAPA potently eliminates both multiple and extensively drug-resistant (MDR and XDR) clinical isolates of M. tuberculosis in a mouse model by inducing robust T-cell memory and polyfunctional T-CM responses. Furthermore, cotreatment reduces the expression of latency-associated genes of M. tuberculosis in human macrophages. Therefore, CFZ and RAPA cotherapy holds promise for treating patients infected with MDR and XDR strains of M. tuberculosis. Emergence of drug-resistant variants of Mycobacterium tuberculosis is one of the major concerns limiting the WHO end tuberculosis program. Here, we have demonstrated the antimycobacterial and immunomodulatory potential of 2 repurposed drugs, clofazimine and rapamycin, against MDR and XDR tuberculosis.

Automated summary

Tuberculosis caused by Mycobacterium tuberculosis is becoming increasingly drug resistant, highlighting the urgent need for alternative therapies. Combined treatment with antibiotics and an immunomodulator, such as clofazimine and rapamycin, shows promise in eliminating both multiple drug-resistant and extensively drug-resistant strains of M. tuberculosis. This treatment induces robust T-cell memory and polyfunctional T-CM responses, reducing the expression of latency-associated genes and providing a potential solution for treating drug-resistant tuberculosis.