Repurposing Tamoxifen as Potential Host-Directed Therapeutic for Tuberculosis
Ralf Boland, Matthias T. Heemskerk, Gabriel Forn‐Cuní, Cornelis J. Korbee, Kimberley V. Walburg, Jeroen J. Esselink, Carina Carvalho dos Santos, Amy M. de Waal, Daniel C. M. van der Hoeven, Elisa van der Sar, Alex S. de Ries, Jiajun Xie, Herman P. Spaink, Michiel van der Vaart, Mariëlle C. Haks, Annemarie H. Meijer, Tom H. M. Ottenhoff
Abstract
Tuberculosis (TB) is the world's most lethal infectious disease caused by a bacterial pathogen, Mycobacterium tuberculosis. This pathogen evades the immune defenses of its host and grows intracellularly in immune cells, particularly inside macrophages. There is an urgent need for novel therapeutic strategies because treatment of TB patients is increasingly complicated by rising antibiotic resistance. In this study, we explored a breast cancer drug, tamoxifen, as a potential anti-TB drug. We show that tamoxifen acts as a so-called host-directed therapeutic, which means that it does not act directly on the bacteria but helps the host macrophages combat the infection more effectively. We confirmed the antimycobacterial effect of tamoxifen in a zebrafish model for TB and showed that it functions by promoting the delivery of mycobacteria to digestive organelles, the lysosomes. These results support the high potential of tamoxifen to be repurposed to fight antibiotic-resistant TB infections by host-directed therapy.