Tyloxapol inhibits ESX-1 secretion in <i>Mycobacterium marinum</i>

Tuberculosis, which is caused by <i>Mycobacterium tuberculosis</i> , is one of the world's deadliest diseases. We lack a clear understanding of how <i>M. tuberculosis</i> and related mycobacterial species cause disease. In the 1950's, it was reported that treating <i>M. tuberculosis</i> infected animals with tyloxapol improved the survival and in some cases protected the animals from death. Tyloxapol is a detergent that is commonly added to mycobacterial cultures to promote dispersed growth in the laboratory. Later studies suggested that tyloxapol altered the interaction between <i>M. tuberculosis</i> and the phagosomal membrane during macrophage infection. The ability to escape the phagosome is essential for mycobacteria to cause disease, and is mediated by a Type VII protein secretion system, ESX-1. Using <i>M. marinum</i> , a well-established model for understanding the molecular mechanisms of ESX-1 secretion, we show that tyloxapol used at more than 100-fold less than what is commonly used to grow mycobacteria in the lab, inhibits ESX-1 secretion. Our findings have widespread implications on how we interpret our findings as a field, and may explain why tyloxapol impacted <i>M. tuberculosis</i> infection of both animals and macrophages. Our study also indicates that tyloxapol can be used as a tool to understand the molecular mechanisms of ESX-1 protein secretion.