Identification of chemicals and pathways targeting intracellular mycobacteria by modulating the host

Pathogenic mycobacteria interact extensively with host cells in order to
establish and maintain their intracellular niche. We developed a combined experimental and computational approach to identify pharmacological modulators of intracellular mycobacteria survival and gain insights into their mode of function. To this end, we established a high content assay to quantify intracellular mycobacteria in primary human macrophages. We screened the assay with a chemical library containing FDA-approved drugs,identified compounds causing the destruction of the pathogen, and validated three compounds for intracellular killing of M. tuberculosis.
Using a multi-parametric image analysis platform previously used to profile genes with respect to endocytosis (Collinet et al., 2010), we profiled the activity of the chemicals. By integrating the profiles of siRNAs and the profiles of the chemicals, we could demonstrate that two compounds modulate autophagy, whereas the third accelerates endosomal progression. This approach demonstrates that it is possible to exploit the multi-parametric profiles of siRNA and compound libraries to identify cellular mechanisms modulated by chemicals. This strategy could open new opportunities of selective pharmacological modulation of host trafficking pathways in the fight against intracellular pathogens.