Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, kills over 1 million people annually and drug resistance to current therapies is rapidly increasing. We have explored drug treatments to potentiate host responses to mycobacterial infection using a novel screening technique in Mycobacterium marinum (Mm) infected zebrafish to discover FDA-approved drugs that ameliorate Mm infection through host-directed processes. From this screen, we uncovered 10 novel compounds that reduce Mm burden in a host-dependent manner. Using CRISPR/cas9, we have found the target of one small moledule that ultimately benefits the host to control Mm infection by potentiating host innate immune signalling pathways. We have shown that this drug induces cell death and may alter the innate immune response through inflammatory cues. Utilizing the validated zebrafish:Mm infection model, this work will assist in development of novel therapeutics for human:Mtb infections.