An In Vivo Platform for Rapid High-Throughput Antitubercular Drug Discovery

SummaryTreatment of tuberculosis, like other infectious diseases, is increasingly hindered by the emergence of drug resistance. Drug discovery efforts would be facilitated by facile screening tools that incorporate the complexities of human disease. Mycobacterium marinum-infected zebrafish larvae recapitulate key aspects of tuberculosis pathogenesis and drug treatment. Here, we develop a model for rapid in vivo drug screening using fluorescence-based methods for serial quantitative assessment of drug efficacy and toxicity. We provide proof-of-concept that both traditional bacterial-targeting antitubercular drugs and newly identified host-targeting drugs would be discovered through the use of this model. We demonstrate the model’s utility for the identification of synergistic combinations of antibacterial drugs and demonstrate synergy between bacterial- and host-targeting compounds. Thus, the platform can be used to identify new antibacterial agents and entirely new classes of drugs that thwart infection by targeting host pathways. The methods developed here should be widely applicable to small-molecule screens for other infectious and noninfectious diseases.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slideHighlights► A larval zebrafish-M. marium platform for in vivo antitubercular drug discovery ► High-throughput husbandry and reversible anesthesia in 96-well format ► Fluorimetric in situ measurement of drug efficacy and toxicity ► Detection of host-acting compounds and identification of a new drug synergy