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Cell Rep. 2012 Jul 26;2(1):175-84. doi: 10.1016/j.celrep.2012.06.008. Epub 2012 Jul 20.

An in vivo platform for rapid high-throughput antitubercular drug discovery.

Author information

1
Department of Microbiology, University of Washington, Seattle, WA 98195, USA.

Abstract

Treatment 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.

PMID:
22840407
PMCID:
PMC3433401
DOI:
10.1016/j.celrep.2012.06.008
[Indexed for MEDLINE]
Free PMC Article

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