Using High Throughput Screening to Acquire Promising Drug Candidates Against Mycobacterium tuberculosis

Abstract

Mycobacterium tuberculosis currently affects 1/3 of the world's population. Over the past 20 years tuberculosis has become more resistant to all front line drugs used against it. Because of this, the threat of Multi Drug Resistant (MDR-TB) and Extensive Drug Resistant (XDR-TB) strains has grown greater and emerges as a world health issue. Modern travel has greatly facilitated the spread of these resistant strains. For this reason, more front line drugs are urgently needed in the fight against TB infection. High Throughput Screening can be used to both find and analyze promising drug candidates. Using automation, thousands of compounds can be tested against an attenuated strain of Tuberculosis and separate the promising compounds from the ineffective ones. We have found a select subset of candidates from our custom built ~52,000 compound diversity library which show potent inhibitory effects against our mc^2-7000 attenuated TB strain. These compounds have IC50s ranging from 1.98 muM to 11.3 muM and should be considered for future development as drugs against TB. Among the active compounds, we have found enrichment for hydrazines, as well as representation of several chemi-classes including quinolones. To determine possible toxicity issues, we have also vetted these compounds against a strain of human lymphoma; all of our promising compounds meet the threshold for non-cytoxicity.