Abstract
Tuberculosis (TB) is an infectious bacterial disease that kills approximately 1.3 million people every year. Despite global efforts to reduce both the incidence and mortality associated with TB, the emergence of drug resistant strains has slowed any progress made towards combating the spread of this deadly disease. The current TB drug regimen is inadequate, takes months to complete and poses significant challenges when administering to patients suffering from drug resistant TB. New treatments that are faster, simpler and more affordable are urgently required. Arguably, a good strategy to discover new drugs is to start with an old drug. Here, we have screened a library of 1200 FDA approved drugs from the Prestwick Chemical library using a GFP microplate assay. Drugs were screened against GFP expressing strains of Mycobacterium smegmatis and Mycobacterium bovis BCG as surrogates for Mycobacterium tuberculosis, the causative agent of TB in humans. We identified several classes of drugs that displayed antimycobacterial activity against both M. smegmatis and BCG, however each organism also displayed some selectivity towards certain drug classes. Variant analysis of whole genomes sequenced for resistant mutants raised to florfenicol, vanoxerine and pentamidine highlight new pathways that could be exploited in drug repurposing programmes.
Highlights
Tuberculosis (TB) remains a major global health issue, despite it being over twenty years since the World Health Organisation (WHO) declared TB a global emergency [1]
To identify which of the 1200 FDA approved drugs in the Prestwick Chemical Library inhibit the growth of mycobacteria, a medium throughput fluorescence screen was used to measure GFP expression in strains of both M. smegmatis and BCG (GFP microplate assay [GFPMA]) [10]
It was observed during a screen of the LOPAC library against M. tuberculosis, M. smegmatis and BCG that 50% of the drugs inhibiting M. tuberculosis were not identified in M. smegmatis while it was only 21% of the drugs that were not identified in BCG
Summary
Tuberculosis (TB) remains a major global health issue, despite it being over twenty years since the World Health Organisation (WHO) declared TB a global emergency [1]. In 2016, TB killed around 1.3 million people and ranks alongside HIV as the leading cause of death globally. It has been estimated that almost 6.3 million new cases of TB are to have occurred in 2016; 46% of these new TB cases were individuals co-infected with HIV. An estimated 4.1% of new TB cases and 19% of previously treated TB cases are infections caused by Multi-. FDA drugs active against mycobacteria necessarily those of Public Health England or the Department of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript
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