Journal
TUBERCULOSIS
Volume 89, Issue 5, Pages 364-370Publisher
CHURCHILL LIVINGSTONE
DOI: 10.1016/j.tube.2009.07.002
Keywords
Mycobacterium tuberculosis; Alamar blue; Anti-tuberculosis agents; Therapeutics; Johns Hopkins clinical compound library; Novel inhibitors
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Funding
- MRC Technology and the Medical Research Council
- MRC Technology Development Gap
- MRC [MC_U117585867] Funding Source: UKRI
- Medical Research Council [MC_U117585867] Funding Source: researchfish
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Mycobacterium tuberculosis has an on-going impact on global public health and new therapeutics to treat tuberculosis are urgently required. The emergence of drug resistant tuberculosis poses a serious threat to the control of this pathogen, and the development of drugs that are active against the resistant strains is vital. A medium-throughput assay using the Alamar Blue reagent was set-up to identify novel inhibitors of M. tuberculosis from a library of known drugs, for which there has already been extensive research investigating their suitability and safety as human therapeutics. Of the 1514 compounds screened, 53 were demonstrated to possess inhibitory properties against M. tuberculosis at a concentration of 5 mu M or below. Of these, 17 were novel inhibitors while 36 were known tuberculosis drugs or had been previously described as possessing anti-tuberculosis activity. Five compounds were selected as those which represent the most promising starting points for new anti-tuberculosis agents. It was demonstrated that all five were active against intracellular M. tuberculosis in a macrophage model of infection. The anti-tuberculosis agents identified in this screen represent promising new scaffolds on which future drug development efforts can be focused. (C) 2009 Published by Elsevier Ltd.
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