New anti-tuberculosis agents amongst known drugs

Abstract

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 5microM 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.

Figure 1

Distribution of anti-tuberculosis activity in the Johns Hopkins Library of known drugs: 53 compounds exhibited more than 80% growth inhibition at 5 μM. Of these, 17 compounds were novel anti-tuberculosis agents: 3 of these were oral, 6 were intravenous and 8 were topical therapeutics.

Figure 2

Intracellular activity of Johns Hopkins drugs in a bone marrow derived macrophage model of infection. Primaquine (A), Pentamide (B), Nialamide (C), Pyrvinium pamoate (D), Thiostrepton (E), and Isoniazid (F) were incubated with macrophages for 5 days and the surviving bacilli enumerated by colony counts. Inhibition of growth is shown as a percentage of the untreated control.