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Abstract
The prevalence of lung disease due to infections with nontuberculous mycobacteria (NTM) has been increasing and surpassed tuberculosis (TB) in some countries. Treatment outcomes are often unsatisfactory, highlighting an urgent need for new anti-NTM medications. Although NTM in general do not respond well to TB specific drugs, the similarities between NTM and Mycobacterium tuberculosis at the molecular and cell structural level suggest that compound libraries active against TB could be leveraged for NTM drug discovery. Here we tested this hypothesis. The Pathogen Box from the Medicines for Malaria Venture (MMV) is a collection of 400 diverse drug-like compounds, among which 129 are known to be active against M. tuberculosis. By screening this compound collection against two NTM species, Mycobacterium abscessus and Mycobacterium avium, we showed that indeed the hit rates for NTM among TB active compounds is significantly higher compared to compounds that are not active against TB. MIC/dose response confirmation identified 10 top hits. Bactericidal activity determination demonstrated attractive potency for a subset of the confirmed hits. In vivo pharmacokinetic profiling showed that some of the compounds present reasonable starting points for medicinal chemistry programs. Three of the top hits were oxazolidinones, suggesting the potential for repositioning this class of protein synthesis inhibitors to replace linezolid which suffers from low potency. Two hits were inhibitors of the trehalose monomycolate transporter MmpL3, suggesting that this transmembrane protein may be an attractive target for NTM. Other hits are predicted to target a range of functions, including cell division (FtsZ), DNA gyrase (GyrB), dihydrofolate reductase, RNA polymerase and ABC transporters. In conclusion, our study showed that screening TB active compounds for activity against NTM resulted in high hit rates, suggesting that this may be an attractive approach to kick start NTM drug discovery projects. In addition, the work identified a series of novel high value NTM hits with associated candidate targets which can be followed up in hit-to-lead projects for the discovery of new NTM antibiotics.
Highlights
Nontuberculous mycobacteria (NTM)—relatives of the tuberculosis (TB) causative agent Mycobacterium tuberculosis, have recently emerged as a new threat to humans (Griffith and Aksamit, 2016; Stout et al, 2016)
A primary screen was performed using 20 μM final drug concentration for all 400 Pathogen Box compounds against two clinical strains, M. abscessus Bamboo and M. avium 11
These results show that for both M. abscessus and M. avium the hit rate was significantly higher for TB actives as compared to non-TB active compounds (Figure 2)
Summary
Nontuberculous mycobacteria (NTM)—relatives of the tuberculosis (TB) causative agent Mycobacterium tuberculosis, have recently emerged as a new threat to humans (Griffith and Aksamit, 2016; Stout et al, 2016). M. abscessus has been shown to possess conserved molecular strategies for host adaptation and persistence with M. tuberculosis, as described in a recent transcriptome study (Miranda-CasoLuengo et al, 2016). These similarities between NTM and M. tuberculosis suggest that advances made in TB research over the past decade in terms of both understanding the biology and the generation of chemical matter, may be leveraged for NTM drug discovery (Raju et al, 2016). We aimed at testing the hypothesis that screening TB actives would yield high hit rates for NTM and could be considered as an attractive strategy for NTM drug discovery
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