NTM drug discovery: status, gaps and the way forward

Abstract

Incidence of pulmonary diseases caused by non-tuberculous mycobacteria (NTM), relatives of Mycobacterium tuberculosis, is increasing at an alarming rate, surpassing tuberculosis in many countries. Current chemotherapies require long treatment times and the clinical outcomes are often disappointing. There is an urgent medical need to discover and develop new, more-efficacious anti-NTM drugs. In this review, we summarize the current status of NTM drug development, and highlight knowledge gaps and scientific obstacles in NTM drug discovery. We propose strategies to reduce biological uncertainties and to begin to populate a NTM drug pipeline with attractive leads and drug candidates.

Figure 1

Non-tuberculous mycobacteria (NTM) drug pipeline. Agents currently in discovery or development for the treatment of NTM pulmonary disease are shown. Compounds in the ‘Discovery’ column are from literature. The asterisks (*) indicate repurposed drugs in the discovery stage. A ‘Preclinical’ column is not included because no NTM candidates are currently in preclinical development. Drugs under ‘Phase I–IV’ are from ClinicalTrials.gov (https://clinicaltrials.gov) and more details are shown in Table S1 (see supplementary material online). Phase I and II are combined in one column: the first three trials are in Phase II and the last one is a Phase I/II trial. ^aGaseous nitric oxide is composed of 0.5% NO and 99.5% nitrogen. Abbreviations: M. abs, Mycobacterium abscessus; MAC, Mycobacterium avium complex; PD, pulmonary disease; CF, cystic fibrosis; FAS-II, type II fatty acid synthase; NDH-2, type II NADH-quinone oxidoreductase.

Figure 2

Proposed workflow for non-tuberculous mycobacteria (NTM) drug discovery. Activities and assays from whole-cell library screening to the preclinical development compound are shown. Light blue boxes indicate NTM-specific assays discussed in more detail in the text. Assay and model gaps are in bold. Gray box indicates generic drug discovery activities and assays described elsewhere [148,149]. Abbreviations: PK, pharmacokinetics; tox, cytotoxicity assays.