Abstract
Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) causing serious infections especially among cystic fibrosis patients. Extremely limited therapeutic options against M. abscessus and a rise in infections with this mycobacterium require novel chemotherapies and a better understanding of how the bacterium causes infection. Different from most RGM, M. abscessus can survive inside macrophages and persist for long durations in infected tissues. We recently delineated differences in the infective programs followed by smooth (S) and rough (R) variants of M. abscessus. Unexpectedly, we found that the S variant behaves like pathogenic slow growing mycobacteria, through maintaining a block on the phagosome maturation process and by inducing phagosome-cytosol communications. On the other hand, R variant infection triggers autophagy and apoptosis, reminiscent of the way that macrophages control RGM. However, the R variant has an exquisite capacity to form extracellular cords, allowing these bacteria to rapidly divide and evade phagocytosis. Therefore, new chemotherapeutic interventions against M. abscessus need to efficiently deal with both the reservoir of intracellular bacilli and the extracellular cords. In this context, we recently identified two chemical entities that were very effective against both M. abscessus populations. Although being structurally unrelated these two chemotypes inhibit the activity of the essential mycolic acid transporter, MmpL3. In this Perspective, we aimed to highlight recent insights into how M. abscessus interacts with phagocytic cells and how the inhibition of mycolic acid transport in this pathogenic RGM could be an efficient means to control both intracellular and extracellular populations of the bacterium.
Highlights
Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) increasingly acknowledged as a serious non-tuberculous mycobacterial (NTM) pathogen (Mougari et al, 2016; Diel et al, 2017)
Under the transmission electron microscope, we observed large clumps of R variant bacteria lodged in phagocytic cups still on the exterior of the macrophage cells, either just prior to being phagocytosed or prohibiting their phagocytosis because of their sheer size (Roux et al, 2016)
Modeling of the three-dimensional structure of MmpL3 revealed a large cavity formed by transmembrane helices 5, 7, 8, 9, and 10 where the piperidinol-based compound could potentially bind (Dupont et al, 2016). Both the piperidinolbased and indole-2-carboxamide compounds showed good activity against M. abscessus both extracellularly (Table 1) and intracellularly in macrophages and improved the survival of zebrafish embryos infected with the R strain in the case of the piperidinol-based compound (Dupont et al, 2016)
Summary
Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) increasingly acknowledged as a serious non-tuberculous mycobacterial (NTM) pathogen (Mougari et al, 2016; Diel et al, 2017). We discuss the recent discovery of compounds targeting mycolic acid transport in the bacterium, which are efficient on extracellular and intracellular bacteria, on S and R forms.
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