Are phylogenetic position, virulence, drug susceptibility and in vivo response to treatment in mycobacteria interrelated?
Graphical abstract
Highlights
► The most virulent mycobacteria are phylogenetically related. ► The most virulent mycobacteria show high levels of drug susceptibility. ► Infection by the most virulent species is best treatable. ► Drug susceptibility may be acquired and reflect limited competition in their niches. ► Synthetic rather than microbe-derived antibiotics may help to improve outcomes.
Introduction
Phylogenetic analyses on the basis of multiple house-keeping genes and whole genome sequences have offered new insights in the phylogeny of the genus Mycobacterium (Devulder et al., 2005, Stinear et al., 2008). This genus yields obligate pathogens, the M. tuberculosis complex and M. leprae, as well as opportunistic pathogens (e.g. M. avium, M. intracellulare, M. kansasii, M. marinum, M. malmoense) and saprophytes (e.g. M. phlei, M. sphagni, M. gordonae); the opportunists and saprophytes are generally referred to as nontuberculous mycobacteria (NTM). Microbiologists and clinicians involved in treatment of mycobacterial disease will recognize that the most virulent mycobacteria (measured as the percentage of patients, from whom the respective bacteria are isolated, that have true disease caused by the isolated mycobacteria) are phylogenetically related and infections by these organisms are best treatable (Devulder et al., 2005, Griffith et al., 2007, Hoefsloot et al., 2009, Jenkins et al., 2008, O’Brien et al., 1987, van Ingen et al., 2008a, van Ingen et al., 2009a). These species (the M. tuberculosis complex, M. leprae, M. marinum, M. ulcerans, M. kansasii, M. szulgai, M. malmoense) are characterized high levels of natural drug susceptibility (van Ingen et al., 2010).
In this paper, we review studies of phylogeny, drug susceptibility, and clinical relevance to support our hypothesis that drug susceptibility in mycobacteria is acquired and reflects the level of competition in -and adaptation to- the (environmental) niche of the mycobacteria. In turn, mycobacteria that inhabit the most competitive niches are the least adapted to humans, thus of low clinical significance, but most tolerant to antibiotics, lowering the chances of cure in case of infection (e.g. M. avium complex, M. simiae, M. abscessus) (Griffith et al., 2007, van Ingen et al., 2008b, van Ingen et al., 2009c).
Section snippets
What do mycobacterial genetics tell us about virulence?
The phylogeny of the genus Mycobacterium was long based on 16S rRNA gene sequences; only recently, multi-gene sequence analysis was applied to mycobacteria, revealing novel insights in the phylogenetic relationships between the various Mycobacterium species. The first published analysis by Devulder et al. (2005) revealed some very interesting findings. First, the obligate pathogens of the Mycobacterium tuberculosis complex appear phylogenetically most closely related to the most virulent NTM
How is virulence in humans related to bacterial drug susceptibility?
Mycobacteria are relatively resistant to antimicrobial compounds owing to the impermeable cell wall and broad repertoire of efflux pumps characteristic for the genus (Rodrigues et al., 2008). The issue of drug resistance in mycobacteria hit the news with the emergence of multi- and extensively drug-resistant M. tuberculosis (WHO, 2008). Here, drug resistance is acquired owing to inadequate antimicrobial therapy. Yet, even higher levels of drug resistance are common in NTM (van Ingen et al., 2010
How are virulence and drug susceptibility related to treatment outcome?
Perhaps as a consequence of their lowered defenses, disease caused by the more virulent Mycobacterium species generally has a more favorable treatment outcome, compared to disease by the more resistant, less virulent species. Case series of disease caused by the relatively drug-susceptible M. malmoense, M. szulgai and M. kansasii reported cure rates of 70%, 92% and 78% (Hoefsloot et al., 2009, van Ingen et al., 2008a, van Ingen et al., 2009a), whereas cure rates of disease caused by species
Challenges to the hypothesis
A few important NTM species clearly seem to contradict our hypothesis. For example, M. xenopi is characterized by relatively high levels of drug susceptibility (Table 1) (Tortoli and Simonetti, 1995, van Ingen et al., 2010), yet of mediocre clinical significance (Marras et al., 2007, van Ingen et al., 2008c) and difficult to treat in the setting of human infection (Griffith et al., 2007, Jenkins et al., 2008, van Ingen et al., 2008c). M. xenopi is rarely recovered from environmental samples,
Conclusion
In summary, we hypothesize that the most virulent nontuberculous Mycobacterium species show high levels of drug susceptibility, reflecting an adaptation to closer-to-human niches where competition by antimicrobial compound-producing microorganisms is low. These niches may select for virulence in humans. In addition, the most virulent species are infrequently encountered in environmental samples. The exact niches from which NTM infect humans warrant further investigation. Their lowered defenses
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