Lipidomics and genomics of Mycobacterium tuberculosis reveal lineage-specific trends in mycolic acid biosynthesis.
Bottom Line: We found significant variations in the MA patterns between different MTBC strains and lineages.By interrogating the whole genome sequences of these MTBC strains, we identified relevant single-nucleotide polymorphisms that may sustain the lineage-specific MA patterns.Our results show that the strain genetic background influences MA metabolism and suggests that strain diversity should be considered in the development of new anti-tuberculosis drugs that target MA synthesis.
Affiliation: Mycobacterial Division Research, NIMR, MRC, NW71AA, London, United Kingdom; Department of Medical Parasitology and Infection Biology, Swiss TPH, 4002, Basel, Switzerland; University of Basel, 4002, Basel, Switzerland.Show MeSH
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Mentions: MAs in MTBC comprise molecules that vary in length and by the presence or absence of specific chemical groups created by various enzymatic modifications of the meromycolic chain precursor (Fig. 2) (Takayama et al. 2005). We used MS (Shui et al. 2012) to measure 80 MA species synthesized by our set of MTBC clinical isolates. Each strain was tested once and considered as a biological replicate within its respective lineage for downstream analysis. Arrows in Figure 2 indicate the actual fragmentation pattern of precursor/product ion pairs we used to discriminate among the different MA species. We observed substantial variability in the relative quantities of individual MA species between the different strains using a mean-row centered heat-map (Fig. 3). It is noteworthy that individual strain diversity in MA profiles within the same lineages could be observed. Although, since analysis of nsSNPs in the MA pathway discriminated between different MTBC lineages, we first compared the abundance of each major structural MA variant among these lineages (Fig. 4A). Earlier studies described alpha-MAs as the most prominent MA species in MTBC, followed by methoxy-MAs and keto-MAs (Watanabe et al. 2001). We observed a similar pattern for the two “modern” lineages (i.e. Lineages 2 and 4). However, the proportion of methoxy- and keto-MAs in the “ancient” Lineage 1 and the proportion of alpha- and methoxy-MAs in Lineage 6 differed (Fig. 4A).
Affiliation: Mycobacterial Division Research, NIMR, MRC, NW71AA, London, United Kingdom; Department of Medical Parasitology and Infection Biology, Swiss TPH, 4002, Basel, Switzerland; University of Basel, 4002, Basel, Switzerland.