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: A recent analysis suggested strong purifying selection in genes important for the physiology of MTBC (Pepperell et al. 2013). Therefore, we would expect that essential genes, such as those involved in MA metabolism, should be conserved. However, because MA metabolism is also the primary target of isoniazid and ethionamide, two main antibiotics currently used to treat tuberculosis, the genes involved in MA metabolism may be under diversifying selection. To explore the extent to which the MA machinery might differ across the different lineages of MTBC, we first studied the genome sequences of 35 clinical strains from four main MTBC lineages, which we used subsequently for MA profiling (see below). These 35 strains included representatives of the so-called “modern” and “ancient” phylogenetic lineages, the latter branching earlier in the evolution of MTBC (Brosch et al. 2002; Hershberg et al. 2008). Figure 1A displays the phylogeny among strains derived from neutral DNA sequence variation (synonymous single-nucleotide polymorphisms: sSNPs), which shows the same relationships among lineages as the genome-based MTBC phylogenies described previously (Comas et al. 2009).
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.