Lipidomics and genomics of Mycobacterium tuberculosis reveal lineage‐specific trends in mycolic acid biosynthesis

Mycolic acids (MAs) are α‐alkyl, β‐hydroxy long‐chain fatty acids found in abundance in the cell envelope of the Mycobacterium tuberculosis complex (MTBC). MAs form an efficient permeability barrier, modulate host innate immune responses, and are the targets of several anti‐tuberculosis drugs. Using mass spectrometry, we measured the relative abundance of 80 MA species across 36 clinical isolates of MTBC covering four major phylogenetic lineages. We found significant variations in the MA patterns between different MTBC strains and lineages. MA patterns of “ancient” lineages contrasted those from “modern” lineages, with a lower representation of alpha‐mycolates among Lineage 6 strains and an inversion of the methoxy: keto‐mycolates ratio in Lineage 1 strains. 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. Mycolic acids are involved in Mycobacterium tuberculosis pathogenicity and its metabolism is targeted by several current anti‐tuberculosis drugs. Functional single‐nucleotide polymorphisms support our observation that phylogenetic lineages of Mycobacterium tuberculosis complex MTBC differ in their mycolic acid content. Inherent mycolic acid metabolism differences may account for lineage‐specific variability in drug sensitivity and resistance development propensity.