Four hundred and thirty-seven proteins showed changes in at least one amino acid (excluding PPE and PE-PGRS genes). The most striking changes in CDS sequences LDK378 involve nucleotide deletions or insertions, which render affected genes longer or shorter. The most affected genes, < 90% identity, include several conserved

hypothetical proteins or hypothetical proteins and enzymes involved in redox, transcription regulation and carbohydrate metabolisms reactions, among others. Some of these genes have been studied previously: (1) Rv2959c encodes for an enzyme that catalyses the O-methylation of the hydroxyl group located on carbon 2 of the rhamnosyl residue linked to the phenolic group of PGL and p-HBAD produced by M. tuberculosis (Perez et al., 2004); (2) Rv1446 protein was detected as upregulated in INH-resistant strains (Jiang et al., 2006); (3) Rv1028c is a sensor protein that PD-0332991 in vitro has been shown to interact with Rv1690 and Rv1368 (Steyn et al., 2003); (4) Rv0670 encodes for an endonuclease that is repressed by Rv0586 (Santangelo Mde et al., 2009); (5) Rv0136 encodes a cytochrome P450 that was detected using mass spectrometry in M. tuberculosis extracts (Malen et al., 2010); and (6) Rv3911 encodes for a sigma factor that positively

regulate genes related to the synthesis of surface or secreted molecules (Raman et al., 2006). Remarkably, the dosR regulon accumulated a higher proportion of mutations in its coded proteins compared to the genome average, 11.8% vs 16.7%, respectively. The more severe case is one deletion that affects the operon composed by Rv1996 and Rv1997 genes. This deletion completely eliminates the Rv1996 gene and its promoter region, leaving Rv1997 as a pseudogene. Other dosR-affected ORFs are Rv0572,vRv1733,vRv2028,vRv0574, Rv1812 and Rv2627, although in this case, minor changes in one or few

amino acids were observed. DosR regulon 3-mercaptopyruvate sulfurtransferase genes are induced under conditions such as low oxygen tension, nutrient deprivation, low pH, high levels of reactive oxygen and nitrogen intermediates, host-derived carbon monoxide (Kumar et al., 2008; Shiloh et al., 2008) as well as in IFNγ-stimulated macrophages (Schnappinger et al., 2003; Lin & Ottenhoff, 2008), and activation of this regulon is considered important in the nonreplication persistence stage of Mtb under hypoxic and other stress conditions (Rustad et al., 2008). A role for DosR as a virulence regulon has been proposed based on studies of the W/Beijing lineages of M. tuberculosis that constitutively overexpress DosR regulon genes (Reed et al., 2007) and accumulates high levels of triacylglycerides. Such lipid accumulation is reduced by the deletion of gene Rv3130c/tgs1, part of DosR, which encodes for a triacylglycerol synthase (Daniel et al., 2011).