## 2 Genomics  
### Target Identification  
The _M.tb_ H37 Rv genome was sequenced in 1998, revealing \(\sim\)4000 potential drug targets, of which \(\sim\)50% were assigned a tentative function [8; 9]. _M.tb_ H37 Rv was selected for sequencing as the type strain for _M.tb_. _M.tb_ H37 was isolated from a patient in 1905 and serially passaged in the laboratory, a resulting strain was named H37 Rv, with \"R\" standing for rough morphology and \"_v_\" for virulent [8]. It has become a commonly used laboratory strain of pathogenic _M.tb_, a genomic reference for clinical isolates, and a starting point for drug discovery. Since then, comprehensive whole genome sequencing of _M.tb_ clinical isolates recovered from patients with TB has uncovered a core genome and mapped the accumulation of single nucleotide polymorphisms (SNPs) in protein coding genes [10]. Comparative genomics has also enabled drug specificity (across microbial species) and toxicity (to mammals) to be anticipated, based on the presence or absence of target protein coding sequences. The application of genomics to _M.tb_ has therefore provided a framework of potential drug targets. Manipulation of gene function, through gene inactivation strategies, has aided recognition of pathways that are essential to _M.tb_ in different microenvironments, thus highlighting targets for drug discovery programs [6]. Gene deletion methods designed to generate unmarked single gene knockout mutants have been employed alongside global approaches using transposons (Tn) to inactivate gene function [11]. Tn libraries are generated by disrupting genes through random insertion of a transposon throughout the genome, then applying a selective pressure to measure gene essentiality. DNA microarrays were initially used to map the changing abundance of thousands of Tn mutants, transposon site hybridization (TraSH) [12]; more recently coupled to whole genome sequencing (Tn-seq) for greater genomic resolution [13]. Tn mutant screening has been used to map the genetic pathways required for growth of _M.tb_ and _Mycobacterium bovis_ Bacillus Calmette-Guerin (BCG) in vitro [14]. Here, a _Himar1_ based Tn  
Figure 1: The application of omics tools to antimicrobial drug discovery pathways. In a discovery biology approach, omics methodologies are used early in the process to identify new targets for investigation. In a discovery chemistry setting, omics techniques are useful further down the road to identify mechanism of action of lead compounds. delivery method using a transducing bacteriophage generated a library of \(\sim\)100,000 independent clones. A total of 614 genes essential for in vitro growth were found to be evenly distributed throughout the mycobacterial chromosome. In addition, many genes that were shown to be essential for growth appeared to be co-transcribed in operons. Essential genes were identified in amino acid, co-factor and nucleic acid biosynthesis pathways; genes of unknown function were also classified as essential. Many genes assumed to be essential that were predicted to be involved in cell wall and protein metabolism were shown to be dispensable. This is likely due to functional redundancy; for example, _purT_ and _purN_ both offer alternative pathways for purine de novo biosynthesis and so neither gene was essential [15], providing valuable information that allows non-essential targets to be dropped from drug discovery portfolios. A fundamental pathogenic trait of _M.tb_ is the ability to survive and replicate in phagocytes, avoiding phagosome-lysosome fusion and adapting to an intracellular lifestyle [16]. Therefore, to define pathways that are essential for intra-macrophage survival, [PERSON] et al. mapped genes required for intracellular growth using high content imaging alongside multiplexed cytokine analysis of macrophages infected with _M.tb_ Tn mutant libraries [17]. Systematic, multiparametric analysis of _M.tb_ Tn mutants impaired for intracellular growth identified functional relationships between _M.tb_ Tn mutants and macrophage cytokine profiles.