Multi-omics strategies are indispensable tools in the search for new anti-tuberculosis drugs. Omics methodologies, where the ensemble of a class of biological molecules are measured and evaluated together, enable drug discovery programs to answer two fundamental questions. Firstly, in a discovery biology approach, to find new targets in druggable pathways for target-based investigation, advancing from target to lead compound. Secondly, in a discovery chemistry approach, to identify the mode of action of lead compounds derived from high-throughput screens, progressing from compound to target. The advantage of multi-omics methodologies in both of these settings is that omics approaches are unsupervised and unbiased to a priori hypotheses, making omics useful tools to confirm drug action, reveal new insights into compound activity, and discover new avenues for inquiry. This review summarizes the application of Mycobacterium tuberculosis omics technologies to the early stages of tuberculosis antimicrobial drug discovery.

New strategies are required to reduce the worldwide burden of tuberculosis. Intracellular survival and replication of Mycobacterium tuberculosis after macrophage phagocytosis is a fundamental step in the complex host–pathogen interactions that lead to granuloma formation and disease. Greater understanding of how the bacterium survives and thrives in these environments will inform novel drug and vaccine discovery programs. Here, we use in-depth RNA sequencing of Mycobacterium bovis BCG from human THP-1 macrophages to describe the mycobacterial adaptations to the intracellular environment. We identify 329 significantly differentially regulated genes, highlighting cholesterol catabolism, the methylcitrate cycle and iron homeostasis as important for mycobacteria inside macrophages. Examination of multi-functional gene families revealed that 35 PE/PPE genes and five cytochrome P450 genes were upregulated 24 h after infection, highlighting pathways of potential significance. Comparison of the intracellular transcriptome to gene essentiality and immunogenicity studies identified 15 potential targets that are both required for intracellular survival and induced on infection, and eight upregulated genes that have been demonstrated to be immunogenic in TB patients. Further insight into these new and established targets will support drug and vaccine development efforts.

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Tuberculosis (TB) disease causes up to 1.5 million deaths every year and represents an important problem of public health at worldwide level. Here, we quantified the gene expression signatures of granuloma biopsies across human TB pulmonary lesions, and validated the best gene candidates using NanoString technology, profiling 157 samples from 40 TB patients who underwent surgery. We characterised the transcriptional profile of the TB granuloma in comparison to healthy tissue, described an 11-gene signature and measured 7 proteins in plasma associated with it. We demonstrated a gradient of immune-related transcript abundance across the granuloma substructure and evidenced metabolically-active Mycobacterium tuberculosis in the lesions. Patients who converted to sputum negative after two months of starting treatment, showed enriched inflammatory pathways in the lesion several months after, supporting use of sputum culture conversion (SCC) as a prognostic biomarker during clinical management and as a factor to prioritise patients when considering lung surgery.