Abstract
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.
Highlights
Tuberculosis (TB) remains one of the top 10 causes of death worldwide, with 10 million new cases and 1.4 million deaths in 2018
This review summarizes the application of M.tb omics strategies in the early stages of the discovery of new drugs for TB, incorporating genomics (DNA), transcriptomics, proteomics, metabolomics and lipidomics
This approach was used to create libraries containing over 90,000 single guide RNA (sgRNA), generating pools of M.tb strains where the majority of genes have been targeted by Clustered Regularly Interspaced Short Palindromic Repeats interference (CRISPRi), enabling high throughput screening approaches to be applied
Summary
Tuberculosis (TB) remains one of the top 10 causes of death worldwide, with 10 million new cases and 1.4 million deaths in 2018. Multiple logistical and physiological factors contribute to the difficulty of this task (reviewed eloquently elsewhere [3,4,5]) They include biosafety constraints of working with a slow-growing pathogenic bacterium, heterogeneity of clinical disease and bacterial phenotypes in vivo, intracellular and extracellular M.tb sites, drug penetration into lung pathology, the lipid-rich M.tb cell wall as a barrier to drug uptake and intrinsic drug resistance, limited number of validated drug targets, the requirement for combination drug therapy, and the length and cost of clinical trials. We focus on (a) target identification, in this context the recognition of potentially druggable pathways worthy of drug discovery efforts in a target-based approach; (b) mode of action studies, often aimed at progressing hits from whole cell compound screening strategies on the long road to the TB clinic (Figure 1)
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