Early Drug Development and Evaluation of Putative Antitubercular Compounds in the -Omics Era.

Alina Minias,Filip Gąsior,Sabina Podlewska,Daria Zygała,Ewelina Lechowicz,Jarosław Dziadek,Lidia Żukowska,Agnieszka Knast

doi:10.3389/fmicb.2020.618168

Abstract

Tuberculosis (TB) is an infectious disease caused by the bacterium Mycobacterium tuberculosis. According to the WHO, the disease is one of the top 10 causes of death of people worldwide. Mycobacterium tuberculosis is an intracellular pathogen with an unusually thick, waxy cell wall and a complex life cycle. These factors, combined with M. tuberculosis ability to enter prolonged periods of latency, make the bacterium very difficult to eradicate. The standard treatment of TB requires 6–20months, depending on the drug susceptibility of the infecting strain. The need to take cocktails of antibiotics to treat tuberculosis effectively and the emergence of drug-resistant strains prompts the need to search for new antitubercular compounds. This review provides a perspective on how modern -omic technologies facilitate the drug discovery process for tuberculosis treatment. We discuss how methods of DNA and RNA sequencing, proteomics, and genetic manipulation of organisms increase our understanding of mechanisms of action of antibiotics and allow the evaluation of drugs. We explore the utility of mathematical modeling and modern computational analysis for the drug discovery process. Finally, we summarize how -omic technologies contribute to our understanding of the emergence of drug resistance.

Highlights

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis
According to data from Treatment Action Group, there was the funding of US$ 772 million for TB research and development in 2017, which is much less than the target of at least US$ 2 billion per year set at the UN high-level meeting on TB (World Health Organization, 2019)
We explore the utility of mathematical modeling and modern computational analysis for the drug discovery process

Summary

INTRODUCTION

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. The disease is one of the top 10 causes of death of people, according to the WHO. According to data from Treatment Action Group, there was the funding of US$ 772 million for TB research and development in 2017, which is much less than the target of at least US$ 2 billion per year set at the UN high-level meeting on TB (World Health Organization, 2019). Designing a new drug and bringing it to market is a very time-consuming process that can take up many years (Hughes et al, 2011) This process is highly costly, with little prospect of reimbursement from developing countries where tuberculosis is most prevalent. If the chemical is toxic at low doses for the pathogen but not toxic for eukaryotic cells, the compound may be further tested for its effectiveness in intracellular infection models and animal models before reaching the clinical trial phase.

Methods

Findings

CONCLUSION