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

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.

A New Benzothiazolthiazolidine Derivative, 11726172, Is Active In Vitro , In Vivo , and against Nonreplicating Cells of Mycobacterium tuberculosis

“…The use of transcriptomic analysis for understanding a drug’s mode of action provides useful insights into the target pathways affected by the action of the compound ( 36 ). Thanks to the contribution of transcriptomics, we showed that 11726172 treatment perturbs both the metal homeostasis and the cytoplasmic redox potential in mycobacterial cells.…”

An integrated computational approach towards novel drugs discovery against polyketide synthase 13 thioesterase domain of Mycobacterium tuberculosis

“…Essentially, four first-line antibiotics used in the treatment of TB (isoniazid–INH, rifampicin–RMP, ethambutol–EMB, pyrazinamide–PZA) and some other drugs which can be administered to patients infected with resistant strains M. tuberculosis Although TB is curable and preventable, multidrug-resistant TB (MDR-TB) and extensively drug-resistant strains of M. tuberculosis (XDR-TB) remain a global burden rendering the standard treatment ineffective 2 . It is estimated that about 0.5 million of MDR-TB cases reported annually worldwide and nearly 14,000 XDR-TB cases were originated from 81 countries 3 , 4 . Additionally, the management of TB was further aggravated as MDR-TB developed resistant to two of the first-line drugs; RMP and INH, while XDR-TB is resistant to the four essential antitubercular drugs and at least one of the injectable second-line drugs such as amikacin, capreomycin, or kanamycin 5 , 6 .…”