Handling the Hurdles on the Way to Anti-tuberculosis Drug Development

Abstract

The global epidemic of tuberculosis (TB) imposes a sustained epidemiologic vigilance and investments in research by governments. Mycobacterium tuberculosis, the main causative agent of TB in human beings, is a very successful pathogen, being the main cause of death in the population among infectious agents. In 2018, ∼10 million individuals were contaminated with this bacillus and became ill with TB, and about 1.2 million succumbed to the disease. Most of the success of the M. tuberculosis to linger in the population comes from its ability to persist in an asymptomatic latent state into the host and, in fact, the majority of the individuals are unaware of being contaminated. Even though TB is a treatable disease and is curable in most cases, the treatment is lengthy and laborious. In addition, the rise of resistance to first-line anti-TB drugs elicits a response from TB research groups to discover new chemical entities, preferably with novel mechanisms of action. The pathway to find a new TB drug, however, is arduous and has many barriers that are difficult to overcome. Fortunately, several approaches are available today to be pursued by scientists interested in anti-TB drug development, which goes from massively testing chemical compounds against mycobacteria, to discovering new molecular targets by genetic manipulation. This review presents some difficulties found along the TB drug development process and illustrates different approaches that might be used to try to identify new molecules or targets that are able to impair M. tuberculosis survival.

Combined Bioinformatics and Combinatorial Chemistry Tools to Locate Drug‐Able Anti‐TB Phytochemicals: A Cost‐Effective Platform for Natural Product‐Based Drug Discovery

“…The combination of modern combinatorial chemistry, advanced instruments, and multi‐omics data analysis provides a new hope to increase the success rate; additionally, several isolated active phytochemicals with high potency have been structurally modified and chemically combined, or even several active moieties were used separately in hybrid form to gain drug‐ability profiles [39,42,46,48,49] . Newer anti‐TB derivatized drug candidates, such as SQ609, PBTZ169, and BTZ043, possess a piperine‐like phyto‐pharmacophore, which inhibits the synthesis of Mtb‐cell walls [50–52] . Even the most promising tiliacorinine moiety undergoes modification by several drug/pharmaceutical researchers for further therapeutic and pharmacological improvement [53] …”

“…[39,42,46,48,49] Newer anti-TB derivatized drug candidates, such as SQ609, PBTZ169, and BTZ043, possess a piperine-like phyto-pharmacophore, which inhibits the synthesis of Mtb-cell walls. [50][51][52] Even the most promising tiliacor-inine moiety undergoes modification by several drug/ pharmaceutical researchers for further therapeutic and pharmacological improvement. [53] CADD platforms provide several convenient and user-friendly tools for accelerating the lead selection in anti-TB drug development from a large library of phytochemicals.…”

Development of Predictive Classification Models for Whole Cell Antimycobacterial Activity of Benzothiazinones

“…As a consequence, public and non-profit organizations are currently making substantial efforts to revitalize the field of TB antibiotic research and development. The inspiration for leads with novel mechanisms of action is largely catalyzed by innovative screening methods and models, as well as a detailed disease understanding. ,,,− Effective treatments for drug-resistant TB, however, are still lacking and urgently needed.…”

Isoxazole carboxylic acid methyl ester-based urea and thiourea derivatives as promising antitubercular agents

“…Apparently, anti-TB drug discovery research revolves around very limited privileged chemical classes and targets [ 9 , 10 ]. Owing to the challenge in permeability posed by complex waxy nature of Mtb cell envelope, majority of these anti-TB chemotypes and targets are focused on extracellular pathway [ 11 , 12 ].…”