Tuberculosis Drug Discovery: Challenges and New Horizons

Abstract

Over the past 2000 years, tuberculosis (TB) has claimed more lives than any other infectious disease. In 2020 alone, TB was responsible for 1.5 million deaths worldwide, comparable to the 1.8 million deaths caused by COVID-19. The World Health Organization has stated that new TB drugs must be developed to end this pandemic. After decades of neglect in this field, a renaissance era of TB drug discovery has arrived, in which many novel candidates have entered clinical trials. However, while hundreds of molecules are reported annually as promising anti-TB agents, very few successfully progress to clinical development. In this Perspective, we critically review those anti-TB compounds published in the last 6 years that demonstrate good in vivo efficacy against Mycobacterium tuberculosis. Additionally, we highlight the main challenges and strategies for developing new TB drugs and the current global pipeline of drug candidates in clinical studies to foment fresh research perspectives.

Synthesis of Benzothiazinones from Benzoyl Thiocarbamates: Application to Clinical Candidates for Tuberculosis Treatment

“…The application of this method was further extended to synthesize the active pharmaceutical ingredients (APIs) BTZ‐043 [7] 1 and Macozinone [8] 2 , which are masked covalent inhibitors of DprE1 studied in clinical trials to treat multidrug‐resistant tuberculosis infection (Figure 1). [9] …”

Recent Advances in the Luminescence of Arylboronic Acids and their Heteroatom Condensates

“…They are generally stable to oxygen, water, and can tolerate broad pH ranges, making for robust compounds that can be handled in ambient conditions. These attributes have been exploited in various areas of application from catalysis to bioconjugation and drug discovery [8–10] . Further, most boronates present little toxicity, and this fact combined with their slow oxidation into boric acid makes them environmentally friendly.…”

Mutations in rv0678 confer low-level resistance to benzothiazinone DprE1 inhibitors in M. tuberculosis

“…Among these "promiscuous targets" are the trehalose dimycolate transporter MmpL3, the cytochrome bc1 oxidase subunit QcrB, and the decaprenylphosphoryl-β-Dribofuranose-2′-epimerase subunit DprE1, which is involved in the synthesis of arabinogalactan (11)(12)(13)(14). Many distinct chemical scaffolds have been found to inhibit each of these proteins and several of these compounds have advanced to clinical trials (15)(16)(17)(18)(19). Among these are the benzothiazinone (BTZ) DprE1 inhibitors including PBTZ169 (20) and BTZ043 (21,22) which are among the most potent antitubercular compounds discovered thus far, with minimum inhibitory concentrations (MICs) in the low nanomolar range (22).…”