“Upcycling” known molecules and targets for drug-resistant TB

Abstract

Despite reinvigorated efforts in Tuberculosis (TB) drug discovery over the past 20 years, relatively few new drugs and candidates have emerged with clear utility against drug resistant TB. Over the same period, significant technological advances and learnings around target value have taken place. This has offered opportunities to re-assess the potential for optimization of previously discovered chemical matter against Mycobacterium tuberculosis (M.tb) and for reconsideration of clinically validated targets encumbered by drug resistance. A re-assessment of discarded compounds and programs from the “golden age of antibiotics” has yielded new scaffolds and targets against TB and uncovered classes, for example beta-lactams, with previously unappreciated utility for TB. Leveraging validated classes and targets has also met with success: booster technologies and efforts to thwart efflux have improved the potential of ethionamide and spectinomycin classes. Multiple programs to rescue high value targets while avoiding cross-resistance are making progress. These attempts to make the most of known classes, drugs and targets complement efforts to discover new chemical matter against novel targets, enhancing the chances of success of discovering effective novel regimens against drug-resistant TB.

Natural products and their analogues acting against Mycobacterium tuberculosis: A recent update

“…Sequanamycin A (SEQ‐503) (46 , Figure 7) is a macrolide antibiotic and has been revisited to develop analogues with improved anti‐TB potency, pharmacokinetic properties and metabolic stability (Nicolas BAURIN, 2015; Roubert et al, 2022). 46 was modified by a chemical optimization approach to afford compound SEQ‐9 (47 , Figure 7), which has a better mycobacterial potency in acute in vivo murine models with good pharmacokinetic properties (Evans & Mizrahi, 2018; Stec & Abourashed, 2015).…”

“…Such challenges beg the scientific community to up the ante for TB research and explore new therapeutic avenues to tackle persistent infections and cure TB quickly. In recent years reviews have been published on TB, and their themes include TB targets and preclinical and clinical anti‐TB agents for treating susceptible and MDR‐TB strains (Borsari et al, 2017; Gawad & Bonde, 2018; Huszár et al, 2020; J Libardo et al, 2018; Kumar & Kapoor, 2023; Perveen et al, 2022; Roubert et al, 2022). Some studies highlighted natural products, including antimicrobial peptides, as anti‐TB agents (Han et al, 2022; Igarashi, 2017; Quan et al, 2017).…”