Recent advances in inhibitor development and metabolic targeting in tuberculosis therapy

Despite being a preventable and treatable disease, tuberculosis (TB) remained the second leading infectious cause of death globally in 2022, surpassed only by COVID-19. The death rate from TB is influenced by numerous factors that include antibiotic drug resistance, noncompliance with chemotherapy by patients, concurrent infection with the human immunodeficiency virus, delayed diagnosis, varying effectiveness of the Bacille-Calmette-Guerin vaccine, and other factors. Even with the recent advances in our knowledge of Mycobacterium tuberculosis and the accessibility of advanced genomic tools such as proteomics and microarrays, alongside modern methodologies, the pursuit of next-generation inhibitors targeting distinct or multiple molecular pathways remains essential to combat the increasing antimicrobial resistance. Hence, there is an urgent need to identify and develop new drug targets against TB that have unique mechanisms. Novel therapeutic targets might encompass gene products associated with various aspects of mycobacterial biology, such as transcription, metabolism, cell wall formation, persistence, and pathogenesis. This review focuses on the present state of our knowledge and comprehension regarding various inhibitors targeting key metabolic pathways of M. tuberculosis. The discussion encompasses small molecule, synthetic, peptide, natural product and microbial inhibitors and navigates through promising candidates in different phases of clinical development. Additionally, we explore the crucial enzymes and targets involved in metabolic pathways, highlighting their inhibitors. The metabolic pathways explored include nucleotide synthesis, mycolic acid synthesis, peptidoglycan biosynthesis, and energy metabolism. Furthermore, advancements in genetic approaches like CRISPRi and conditional expression systems are discussed, focusing on their role in elucidating gene essentiality and vulnerability in Mycobacteria.