Harnessing Actinobacteria secondary metabolites for tuberculosis drug discovery: Historical trends, current status and future outlooks.

Tuberculosis (TB) is a leading infectious disease killer and one of the major causes of deaths worldwide. Although TB is a curable and preventable disease, in 2023, approximately 10.8 million people fell ill with TB and there were an estimated 1.25 million of deaths worldwide. Despite some research progress for new drug candidates, drug repurposing, and new regimens, there is still an urgent need for the new medicins to treat TB, especially due to the growing cases of multidrug and extensively drug-resistant (MDR/XDR) strains. Drug resistance is a challenging obstacle to TB care and prevention globally, making TB harder and longer to treat, often with poorer outcomes for patients. The Actinomycetota encompass Gram-positive bacteria that produce a milieu of bioactive metabolites, including antibiotics, antiproliferative drugs, immunosuppressive agents, and other important medical molecules. Actinomycetota have a special place in the therapeutic arsenal to fight TB, as rifamycins, aminoglycosides, and cycloserine are derived from Streptomyces species, one of the most important genera in this phylum. Furthermore, hundreds of antimycobacterial metabolites have been isolated from Actinomycetota and can serve as effective drugs or useful agents for the discovery of new lead compounds to combat TB. The present review covers more than 171 isolated substances as potential antimycobacterial agents discovered between the years 1972 to 2024. Among the most potent compounds, with MIC in the submicromolar range, steffimycins, ilamycins/rufomycins, nosiheptide, actinomycins, lassomycin and boromycin are the most promising compounds. These compounds represent highly promising candidates for development of new antitubercular drugs. Additionally, some of these substances also demonstrated activity against resistant Mycobacterium tuberculosis (Mtb) strains, which is particularly relevant given the difficulty of treating MDR and XDR strains. Thus, actinobacteria have played and continue to play an important role in fight TB, remaining a promising source of antibiotic metabolites. Their unique metabolic diversity enables the production of metabolites with innovative mechanisms of action, making them a strategic reservoir for discovering therapies against untreatable forms of the disease.