Abstract
Isocitrate lyase (ICL), a key enzyme of the glyoxylate shunt in Mycobacterium tuberculosis , is considered a potential therapeutic target for drug-resistant and persistent tuberculosis. Conventional antitubercular drugs show limited activity against bacteria persisting within granulomas, highlighting the need for new treatment strategies. This review summarizes studies published between 2020 and 2025 on the discovery, optimization, formulation, and preclinical evaluation of ICL inhibitors. Lead compounds demonstrate oral bioavailability exceeding 50% and pharmacokinetic profiles compatible with once- or twice-daily dosing. Brain-to-plasma ratios up to 0.78 indicate central nervous system penetration, supporting possible use in tuberculous meningitis. Nanotechnology-based formulations, including PLGA nanoparticles and liposomes, increased intracellular accumulation in infected macrophages and improved lung targeting. Pulmonary delivery systems achieved fine particle fractions above 50% and prolonged lung retention. Available data indicate activity against drug-resistant strains, absence of cross-resistance, and synergistic effects in combination therapy, supporting further development of ICL-targeted agents.