Acting as gatekeepers at the junction between the glyoxylate shunt and the TCA cycle, the isocitrate lyase (ICL) isoforms 1 and 2 are critical metabolic enzymes that enable the virulence and survival of Mycobacterium tuberculosis.1,2,3 Details about the regulation and modulation of ICL enzymatic activities at the protein level is interesting and significant. The redirection of the carbon flow through metabolites between these two key central carbon metabolism pathways may hold key information that enables potential new approaches to treat tuberculosis.4 Herein, we report our work on the activation of ICLs through bacterial lipid metabolites and the inhibition of ICLs through mammalian antimicrobial metabolites. By using X-ray crystallography, mutagenesis and kinetic studies, we reveal in atomic details about how these metabolites modulate the activities of the different ICL isoforms. Our results provide new fundamental knowledge about the central carbon metabolism of M. tuberculosis, opening opportunities for the development of new antitubercular treatments in the long term.