In a three-way collaboration between a tumor immunobiologist (Powell), a chemist with expertise in glutamine (Gln) metabolism (Slusher), and a TB expert (Bishai), we have evaluated novel Gln metabolism inhibitors that are active anticancer drugs for their effectiveness against TB. Our central scientific premises are that (i) a novel Mycobacterium tuberculosis (Mtb) virulence mechanism is release of excess Gln within granulomas leading to Myeloid-derived suppressor cells (MDSC) expansion and an immunotolerant microenvironment that enables pathogen survival and (ii) that Gln metabolism inhibitors may represent a valuable host-directed therapy (HDT) approach for the treatment of TB via MDSC inhibition and enhancement of effector T cell immunity. This application will further define the immunosuppressive roles Gln in the TB granuloma and also investigate a panel of new Gln metabolism inhibitors as TB therapeutics. These studies may pave the way for Gln metabolism inhibitors that are currently being developed as anticancer drugs to be repurposed as host-directed therapies for TB and TB-HIV.