Drug Discovery Platform Targeting M. tuberculosis with Human Embryonic Stem Cell-Derived Macrophages

Abstract

Summary: A major limitation in anti-tuberculosis drug screening is the lack of reliable and scalable models for homogeneous human primary macrophage cells of non-cancer origin. Here we report a modified protocol for generating homogeneous populations of macrophage-like cells from human embryonic stem cells. The induced macrophages, referred to as iMACs, presented similar transcriptomic profiles and characteristic immunological features of classical macrophages and were permissive to viral and bacterial infection, in particular Mycobacterium tuberculosis (Mtb). More importantly, iMAC production was amenable to scale up. To evaluate iMAC efficiency in high-throughput anti-tuberculosis drug screening, we performed a phenotypic screening against intracellular Mtb, involving a library of 3,716 compounds that included FDA-approved drugs and other bioactive compounds. Our primary screen identified 120 hits, which were validated in a secondary screen by dose-intracellular and -extracellular Mtb assays. Our confirmatory studies identified a novel anti-Mtb compound, 10-DEBC, also showing activity against drug-resistant strains. : In this article, Jung-Hyun Kim and colleagues show a protocol for generating macrophage-like cells from PSCs that exhibit features of classical phagocytes, are amenable to scale up, permissive to Mycobacterium tuberculosis infection, and suitable for intracellular high-throughput screening. By performing screening of 3,716 compounds, they found a new, potent anti-tuberculosis drug against drug-resistant strains of M. tuberculosis. Keywords: human embryonic stem cell-derived induced macrophage-like cells (iMACs), Mycobacterium tuberculosis (Mtb), drug discovery platform, anti-tuberculosis compound