Exogenously Scavenged and Endogenously Synthesized Heme Are Differentially Utilized by Mycobacterium tuberculosis
Rebecca K. Donegan, Yibo Fu, Jacqueline Copeland, Stanzin Idga, Gabriel Brown, Owen F. Hale, Avishek Mitra, Hui Yang, Harry A. Dailey, Michael Niederweis, Paras Jain, Amit R. Reddi
Abstract
Mycobacterium tuberculosis infects ~25% of the world's population and causes tuberculosis (TB), the second leading cause of death from infectious disease. Heme is an essential metabolite for M. tuberculosis, and targeting the unique heme biosynthetic pathway of M. tuberculosis could serve as an effective therapeutic strategy. However, since M. tuberculosis can both synthesize and scavenge heme, it was unclear if inhibiting heme synthesis alone could serve as a viable approach to suppress M. tuberculosis growth and virulence. The importance of this work lies in the development and application of genetically encoded fluorescent heme sensors to probe bioavailable heme in M. tuberculosis and the discovery that endogenously synthesized heme is more bioavailable than exogenously scavenged heme. Moreover, it was found that heme synthesis protected M. tuberculosis from macrophage killing, and bioavailable heme in M. tuberculosis is diminished during macrophage infection. Altogether, these findings suggest that targeting M. tuberculosis heme synthesis is an effective approach to combat M. tuberculosis infections.