Iron limitation in M. tuberculosis has broad impact on central carbon metabolism | Communications Biology

An inhibitor of Mycobacterium tuberculosis (Mtb) survival acts as an iron chelator, demonstrating that iron deprivation alters Mtb cholesterol and central carbon metabolism.


Communications Biology

volume 5, Article number: 685 (2022)
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Mycobacterium tuberculosis (Mtb), the cause of the human pulmonary disease tuberculosis (TB), contributes to approximately 1.5 million deaths every year. Prior work has established that lipids are actively catabolized by Mtb in vivo and fulfill major roles in Mtb physiology and pathogenesis. We conducted a high-throughput screen to identify inhibitors of Mtb survival in its host macrophage. One of the hit compounds identified in this screen, sAEL057, demonstrates highest activity on Mtb growth in conditions where cholesterol was the primary carbon source. Transcriptional and functional data indicate that sAEL057 limits Mtb’s access to iron by acting as an iron chelator. Furthermore, pharmacological and genetic inhibition of iron acquisition results in dysregulation of cholesterol catabolism, revealing a previously unappreciated linkage between these pathways. Characterization of sAEL057’s mode of action argues that Mtb’s metabolic regulation reveals vulnerabilities in those pathways that impact central carbon metabolism.

Mycobacterium tuberculosis (Mtb), the causative agent of the pulmonary disease tuberculosis (TB), has evolved to be a highly specialized and successful human pathogen. Mtb’s success may be attributed to the bacterium’s ability to adopt an intracellular lifestyle that overcomes nutrient availability and environmental stressors1. This phenotypic plasticity ensures Mtb’s persistence even in the face of a robust immune response or prolonged antibiotic treatment2,3,4. Understanding the pathways that Mtb mobilizes to maintain its survival is of considerable importance to the development of new therapeutic strategies to eradicate TB.

Iron is an essential micronutrient for almost all living organisms and has been implicated in the survival of many different human pathogens5. The utility of iron derives from the metal’s ability to transition between oxidation states, making it an important enzyme cofactor in several essential biological processes, including DNA replication6 and electron transport7. Due to restricted iron availability within the host, many pathogens have evolved elaborate mechanisms for scavenging iron from host storage proteins. In most bacteria, this is accomplished with siderophores, which are small molecules with high avidity for iron8. Mtb possesses two such siderophores—mycobactin, a nonsoluble siderophore that remains cell wall-associated, and carboxymycobactin, the soluble form of mycobactin that is secreted into the extracellular environment9. Both of these siderophores chelate and bind to ferric iron (Fe3+), which is then transported back into the bacterial cell. The iron is reduced to ferrous iron (Fe2+), which facilitates its release for utilization or storage. Intracellular iron levels are tightly regulated by the iron-sensing transcriptional activator/repressor IdeR, as both low and high iron concentrations can be toxic to the bacteria10.

A recent assessment of the relative fitness of Mtb in a murine challenge model has revealed that the bacteria experience different host-dependent stressors that are linked to both the physiological states and the ontogenic origin of their host macrophage populations11,12,13. In broad terms, the resident alveolar macrophages (AMs) are more permissive to bacterial growth than the recruited, blood monocyte-derived interstitial macrophages (IMs). Dual RNA-seq analysis of host and bacteria demonstrated that Mtb in IMs experienced iron deprivation as a consequence of the iron-sequestration program mobilized by their host cells12. These bacilli exhibit upregulation of genes involved in mycobactin synthesis (mbtA-L) and iron import (irtA-B), which contrasts directly with those bacteria residing in AMs that show upregulation of transcripts for the iron storage protein (bfrB), indicating iron-replete conditions. These observations suggest that iron availability may be one of the major factors at the immune-metabolic interface involved in the control of Mtb infection11,14. These data also agree with earlier evidence that the intravacuolar iron levels in Mtb-infected macrophages varied directly with bacterial fitness and inversely with macrophage activation status15.