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

• Published in: Communications biology Vol. 5; no. 1; p. 685
• Main Authors: Theriault, Monique E., Pisu, Davide, Wilburn, Kaley M., Lê-Bury, Gabrielle, MacNamara, Case W., Michael Petrassi, H., Love, Melissa, Rock, Jeremy M., VanderVen, Brian C., Russell, David G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 09.07.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38/39; 38/90; 38/91; 631/326/421; 692/699/255/1856; Biology; Biomedical and Life Sciences; Carbon; Carbon sources; Cholesterol; Iron; Life Sciences; Lipid metabolism; Lung diseases; Macrophages; Metabolism; Mycobacterium tuberculosis; Tuberculosis
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-03650-z

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