Iron Homeostasis in Mycobacterium tuberculosis: Mechanistic Insights into Siderophore-Mediated Iron Uptake

Abstract

Mycobacterium tuberculosis requires iron for normal growth but faces a limitation of the metal ion due to its low solubility at biological pH and the withholding of iron by the mammalian host. The pathogen expresses the Fe 3؉ -specific siderophores mycobactin and carboxymycobactin to chelate the metal ion from insoluble iron and the host proteins transferrin, lactoferrin, and ferritin. Siderophore-mediated iron uptake is essential for the survival of M. tuberculosis, as knockout mutants, which were defective in siderophore synthesis or uptake, failed to survive in low-iron medium and inside macrophages. But as excess iron is toxic due to its catalytic role in the generation of free radicals, regulation of iron uptake is necessary to maintain optimal levels of intracellular iron. The focus of this review is to present a comprehensive overview of iron homeostasis in M. tuberculosis that is discussed in the context of mycobactin biosynthesis, transport of iron across the mycobacterial cell envelope, and storage of excess iron. The clinical significance of the serum iron status and the expression of the iron-regulated protein HupB in tuberculosis (TB) patients is presented here, highlighting the potential of HupB as a marker, notably in extrapulmonary TB cases.

Mycobacterium marinum produces distinct mycobactin and carboxymycobactin siderophores to promote growth in broth and phagocytes

“…Thus, all dominant m/z peaks in the region of interest are accounted for. Intriguingly, in MBT of M. marinum , the long acyl side chain (R 2 ) is attached adjacent to the central ester group, whereas in MBT of M. tuberculosis , M. smegmatis , and other mycobacterial species, the long acyl chain is attached to the peripheral hydroxamate moiety (Chao et al, ; Sritharan, ).…”

“…Thus, all dominant m/z peaks in the region of interest are accounted for. Like for MBT, in cMBT of M. marinum , the acyl side chain with a terminal carboxyl group (R 2 ) is attached adjacent to the central ester group, whereas in cMBT of M. tuberculosis , M. smegmatis , and other mycobacterial species, the corresponding chain is attached to the peripheral hydroxamate moiety (Chao et al, ; Sritharan, ). In summary, M. marinum produces distinct MBT and cMBT siderophores, where the long acyl chain or the shorter, terminally carboxylated acyl chain is attached adjacent to the central ester group rather than to the peripheral hydroxamate.…”

Siderophores in Iron Metabolism: From Mechanism to Therapy Potential

“…Multidrug resistance in M. tuberculosis , the well-known bacterium that causes tuberculosis (Table 1), is dramatically increasing [56]. The biosynthesis pathways of siderophores produced by M. tuberculosis , mycobactin and the carboxylated form carboxymycobactin (Table 1), are well-understood and have been pharmacologically targeted [57]. The second step of mycobactin biosynthesis is mediated by 2,3-dihydroxybenzoate-AMP ligase (MbtA), an adenylate-forming enzyme [58].…”

Ferrous iron efflux systems in bacteria

“…IdeR, a member of DtxR family, is the major iron-dependent transcriptional regulator in M. tuberculosis 10, 11 . IdeR represses transcription of genes involved in iron uptake and siderophore biosynthesis and activates expression of genes encoding iron-storage proteins such as bacterioferritin and a ferritin-like protein 10, 11 . Since M. tuberculosis is primarily a pathogen of the mammalian respiratory system it might frequently encounter oxidative stress.…”

“…In the case of iron homeostasis, bacteria monitor intracellular iron levels using metal-sensing (metalloregulatory) proteins 7, 8 . The ferric uptake regulator (Fur) protein is the most widespread bacterial iron sensor 9 , but it can be replaced by functionally analogous proteins such as IdeR (in actinomycetes) 10, 11 and Irr (in alpha-proteobacteria) 12–14 . Fur helps to maintain iron homeostasis by regulating genes implicated in iron uptake, storage, and efflux 15 .…”