Iron Acquisition in Mycobacterium tuberculosis

Abstract

The highly contagious disease tuberculosis (TB) is caused by the bacterium Mycobacterium tuberculosis (Mtb), which has been evolving drug resistance at an alarming rate. Like all human pathogens, Mtb requires iron for growth and virulence. Consequently, Mtb iron transport is an emerging drug target. However, the development of anti-TB drugs aimed at these metabolic pathways have been restricted by the dearth of information on Mtb iron acquisition. In this review, we describe the multiple strategies utilized by Mtb to acquire ferric iron and heme-iron. Mtb iron uptake is a complex process, requiring biosynthesis and subsequent export of Mtb siderophores, followed by ferric iron scavenging and ferric-siderophore import into Mtb. Additionally, Mtb possesses two possible heme uptake pathways, and an Mtb-specific mechanism of heme degradation that yields iron and novel heme-degradation products. We conclude with perspectives for potential therapeutics that could directly target Mtb heme and iron uptake machineries. We also highlight how hijacking Mtb heme and iron acquisition pathways for drug import may facilitate drug transport through the notoriously impregnable Mtb cell-wall.

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.…”

“…M. marinum and other pathogenic or environmental Mycobacterium species produce two variants of mycobactin, the hydrophobic MBT and the hydrophilic cMBT. Intriguingly, in M. marinum mycobactins, the long acyl side chain (MBT) or the acyl chain with a terminal carboxyl group (cMBT) is attached adjacent to the central ester group of the mycobactin core structure (Figures 1b,e and S3, S4: R 2 ), whereas in M. tuberculosis , M. smegmatis , and other mycobacterial species, the long (carboxylated) acyl chain is attached to the peripheral hydroxamate moiety (Chao et al, ; Sritharan, ). The functional consequences (if any) of these peculiar modifications of M. marinum MBT and cMBT are not clear.…”

“…Pathogenic mycobacteria, such as M. marinum or M. tuberculosis , replicate in host cells in a distinct, membrane‐bound pathogen vacuole called MCV, followed by rupture of the vacuole membrane and exit of the bacteria to the cytoplasm (Cardenal‐Munoz et al, ; Koliwer‐Brandl et al, ; Russell, ). The MCV represents a metal ion‐poor environment (Chao et al, ), which is depleted of iron due to the activity of NRAMP‐1, a proton‐driven transporter of ferric iron (Bozzaro, Buracco, & Peracino, ; Buracco et al, ; Buracco, Peracino, Andreini, Bracco, & Bozzaro, ; Peracino, Buracco, & Bozzaro, ).…”

“…The release/export pathway of newly synthesised M. marinum mycobactins across the bacterial inner membrane is not known. M. tuberculosis utilises for this process two transmembrane “mycobacterial membrane protein large” (MmpL) proteins, MmpL4 and MmpL5, along with adaptors of the family of “mycobacterial membrane protein small” (MmpS) proteins, MmpS4 and MmpS5, which associate with the inner membrane on the periplasmic side (Wells et al, ; Chalut, ; Chao, Sieminski, Owens, & Goulding, ). It remains unclear how exactly mycobactins are exported across the periplasm, the cell envelope (cell wall and outer membrane), and the capsule.…”