Siderocalin Combats Mycobacterial Infections - Iron Acquisition by the Genus Mycobacterium - page 56

To acquire host iron, pathogenic mycobacteria use two structurally-related fam-
ilies of siderophores: mycobactins and carboxymycobactins (Fig. 4.2 ) [ 21 ]. Both
families use one hydroxyphenyl-oxazoline and two hydroxamate groups to coordi-
nate iron. The iron binding units are linked by a lysine derived backbone with vari-
ous alkyl substituents. The mycobactins have one hydroxamate attached to a long
saturated or unsaturated alkyl chain (n = 6-17), making the siderophores lipo-
philic [ 22 - 24 ]. The carboxymycobactins have the same hydroxamate attached to
a shorter saturated alkyl chain (n = 3-10) that terminates in a carboxylate, making
the siderophores hydrophilic [ 10 , 22 , 25 ]. The opposite solubility of carboxymy-
cobactins and mycobactins is a distinguishing feature between the two siderophore
families.
Synthesis of both carboxymycobactin and mycobactin is a response to iron-
limited conditions and the structural similarity of the two alludes to an analogous
biosynthesis. Both siderophore families are products of the same non-ribosomal
peptide synthetase encoded by the gene loci mbt - 1 and mbt - 2 [ 26 - 28 ]. Each gene
loci contains binding sites for IdeR, an iron-responsive DNA-binding protein.
IdeR binds iron in iron-replete conditions and represses siderophore biosynthesis.
When iron levels fall, apo-IdeR releases DNA and siderophore synthesis is dere-
pressed [ 26 , 29 ].
Even though the structure and regulation of carboxymycobactin and myco-
bactin are directly related, the mechanism of iron acquisition is dissimilar due to
the differing solubilities of each siderophore. Hydrophilic carboxymycobactin
is secreted to the extracellular environment to bind host iron and transport it to
the pathogen. This mechanism has been observed in most bacterial siderophores;
however, the extracellular environment of mycobacteria is unique because the
pathogen inhabits macrophage phagocytes. To grow in the iron-limiting conditions
found in macrophages, M. tuberculosis needs carboxymycobactin to steal iron
from the host [ 29 , 30 ]. Human transferrin, lactoferrin, and ferritin, the major iron
storage protein of mononuclear phagocytes, all release iron to carboxymycobactin
[ 31 ]. Both exogenous and endogenous iron sources supply M. tuberculosis with
iron, although it is not known if carboxymycobactins are confined to the mycobac-
terial phagosome or if they go to the macrophage cytoplasm and beyond to chelate
iron [ 32 , 33 ]. Carboxymycobactin may not need to travel out of the phagosome
because transferrin endocytosed by the macrophage is trafficked to the phagosome
[ 34 , 35 ].
Following iron chelation, the ferric carboxymycobactin complex transports iron
to the mycobacterial cytoplasm by two different mechanisms. The first depends on
an ABC transport system. The transmembrane proteins IrtA and IrtB transport fer-
ric carboxymycobactin using energy from ATP hydrolysis. These transporters are
required for using ferric carboxymycobactin and for replication of M. tuberculosis
in media, macrophages, and mice [ 36 ].
The other transport model indicates that ferric carboxymycobactin may pass
through the cell wall through a porin to the periplasm where the lipophilic mycobac-
tins are localized in the cell membrane. The mycobactins receive the iron from fer-
ric carboxymycobactin and passively carry it across the cell membrane [ 21 , 37 , 38 ].