Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 67

case of Gram-negative bacteria (left panel). The action of a TonB/ExbB/ExbD sys-
tem allows the ferri-siderophore to access the periplasmic space where it is rec-
ognized by a periplasmic binding protein (PBP) that assists in the delivery to the
cytoplasm (4) in an ATP-dependent process (5). Iron release from the siderophore
may occur by metal reduction to its ferrous form, which displays a reduced affinity
with the chelator. Degradation of the ferric-siderophore can also occur in order to
release the metal. Siderophore-acquisition by Gram-positive bacteria occurs is a
comparable fashion (right panel), where the ATP-Binding Cassette (ABC) proteins
involved in the active transport of ferric-siderophores are related to the system
found in Gram-negative bacteria [ 21 - 25 ].
5.3 Siderophore System in M . tuberculosis
To acquire iron, M. tuberculosis secretes two structurally-related siderophores
(Fig. 5.3 ). Mycobactin T ( 6 ) discovered by Snow in 1965, is characterized by the
presence of a long hydrophobic alkyl chain [ 29 , 30 ]. Initially proposed to func-
tion as a membrane-bound, temporary Fe 3 + -storage, recent evidence indicates
that Mycobactin T is a more active player in the iron-uptake by M. tuberculosis
[ 31 , 32 ]. The second chelator, carboxymycobactin T ( 7 ), was isolated in 1995 by
Gobin from virulent M. tuberculosis ATCC 35801 and avirulent M. tuberculosis
H 37 Ra. Initially referred to as exochelin, its structure was found to be similar to
that of mycobactin T albeit with a shorter alkyl chain and the presence of an ion-
izable group, rendering a more water-soluble siderophore [ 33 , 34 ]. Analogous to
other siderophore systems, under iron-sufficient conditions the biosyntheses of
mycobactin T and carboxymycobactin T are regulated at the genetic level by the
ferrous-complex of the repressor protein IdeR [ 35 ]. A comprehensive review by
Quadri describes the recent findings regarding mycobacterial iron acquisition [ 36 ].
A clearer idea regarding role of the hydrophobic mycobactin T was observed
when Luo et al. [ 32 ] studied the effect of mycobactin in iron-uptake within human
macrophages. By monitoring the formation of ferric-siderophore, mycobactin J ( 4 )
was demonstrated to be capable of acquiring iron from the macrophage's intra-
cellular pools. The addition of metal-complexes of human transferrin (hTf) influ-
enced the formation of the ferric-siderophore possibly by metal release from the
Fig. 5.3 Siderophores secreted by M. tuberculosis [ 34 , 61 , 62 ]