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macrophage's tranferrin receptors, since mycobactin is not efficient in removing
iron from transferrin. Both mycobactin J and its ferric-complex were recovered
from the cell-aqueous phase. However, fluorescent confocal microscopy showed
that although mycobactin J freely diffuses between the phagosome and the intra-
cellular environment, Fe 3 + -MbJ generally is localized in lipid droplets of the cell
wall [ 32 ]. Work performed by Gobin showed that carboxymycobactin T was capa-
ble of removing iron from 40 % saturated hTf, the approximate levels found in
human serum. Carboxymycobactin T can also remove the metal from lactoferrin
and ferritin although at a slower rate. Potentially operating as a cooperative sys-
tem, carboxymycobactin T can serve as a source of iron for mycobactin T [ 33 , 34 ].
Information regarding the role of carboxymycobactin T was obtained through
the identification of the genes irtA and irtB. Rodriguez et al. studied the role of the
transporter IrtAB in M. tuberculosis . Without affecting siderophore biosynthesis,
selective mutation interfered with the bacterial ability to use ferric-carboxymyco-
bactin T. Under iron-sufficient conditions, the irtAB mutants did not display growth
deficiencies. While single mutations (irtA, irtB) were better tolerated, the double
irtAB mutant was incapable of growing in iron-deficient conditions. Remarkably,
ferric-carboxymycobactin T was used efficiently without the assistance of myco-
bactin T by a mycobactin mutant of M. tuberculosis , a strain incapable of synthesiz-
ing siderophores [ 35 , 37 ]. It is not clear if mycobactin T uses the IrtAB transporter
or if it diffuses through the cell envelope due to its hydrophobicity. In any case,
similar to other bacterial siderophore systems, the release of iron from the myco-
bactin T or carboxymycobactin T in M. tuberculosis , could take place by metal
reduction to its ferrous form. Evidence for this was obtained when Ratledge [ 38 ]
studied the reductase-triggered iron release from ferric-mycobactin S in M. smeg-
matis [ 38 - 40 ]. Details about iron delivery into the mycobacterial cytoplasm and the
exact mechanism of acquisition in vivo are still the subject of current research.
5.4 Siderophore-Antibiotic Conjugates
The importance of iron has prompted bacteria to develop the ability to recog-
nize exogenous ferric-siderophores in order to obtain a competitive advantage.
Sideromycins are naturally occurring siderophore-antibiotic conjugates (Fig. 5.4 )
synthesized by a variety of bacteria to counter the thievery of metallic complexes.
The albomycins ( 8 ) are hydroxamate-based sideromycins containing a lethal
seryl-t-RNA synthetase inhibitor that is released by the activity of a serine pepti-
dase N in some bacteria. The inability of other bacteria to actively transport the
ferric-albomycin and the lack of the enzymatic activity to release the antibiotic
moiety, results in no inhibitory activity by these compounds [ 41 , 42 ]. Microcin
MccE492m ( 9 ) is an enterobactin-based, peptide antibiotic-conjugate. Microcins
are pH and heat stable peptides secreted by enterobacteria under nutrient restric-
tive environments. MccE492m, secreted by K. pneumonaie RYC492, displays
potent and specific inhibitory activity (MIC = 0.2-1.2 μ M) against Escherichia
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