Mycobacterial Iron Acquisition Mechanisms - Iron Acquisition by the Genus Mycobacterium - page 46

siderophores in the double deletion mutant was due to decreased production of
these siderophores because the mycobactin core biosynthetic enzyme MbtG may
be inner membrane associated [ 40 ]. It was postulated that mmpS4 and mmpS5 are
genes encoding components of a siderophore export system essential for virulence
of M. tuberculosis [ 40 ] and the inability to export carboxymycobactin might lead
to inefficient siderophore synthesis, coupling synthesis with secretion. The alveo-
lar macrophage in which M. tuberculosis grows maintains a low level of phago-
somal iron yet the wild-type pathogen overcomes this iron-withholding defense
probably using its mycobactin class of siderophores. It is uncertain if the low-
ered amounts of siderophore produced by the mmpS4 and mmpS5 double deletion
mutant altered iron acquisition and thereby affected virulence.
3.4 Mycobacterial Iron Acquisition from Heme
Similar to many other pathogenic microorganisms, the mycobacteria have not
ignored the 70 % of total iron in a mammal that is present in heme [ 41 - 43 ]. The
growth defect noted in an M. tuberculosis strain deficient in production of the
mycobactin class of siderophores could be satisfied with heme [ 42 ]. It is uncer-
tain how heme is taken up by the mycobacteria and heme must be degraded for
redistribution of iron into various metabolic systems. Lysins and proteases may be
required to make heme available. Contact dependent hemolytic activity has been
reported in Mycobacterium avium and M. tuberculosis [ 43 , 44 ].
Whereas in liquid medium, heme restored growth of a double deletion mutant
of the mmpS4 and mmpS5 genes (described above in Sect. 3.4 ) to the wild-type
level, growth of the double mutant on agar was not fully restored by addition of
hemoglobin to the agar [ 40 ]. Interestingly, this growth impairment of the double
mutant was abolished if the double mutant also could not synthesize the carboxy-
mycobactin/mycobactin siderophore group, illustrating one of the complexities of
iron acquisition from sources other than the siderophores.
3.5 Ferritin and Mycobacterial Persistence in Animals
Because of the capacity of iron to catalyze production of free radicals, it is essen-
tial the mycobacteria sequester intracellular iron yet make the metal readily avail-
able for insertion into metabolism. Most of the intracellular iron may be present
in iron storage proteins [ 46 ] and two iron storage proteins have been identified,
namely BfrA (a bacterioferritin) and BfrB (a ferritin-like protein) [ 47 ]. Disruption
of the relevant genes bfrA and bfrB in M. tuberculosis significantly lowered in
vitro growth of the microorganism and attenuated growth in human macrophages
[ 48 ]. The expression of both iron storage genes is regulated by the iron control
protein IdeR. A mutant strain of M. tuberculosis lacking both bfrA and bfrB also is