A History of Iron Metabolism in the Mycobacteria - Iron Acquisition by the Genus Mycobacterium - page 32

The only species of Mycobacterium that failed to produce detectable amounts
of carboxymycobactin was M. microti which also appeared not to produce a myco-
bactin [ 99 ]. This species therefore is an oddity amongst the mycobacteria in pro-
ducing neither mycobactin nor a carboxymycobactin and clearly would warrant
further investigation as to what is its mechanism of iron acquisition. It is, however,
a genuine mycobacterium in that it is the causative organism of tuberculosis in
voles and other rodents but has also been associated with some isolated cases of
TB in humans [ 107 ]. Some investigation into iron metabolism in this species may
therefore be warranted.
What came as a complete surprise during this phase of our work was the find-
ing of a carboxymycobactin in culture filtrates of M. smegmatis grown iron defi-
ciently [ 108 ]. The presence of exochelin MS in this species had appeared to be
sufficient to account for iron uptake in the saprophyte so the presence of a second,
and alternative, method of iron acquisition was unexpected. However, the amounts
of carboxymycobactin (10-25 μ g/ml) that were produced were, at most, only
10 % of the total siderophores. Also it was produced later in the growth of the cells
indicating that the exochelin-dependent route of iron assimilation was probably
the major one. It was also noted that the amount of carboxymycobactin was some
20 times higher when glycerol was used as a carbon source instead of glucose.
The structure of this carboxymycobactin was subsequently determined [ 104 ] and
was found to resemble the structure of mycobactin S with a family of short car-
boxylic acids attached to the mycobactin nucleus. Some eight variants of the mol-
ecule were identified [ 6 , 104 ] and this could then partly explain why Barclay and
Ratledge [ 61 , 99 ] found such a plethora of iron-binding molecules when they first
examined the carboxymycobactins from pathogenic mycobacteria by high resolu-
tion chromatographic techniques.
2.6 Putting it All Together
How the various components of iron metabolism come together to present a coher-
ent picture of iron uptake and transport in mycobacteria still has a long way to
go. But we are getting there. It is not, however, the remit of this chapter to go
into the details of how the various components enumerated above dovetail together
but, for the sake of completeness, I have included the very first model that was
proposed in 1975 for iron transport in the mycobacteria (Fig. 2.10 ) that does not
distinguish between the water-soluble exochelins of the saprophytic strains and the
chloroform-soluble ones of the pathogens [ 100 ]. A more detailed model proposed
in 1999 is given in Fig. 2.11 . In this model, besides the major routes of iron uptake
via the exochelins and carboxymycobactins, the uptake of iron chelated to citrate
was worked out by Ann Messenger [ 93 ] and assimilation of iron by direct binding
of a mycobacterial cell to transferrin or lactoferrin was proposed by Lambrecht
and Collins [ 106 ] probably involving an extracellular ferric reductase as iden-
tified by Homuth et al. [ 105 ]. This enzyme could also work with ferritin and