Siderophore-Mediated Iron Acquisition: Target for the Development of Selective Antibiotics Towards Mycobacterium tuberculosis - Iron Acquisition by the Genus Mycobacterium - page 65

Although several approaches can be considered to address the design of novel and
selective agents, extensive research has validated the bacterial iron-uptake systems
as a biological target for this purpose [ 12 - 16 , 17 ]. In this work we describe efforts
leading to M. tuberculosis -speciic (anti-TB) antibiotics by exploiting its iron
acquisition system.
5.2 Bacterial Iron Acquisition
Biological systems require iron. Although it is the fourth most abundant element
on Earths' crust, its bioavailability is limited by the formation of insoluble salts
in aqueous solutions ubiquitous in living organisms. The levels of ferric iron in
solution at pH 7 (10 − 9 -10 − 10 M) are considerably lower than the requirements
for bacterial growth (10 − 6 -10 − 7 M) [ 18 ]. The small and highly charged ferric ion
binds strongly to enzymes and functions as a catalyst in a variety of metabolic
processes, stressing its importance in life. The human body tightly regulates the
iron pools through the action of transferrin in plasma and lactoferrin in secretions.
These molecules further reduce the levels of iron (10 − 15 -10 − 25 M) in our bodies
[ 19 , 20 ]. The nutrient-depleted environment limits the ability of invading micro-
organisms to establish an infection and in order to satisfy their iron requirements,
bacteria and fungi secrete relatively small, high affinity ferric-chelators called
siderophores (Fig. 5.1 ). Hundreds of these molecules have been isolated and char-
acterized [ 21 - 25 ].
While siderophores are structurally diverse, the constituent functional groups
involved in iron binding are characteristically conserved: hydroxamic acids, cat-
echols, α -hydroxy acids and aryl oxazolines. While the structure of certain sidero-
phores like desferrioxamine B ( 1 ) can be recognized by different bacteria, highly
functionalized siderophores like pyoverdin type I ( 5 ) can only be acquired by the
producing organism. The energetic expense of biosynthesizing these molecules
highlights the importance of iron acquisition in bacterial survival. The selective
uptake of certain ferri-siderophores by bacteria of interest e.g., pathogenic strains,
has sparked extensive research focused on antibiotic delivery through the design
of nature-inspired antibiotic conjugates [ 13 , 15 , 26 ], and even bacterial detection
through immobilized siderophores [ 27 - 28 ]. The chemical modification and even
total syntheses of these derivatives is a challenging task. However, the assembly of
remarkably selective and highly potent antibacterial agents validates the efficacy
of this field of study.
Siderophore biosynthesis is a highly regulated process (Fig. 5.2 ). Within an
iron-sufficient environment the chelator assembly is repressed at the genetic level
by the action of a Fur-Fe 2 + complex (1). Reduced levels of iron allow the sidero-
phore biosynthesis machinery (SBM) to synthesize and secrete the chelator into
the extracellular environment (2). The siderophore acquires ferric iron from the
environment or, in the case of an infection, the host's pools. After a ferric-complex
has been formed, it is recognized by an outer membrane (OM) receptor (3) in the