Elsevier

Tuberculosis

Volume 95, Issue 2, March 2015, Pages 123-130
Tuberculosis

Review
Iron acquisition strategies in mycobacteria

https://doi.org/10.1016/j.tube.2015.01.004Get rights and content

Summary

Iron is an essential element to most life forms including mycobacterial species. However, in the oxidative atmosphere iron exists as insoluble salts. Free and soluble iron ions are scarce in both the extracellular and intracellular environment which makes iron assimilation very challenging to mycobacteria. Tuberculosis, caused by the pathogen, Mycobacterium tuberculosis, is one of the most infectious and deadly diseases in the world. Extensive studies regarding iron acquisition strategies have been documented in mycobacteria, including work on the mycobacterial iron chelators (siderophores), the iron-responsive regulon, and iron transport and utilization pathways. Under low iron conditions, expression of the genes encoding iron importers, exporters and siderophore biosynthetic enzymes is up-regulated significantly increasing the ability of the bacteria to acquire limited host iron. Disabling these proteins impairs the growth of mycobacteria under low iron conditions both in vitro and in vivo, and that of pathogenic mycobacteria in animal models. Drugs targeting siderophore-mediated iron transport could offer promising therapeutic options. However, the discovery and characterization of an alternative iron acquisition mechanism, the heme transport and utilization pathway, questions the effectiveness of the siderophore-centered therapeutic strategy. Links have been found between these two distinct iron acquisition mechanisms, thus, targeting a few candidate proteins or mechanisms may influence both pathways, leading to effective elimination of the bacteria in the host.

Introduction

Mycobacteria, like most other living organisms, require iron for many vital functions. Iron forms the essential catalytic centre of the active site of various enzymes enabling enzymatic reactions. The ability of iron to receive and donate an electron thereby oscillating between the ferrous (Fe2+) and ferric (Fe3+) oxidative states enables the enzyme to catalyse redox reactions. For this reason, iron is often associated with cytochromes responsible for oxidative phosphorylation and energy production [1]. Iron–sulfur clusters are essential cofactors of many enzymes involved in amino acid and pyrimidine biogenesis, the tricarboxylic acid cycle as well as electron transport [2]. Iron is one of the most abundant elements on earth, however, under the earth's oxidizing environment at physiological pH, iron exists predominantly as insoluble ferric salts such as iron oxide, iron hydroxide and iron phosphate which cannot be assimilated by bacteria. Free iron ions are therefore scarce. Iron acquisition is even more challenging for pathogenic bacteria because iron ions are bound to host iron-binding proteins, such as transferrin and lactoferrin which serve as host iron transporters, the iron storage protein ferritin and iron-protoporphyrins in hemoproteins [3]. During infection, the host restricts the amount of circulating transferrin-bound iron in the body and reduces the uptake of dietary iron utilising iron-deprivation as a host anti-microbial defense mechanism [4], [5], [6]. Pathogenic mycobacteria are, however, able to cause disease despite the severely iron limited host environment. To overcome iron-deprivation mycobacterial pathogens have evolved iron acquiring pathways which are more efficient than those of their vertebrate hosts. In this review, the strategies mycobacteria use to access iron and the iron-dependent gene regulation responsible for the maintenance of iron homeostasis in mycobacteria are discussed. Additionally, a brief opinion is given regarding the selection of iron acquisition machineries as drug targets.

Section snippets

Siderophore-mediated iron acquisition

A major mechanism employed by mycobacteria to compete for the limited available iron is the use of high affinity iron chelators, siderophores, which are predominantly produced during iron deprivation [7]. There are three types of siderophores, mycobactin, carboxymycobactin and exochelin, where mycobactin and carboxymycobactin share a core structure which is distinct from exochelin. Mycobactin is cell envelope-associated and facilitates the transport of iron through the cell envelope into the

Heme transport and its metabolism in mycobacteria

Wells and colleagues used heme as an alternative iron source to successfully rescue their M. tuberculosis mutants in which the mycobactin biosynthetic pathway was disabled under low iron conditions [34]. Heme is an iron-containing prosthetic group found in many hemoproteins, including hemoglobin which are abundant in erythrocytes. In fact, two thirds of iron in veterbrates are incorporated into the heme. Heme is therefore a reservoir of iron for many pathogenic bacteria and their heme

Additional iron acquisition pathway

It is worth mentioning that an additional siderophore-independent iron acquisition mechanism in M. tuberculosis has recently been discovered. A cell surface-localized human holo-transferrin-binding enzyme, glyceraldehyde-3-phosphate dehydrogenase (GAPDH, Rv1436), was found to be able to facilitate the internalization of human transferrin across the mycobacterial cell wall in a GAPDH-dependent manner within infected macrophages. Overexpression of this protein may increase transferrin binding to

The role of ESX-3 in siderophore and heme transport

M. tuberculosis contains five copies of the Type VII protein secretion system, namely ESX-1- to -5 [54], [55]. ESX-1 and ESX-5 are involved in virulence in pathogenic mycobacteria [56], [57], [58], [59], [60]. ESX-3 has shown to be involved in the mycobactin-mediated iron acquisition pathway, but not the exochelin pathway in M. smegmatis [61]. In M. tuberculosis, ESX-3 is essential for in vitro growth [62], [63]. The growth defect of the M. tuberculosis conditional ESX-3 knock-out strain in 7H9

Iron-dependent gene regulation

Mycobacteria utilise elaborate molecular mechanisms to maintain iron homeostasis. Iron acquisition mechanisms are activated in response to low intracellular iron levels to acquire iron from the environment. When there is sufficient intracellular iron, excess iron is stored to prevent it from participating in the Fenton reaction, which would generate harmful hydroxyl radicals [66]. Mycobacteria have developed complex gene regulation mechanisms which respond to different iron levels to maintain

Iron and heme acquisition-centred drug target discovery

Mycobacteria cannot survive without iron; a malfunctioning iron acquisition pathway causes a growth defect in vitro and in macrophages, and attenuates M. tuberculosis in mouse model [27], [34], [61], [65]. Intervention strategies targeting siderophore-mediated iron acquisition could be effective because this pathway is not only essential in M. tuberculosis but also is absent from the human host. Acyl sulfamoyl adenosine (acyl-AMS), an inhibitor to one mycobactin biosynthesis enzyme, MbtA, has

Conclusion

M. tuberculosis utilises elaborate iron-responsive gene regulation and various iron acquisition strategies to maintain intracellular iron homeostasis and overcome the challenges of accessing scarce iron in their natural and host environments. Numerous studies have demonstrated the essentiality of these mechanisms for the survival and virulence of mycobacteria. Therapeutic strategies targeting those pathways offer promising medical solutions for relieving the global burden of tuberculosis.

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