Targeting Iron Acquisition by Mycobacterium tuberculosis

Abstract

Tuberculosis (TB) caused by the pathogen Mycobacterium tuberculosis continues to be a major worldwide health problem. Lack of compliance to the complex, multi-drug therapy regimen has resulted in multidrug-resistant TB and a need for new drug targets. Siderophore molecules used for iron acquisition are good targets because pathogen survival and virulence is directly related to iron availability. Indeed, a key host defense mechanism is the production of siderocalins that sequester iron-laden siderophores and M. tuberculosis replicates poorly in the absence of these siderophores. A number of investigators have recently targeted siderophores or their synthesis for the development of novel anti-tubercular therapeutics. For example, one group has synthesized 'dominant negative' mycobactin siderophore analogues that significantly inhibit bacterial growth. Several other groups have developed agents that directly inhibit enzymes involved in siderophore synthesis. A profoundly different approach is to target the iron dependent regulator protein (IdeR) that represses siderophore synthesis genes and virulence factors when sustainable iron levels have been achieved. Loss of the repression leads to iron overload and oxidative damage. In contrast, enhanced IdeR repression at low iron levels attenuates M. tuberculosis virulence in mice. The structural basis for iron activation and IdeR binding to DNA has been recently reported and these insights have enabled the structure-based design of agents that target IdeR function. Small peptides that either enhance IdeR repression or inhibit IdeR dimerization demonstrate that IdeR activity can be rationally modulated.

Discovery and characterization of a unique mycobacterial heme acquisition system

“…Identification of the genomic region responsible for heme uptake reveals several mycobacterial-specific proteins including a secreted heme-binding protein with a unique fold. Mycobacterial iron acquisition is potentially a therapeutic target (14); the identification of all possible avenues of iron uptake, and thus the discovery of a unique mycobacterial heme uptake system, is central to the development of therapeutic strategies targeting iron acquisition.…”

Analyses of MbtB, MbtE, and MbtF Suggest Revisions to the Mycobactin Biosynthesis Pathway in Mycobacterium tuberculosis

“…Finally, MBT biosynthesis has already proven to be a desirable target for drug development (10,26,45). The use of salicyl-AMP analogs initially developed by Quadri and Tan (10) and extended by others (28,40) as inhibitors of M. tuberculosis growth provides a template for targeting the A domains of the MBT megasynthase for drug development.…”

Is Iron Overload a Risk Factor for Mycobacterium Tuberculosis and a Potential Target of Therapy?

“…, the active form. Therefore siderophore molecules used by mycobacterium for iron acquisition maybe good targets for treatment because the bacteria's survival and virulence is related to host iron availability [11].…”

“…An alternative approach of treatment is gene manipulation through irreversible inhibition of iron dependent regulator protein (IdER). Activation of repressor protein of siderophore synthesis would be advantageous when the pathogen is iron deficient and depends on siderophore synthesis for survival [11]. The role of hepcidin molecules in therapeutics is less certain however determining patient-specific hepcidin activity may be useful in ascertaining risk for TB in endemic regions.…”