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.
Keywords: Mycobacterium tuberculosis, iron acquisition, siderophore, iron dependent regulator
Infectious Disorders - Drug Targets
Title: Targeting Iron Acquisition by Mycobacterium tuberculosis
Volume: 7 Issue: 3
Author(s): Ryan R. Monfeli and Craig Beeson
Affiliation:
Keywords: Mycobacterium tuberculosis, iron acquisition, siderophore, iron dependent regulator
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.
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Cite this article as:
Monfeli R. Ryan and Beeson Craig, Targeting Iron Acquisition by Mycobacterium tuberculosis, Infectious Disorders - Drug Targets 2007; 7 (3) . https://dx.doi.org/10.2174/187152607782110031
DOI https://dx.doi.org/10.2174/187152607782110031 |
Print ISSN 1871-5265 |
Publisher Name Bentham Science Publisher |
Online ISSN 2212-3989 |
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