Elucidating iron transport mechanisms in tuberculosis bug identifies new TB drug targets

It is pathetically true that Mycobacterium tuberculosis, the causative agent of TB is still thriving the test of scientific interventions despite affecting almost one -third of the worlds’ population. The fact that it takes approximately one human life every 15 second somewhere in the world is an unfortunate death statistics unmatched by any other microbe. Researchers from India led by Professor Seyed E Hasnain of the Institute of Life Sciences, at the University of Hyderabad, India have worked out the mechanism of iron uptake system of Mycobacterium tuberculosis, which is considered to be one of the important drug targets.

Iron acquisition and regulation in intracellular pathogens especially mycobacterium is a central survival mechanism working at the interface of host-pathogen interactions and is, therefore, a promising target for intervention. However, the bottleneck so far in targeting this important survival strategy was the absence of understanding of the mechanism of iron acquisition and transport in mycobacterium.

This research, appearing in the May 7 issue of the open-access journal PLoS ONE, has accomplished this challenging task by employing various in vitro and in vivo methods to elucidate how the bacterium that causes TB can import iron from the cell where it lives. It is important to know how the TB bacillus survives in the low iron environment of the human host by making use of its unique iron transport machinery. With this discovery of iron transport machinery in mycobacterium, the field has been made open for targeting this pathway for therapeutic interventions by development of new drugs.

The export of unbound small molecular weight high-affinity iron binding molecules, siderophores, and the subsequent internalization of their iron bound form is the center stage of TB bacilli survival within the host. This report identifies that the two genes which were previously believed as importers were indeed working, in coherence with another binding protein, as an exporter-importer system. This study further highlights that siderophores are actively exported outside the mycobacterial cell and do not passively diffuse as previously understood. These three actively interacting genes augment the iron uptake and provide a feedback for export of only the non-iron bound siderophores and exclusive import of the iron bound forms. The authors of this study believe that the model that has emerged from this study will be a boost to the global efforts to understand the survival strategies of the pathogen and in the process provide a crucial foothold to tame this one of the most deadly pathogen.

This report promises to contribute to the understanding of mycobacterial adaptability and survival mechanisms in highly intricate and fiercely competitive host environments and the role of iron regulatory networks therein.

Source: Public Library of Science