Modelling Growth of Mycobacterium Tuberculosis Under Low-Iron Conditions

Mycobacterium tuberculosis (M.tub) is well-known for its exceptional ability to adapt to considerable variations in host iron levels due to the presence of a wide variety of iron uptake mechanisms. These include lactoferrin and transferrin receptors, siderophores and hemophores. As both excessive and insufficient levels of free iron is detrimental to cellular growth, the virulence of a Mycobacterium tuberculos infection is highly dependent on the pathogen's ability to tightly control iron uptake levels. Therefore, the various pathways through which Mycobacterium tuberculosis absorbs and processes iron present high-interest targets for potential new treatments, assuming relevant genes can be identified.

Flux balance analysis (FBA) is a computational approach well suited to finding interactions between various parallel pathways, if a reliable model can be built for the organism in question. Here, we present a new model for Mycobacterium tuberculosisdeveloped from an amalgamation of multiple pre-existing published models, to which we append reactions and gene associations for which we have experimental evidence. We have analyzed this model using a recently developed method known as GX-FBA (gene-expression FBA), which aims to provide a more accurate prediction of cellular behavior by incorporating gene expression data to identify pathways activated by specific perturbations – in this case, low availability of external iron.

We identify several key pathways, whose elimination (either alone or in conjunction with other pathways) entirely prevents Mycobacterium tuberculosis from absorbing or making use of iron, rendering the pathogen incapable of growth. While several of these findings are corroborated by in vitro experimental data, other potential targets have not yet been subject to in vitro testing and thus, are potentially the focus of further research.