Mycobacterium tuberculosis-Macrophage Interactome: Molecular Network Structure and Resilience against Antibiotics

Resistance to several antibiotics against Mycobacterium tuberculosis is a serious problem to be solved worldwide. In the present work, we made the statistical analysis of the gene regulatory network of Mycobacterium tuberculosis and of the Mycobacterium tuberculosis-macrophage interactome to find the probable cause of this resistance. The results from this analysis show that both the gene regulatory network and the interactoma have a hierarchical free scale modular structure that assures a high degree of resilience of these networks against external perturbations. In particular, the interactome is a complex hybrid network that results from the formation of novel links between the Mycobacterium tuberculosis and macrophage proteins and from the modification of the previously existing links between the native macrophage proteins, which give rise to novel negative and positive feedback loops that modify the dynamical behavior of the interactome and protect the mycobacterium against the attack with antibiotics by taking control of the macrophage immune response and apoptosis. The statistical analysis of the interactome shows that the highly connected mycobacterium proteins inhA, ahpC, kasA, katG and rpsL exert this control by creating new links with the host proteins FAS and NF-{kappa}B. These new hybrid circuits embedded in the hierarchical scale-free modular molecular structure of the interactome produce its high resistance to external perturbations like antibiotics. As consequence, the present work proposes the hypothesis that Mycobacterium tuberculosis antibiotic resistance in vivo during chronic tuberculosis is only a particular case of a more complex problem that is the interactome resilience against antibiotics. Thus, new strategies of drug design are necessary to shatter the complex structure of the Mycobacterium tuberculosis-macrophage interactome.