Metabolic plasticity in synthetic lethal mutants: viability at higher cost

Abstract: The most frequent form of pairwise synthetic lethality (SL) in metabolic networks is known as plasticity synthetic lethality (PSL). It occurs when the simultaneous inhibition of paired functional and silent metabolic reactions or genes is lethal, while the default of the functional reaction or gene in the pair is backed up by the activation of the silent one. Based on a complex systems approach and by using computational techniques on bacterial genome-scale metabolic reconstructions, we found that the failure of the functional PSL partner triggers a critical reorganization of fluxes to ensure viability in the mutant which not only affects the SL pair but a significant fraction of other interconnected reactions forming what we call a SL cluster. Interestingly, SL clusters show a strong entanglement both in terms of silent coessential reactions, which band together to form backup systems, and of other functional and silent reactions in the metabolic network. This strong overlap, also detected at the level of genes, mitigates the acquired vulnerabilities and increased structural and functional costs that pay for the robustness provided by essential plasticity. Finally, the participation of coessential reactions and genes in different SL clusters is very heterogeneous and those at the intersection of many SL clusters could serve as supertargets for more efficient drug action in the treatment of complex diseases and to elucidate improved strategies directed to reduce undesired resistance to chemicals in pathogens.