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The most frequent form of pairwise synthetic lethality (SL) in metabolicnetworks is known as plasticity synthetic lethality (PSL). It occurs when thesimultaneous inhibition of paired functional and silent metabolic reactions orgenes is lethal, while the default of the functional reaction or gene in thepair is backed up by the activation of the silent one. Based on a complexsystems approach and by using computational techniques on bacterialgenome-scale metabolic reconstructions, we found that the failure of thefunctional PSL partner triggers a critical reorganization of fluxes to ensureviability in the mutant which not only affects the SL pair but a significantfraction of other interconnected reactions forming what we call a SL cluster.Interestingly, SL clusters show a strong entanglement both in terms of silentcoessential reactions, which band together to form backup systems, and of otherfunctional and silent reactions in the metabolic network. This strong overlap,also detected at the level of genes, mitigates the acquired vulnerabilities andincreased structural and functional costs that pay for the robustness providedby essential plasticity. Finally, the participation of coessential reactionsand genes in different SL clusters is very heterogeneous and those at theintersection of many SL clusters could serve as supertargets for more efficientdrug action in the treatment of complex diseases and to elucidate improvedstrategies directed to reduce undesired resistance to chemicals in pathogens.

Metabolic plasticity in synthetic lethal mutants: viability at higher cost