  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.
