Topological Complementarity Predicts Synergistic Drug Pairs in Branched Metabolic Networks.

DHPS (folP) and DHFR (folA) form a top-ranked complementary drug pair in the Escherichia coli folate pathway, predicting strong synergy.

• Why it matters: Branched metabolic networks can buffer single-enzyme inhibition via redundant flux routes, so the most sensitive node may not yield the best single target.
• What they did: A topology-driven framework using a kinetic folate pathway model with an extended one-carbon pool scored pairwise synergy versus single drugs.
• The result: In Escherichia coli MG1655, sulfamethoxazole plus trimethoprim showed strong dose-dependent synergy at intermediate inhibition and attenuation at saturation.