SF2312 is a natural phosphonate inhibitor of enolase
Despite their essential role in energy production across most life forms, there are very few microbial antibiotics that specifically target glycolysis. To develop a specific inhibitor of the glycolytic enzyme enolase 2 (ENO2) for treating cancers with a deletion of ENO1 (which encodes enolase 1), we modeled the synthetic compound phosphonoacetohydroxamate (PhAH) into the active site of human ENO2. We predicted that a ring-stabilized analog of PhAH, where the hydroxamic nitrogen is connected to Cα by an ethylene bridge, would enhance binding affinity by stabilizing the inhibitor in a bound conformation.
Surprisingly, a structure-based search revealed that our proposed backbone-stabilized PhAH closely resembles SF2312, a phosphonate antibiotic produced by the actinomycete Micromonospora, which has an unknown mode of action and is effective under anaerobic conditions. In this study, we provide multiple lines of evidence, including a novel X-ray structure, demonstrating that SF2312 is a highly potent inhibitor of enolase, exhibiting low nanomolar activity.