Actinonin (CAS: 13434-13-4)

Peptide deformylase (PDF) catalyzes removal of the N-formyl group from the N-terminal methionine of newly synthesized proteins and is essential for bacterial viability. Actinonin has been identified as a high-affinity inhibitor of bacterial PDF, with dissociation constants in the subnanomolar range. Mechanistic studies reveal a two-step slow-binding inhibition process in which an initial enzyme-inhibitor complex (EI) undergoes conformational tightening to form a highly stable EI* complex with a very slow off-rate. This time-dependent inhibition distinguishes actinonin from rapidly reversible PDF inhibitors. Microbiological studies confirm that reduction of PDF expression increases bacterial susceptibility, validating PDF as the intracellular target. Marine-derived Streptomyces strains produce actinonin with activity against Vibrio anguillarum, and resistance is associated with mutation in the folD gene affecting formyl donor biosynthesis. In mammalian systems, actinonin inhibits human mitochondrial PDF (HsPDF), leading to disruption of mitochondrial protein homeostasis, suppression of oxidative phosphorylation, activation of integrated stress responses, and sensitization of glioblastoma cells to temozolomide. Together, these properties establish actinonin as both an antibacterial research tool and a probe for mitochondrial translation and metabolic regulation.