Peptide deformylase (PDF) (PDF)

Peptide deformylase (PDF) is a highly conserved metalloenzyme essential for the growth and survival of eubacteria, including various gram-negative pathogens such as Haemophilus influenzae and Moraxella catarrhalis [1, 3]. It catalyzes the removal of the N-formyl group from the N-terminal methionine of nascent polypeptide chains, a critical step in bacterial protein maturation [8, 11]. While this process is universal in bacteria, it is absent from the cytoplasm of eukaryotic cells, making PDF an attractive target for novel antibacterial agents [1, 4]. Inhibitors of PDF, such as actinonin and its synthetic derivatives like GSK1322322 and LBM415, typically function by chelating the catalytic metal ion (usually iron or zinc) within the enzyme's active site [1, 7, 15]. Despite its promise, the development of PDF inhibitors has faced challenges, including the presence of a human mitochondrial PDF ortholog that may lead to off-target toxicity and the rapid emergence of resistance through mutations in the formyltransferase or PDF genes [5, 9, 12]. Clinical development has also been hampered by safety issues such as methemoglobinemia observed in some trials [15]. Nevertheless, PDF remains a significant target for addressing multidrug-resistant bacterial infections [6, 10].

Other names

Polypeptide deformylaseFormyl-L-methionyl peptide amidohydrolasedef gene productBacterial peptide deformylase

Inhibition of the peptide deformylase enzyme, which prevents the removal of the N-formyl group from the initiator methionine of nascent bacterial proteins, thereby arresting bacterial growth and protein maturation.