Peptide deformylase as an antibacterial target: a critical assessment

Peptide deformylase (PDF) is among the few antibacterial targets against which novel synthetic inhibitors derived from rationally designed, mechanism-based libraries have progressed into clinical trials. Nearly two decades of investigation led to this milestone; however, increased understanding of resistance to these compounds and recent evidence of catalytically active human mitochondrial PDF impact the perception of PDF as an antibacterial target. There are also many unanswered questions concerning the mechanism of action of PDF inhibitors and the necessity of the formylation/deformylation cycle in bacteria. Nevertheless, the experience gained from research on PDF serves as perhaps the best current illustration of the risks and possibilities associated with novel target-based antibiotic discovery.