The evolution of peptide deformylase as a target: contribution of biochemistry, genetics and genomics.
Although peptide deformylase (PDF, EC 3.5.1.27) was first described in 1968, the instability of enzyme preparations prevented it from being seriously considered as a target until this problem was finally solved in 1998. PDFs essentiality was first demonstrated in Escherichia coli in 1994. Genomic analyses have shown this enzyme to be present in all eubacteria. PDF homologs have also been found in eukaryotes including Homo sapiens. The function and relevance of the human chromosomal homolog to the safety of PDF inhibitors as therapeutic agents is not clear at this stage. Although there is considerable sequence variation between the different bacterial PDFs, there are three strongly conserved motifs that together constitute a critical metal binding site. The observation that PDF is a metalloenzyme has led to the design of inhibitors containing metal chelating pharmacophores. The most potent of these synthetic inhibitors are active against a range of clinically relevant respiratory tract pathogens in vitro and in vivo, including those resistant to current antibiotics. Mutants resistant to PDF inhibitors have been obtained in the laboratory; these resulted from mutations in the genes for transformylase (EC 2.1.2.9) or PDF. The mechanism involved and its frequency were pathogen-dependent. The two most advanced PDF inhibitor leads, which are both reverse hydroxamates, have progressed to phase 1 clinical trials and were well tolerated.
Yuan
Zhengyu
Z
Vicuron Pharmaceuticals Inc., 34790 Ardentech Court, Fremont, CA 94555, USA.
White
Richard J
RJ
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D004195:Disease Models, Animal; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D016680:Genome, Bacterial; D006801:Humans
D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C084507:peptide deformylase