Novel approaches to antimicrobial therapy: peptide deformylase.
Peptide deformylase (PDF) represents one of the most exciting new targets for the development of novel antimicrobial chemotherapies. PDF is an essential bacterial metalloenzyme that deformylates the N-formylmethionine of newly synthesized bacterial polypeptides. Recent progress in understanding the structure and function of PDF has greatly facilitated the drug discovery process. In this article, the potential of PDF as an antimicrobial target is reviewed, and progress in the development of PDF inhibitors (PDFIs) is highlighted. Several structural classes of compounds have been reported as inhibitors of PDF. However, the real challenge has been in obtaining molecules with potent in vivo antibacterial activity against a range of drug-resistant pathogens. One of the more encouraging compounds reported, BB-83698 (British Biotech plc/Genesoft Inc), has shown in vivo efficacy against Streptococcus pneumoniae in both mouse thigh and lung infection models at doses equivalent to existing therapies. The published data suggest that PDFIs are a promising new class of antimicrobial agent best suited to treat respiratory tract infections (RTIs), but with the potential for activity against a variety of other pathogens. It is anticipated that the first PDFI targeting RTIs will enter the clinic soon.
Waller
Andrew S
AS
British Biotech Pharmaceuticals Ltd, Watlington Road, Oxford, OX4 6LY, UK.
Clements
John M
JM
D000581:Amidohydrolases; D000626:Aminopeptidases / Q000037:antagonists & inhibitors*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D001424:Bacterial Infections / Q000188:drug therapy*; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use*; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; C425109:BB3497; D004791:Enzyme Inhibitors; D006877:Hydroxamic Acids; D000626:Aminopeptidases; D000581:Amidohydrolases; C084507:peptide deformylase