Proteomic study of peptide deformylase inhibition in Streptococcus pneumoniae and Staphylococcus aureus.
Peptide deformylase (PDF) is an essential enzyme in both gram-negative and gram-positive bacteria. It hydrolyzes formylated N-terminal peptides to generate free N-terminal peptides during the process of protein maturation. Inhibition of this enzyme results in cessation of bacterial growth. We have examined the effect of a potent PDF inhibitor, LBM-415 (also known as VIC-104959), on the proteomes of Staphylococcus aureus and Streptococcus pneumoniae using two-dimensional electrophoresis. Both S. aureus and S. pneumoniae showed accumulation of many N-terminal formylated peptides/proteins upon PDF inhibition. In S. pneumoniae, formylated peptide/protein accumulation was time dependent. Following inhibition, subsequent removal of the inhibitor resulted in deformylation of formylated peptides/proteins; this recovery process was also time dependent. If instead the inhibited cells were maintained in the presence of sub-MIC levels of the PDF inhibitor, the formylated peptides/proteins remained for a much longer time, which correlated with a prolonged postantibiotic effect in vitro. These observations may have broader implications for the application of this class of antibiotics in vivo.
Wang
Wen
W
Vicuron Pharmaceuticals, 34790 Ardentech Court, Fremont, CA 94555, USA.
White
Richard
R
Yuan
Zhengyu
Z
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D001426:Bacterial Proteins / Q000032:analysis* / Q000235:genetics; D015180:Electrophoresis, Gel, Two-Dimensional; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D010449:Peptide Mapping; D010455:Peptides / Q000494:pharmacology; D020543:Proteome / Q000032:analysis*; D013211:Staphylococcus aureus / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D013296:Streptococcus pneumoniae / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development
D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; C487638:NVP PDF 713; D010455:Peptides; D020543:Proteome; D000581:Amidohydrolases; C084507:peptide deformylase