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Proteomic study of peptide deformylase inhibition in Streptococcus pneumoniae and Staphylococcus aureus
Wen Wang1, Richard White, Zhengyu Yuan
1Vicuron Pharmaceuticals, 34790 Ardentech Court, Fremont, CA 94555, USA.
Abstract:
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.
Insights
Inhibiting peptide deformylase (PDF) in bacteria like Staphylococcus aureus and Streptococcus pneumoniae causes essential proteins to accumulate in a formylated state, halting growth. This effect is reversible and may inform new antibiotic strategies.
Area of Science:
- Microbiology
- Biochemistry
- Proteomics
Background:
- Peptide deformylase (PDF) is a crucial enzyme for bacterial protein maturation in both gram-negative and gram-positive bacteria.
- PDF inhibition leads to the cessation of bacterial growth.
- LBM-415 is a potent inhibitor of PDF.
Purpose of the Study:
- To investigate the proteomic effects of PDF inhibition by LBM-415 in Staphylococcus aureus and Streptococcus pneumoniae.
- To understand the time-dependent nature of formylated peptide accumulation and subsequent deformylation.
- To explore the correlation between PDF inhibition and the postantibiotic effect.
Main Methods:
- Two-dimensional electrophoresis was used to analyze the proteomes of S. aureus and S. pneumoniae.
- Bacterial cultures were treated with the PDF inhibitor LBM-415.
- Proteomic analysis was performed at various time points during inhibition and recovery.
Main Results:
- PDF inhibition resulted in the accumulation of N-terminal formylated peptides/proteins in both S. aureus and S. pneumoniae.
- Formylated peptide/protein accumulation in S. pneumoniae was observed to be time-dependent.
- Removal of the inhibitor led to a time-dependent deformylation, while sub-inhibitory concentrations prolonged formylated peptide presence.
Conclusions:
- PDF inhibition effectively causes the accumulation of formylated peptides, impacting bacterial protein maturation.
- The reversibility and duration of formylated peptide accumulation are time-dependent and influenced by inhibitor concentration.
- These findings suggest potential applications for PDF inhibitors in developing novel antibiotic therapies with prolonged effects.
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