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Comparative spectrum and activity of NVP-PDF386 (VRC4887), a new peptide deformylase inhibitor
Ronald N Jones1, Paul R Rhomberg
1The JONES Group/JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317, USA.
Abstract:
The antibacterial activity of NVP-PDF386 (VRC4887), a novel peptide deformylase (PDF) inhibitor, was tested against over 1000 recent clinical isolates collected during 2001 and 2002. The MIC(50/90) (mg/L) results for NVP-PDF386 (VRC4887) were: Staphylococcus aureus (SA) 0.5/1, coagulase-negative staphylococci (CoNS) 0.5/1, Streptococcus pneumoniae 0.25/0.5, other streptococci 0.25/0.5, enterococci 1/2, Moraxella catarrhalis 0.25/0.25, Haemophilus influenzae 8/32 and Enterobacteriaceae or non-fermentative Gram-negative bacilli >32/>32 mg/L. No differences in NVP-PDF386/(VRC4887) MIC distributions were observed between methicillin-resistant (MR) S. aureus and methicillin-susceptible (MS) S. aureus, MR-CoNS and MS-CoNS, penicillin-susceptible and non-susceptible streptococci, and macrolide-susceptible and -resistant strains. The potency of NVP-PDF386 (VRC4887) compared favourably with those of control compounds, including glycopeptides, oxazolidinones, a streptogramin combination and other agents with activity focused against Gram-positive cocci.
Insights
NVP-PDF386 (VRC4887), a novel peptide deformylase (PDF) inhibitor, shows potent antibacterial activity against Gram-positive bacteria, including resistant strains. Its effectiveness against Gram-negative bacteria was limited in this study.
Area of Science:
- Microbiology
- Pharmacology
- Infectious Diseases
Background:
- Emerging antibiotic resistance necessitates the development of novel antibacterial agents.
- Peptide deformylase (PDF) is a validated target for antibacterial drug discovery.
- NVP-PDF386 (VRC4887) is a novel inhibitor targeting bacterial PDF.
Purpose of the Study:
- To evaluate the in vitro antibacterial activity of NVP-PDF386 (VRC4887).
- To assess the compound's spectrum of activity against recent clinical isolates.
- To compare its potency against Gram-positive and Gram-negative pathogens.
Main Methods:
- Minimum Inhibitory Concentrations (MICs) were determined for over 1000 clinical isolates.
- Testing included various Gram-positive cocci and Gram-negative bacteria.
- Activity was assessed across resistant and susceptible phenotypes.
Main Results:
- NVP-PDF386 (VRC4887) demonstrated potent activity against Staphylococcus aureus, coagulase-negative staphylococci, and Streptococcus pneumoniae (MIC50/90: 0.5/1, 0.5/1, and 0.25/0.5 mg/L, respectively).
- Activity was consistent across methicillin-resistant/susceptible S. aureus and coagulase-negative staphylococci, and penicillin-susceptible/non-susceptible streptococci.
- Limited activity was observed against Enterobacteriaceae and non-fermentative Gram-negative bacilli (MIC50/90 >32 mg/L).
- Potency favorably compared to glycopeptides, oxazolidinones, and streptogramins.
Conclusions:
- NVP-PDF386 (VRC4887) exhibits significant antibacterial potential, particularly against Gram-positive pathogens.
- The compound's activity is unaffected by common resistance mechanisms in staphylococci and streptococci.
- Further investigation into NVP-PDF386 (VRC4887) as a therapeutic agent for Gram-positive infections is warranted.
