Comparative spectrum and activity of NVP-PDF386 (VRC4887), a new peptide deformylase inhibitor
Ronald N. Jones1,2 and
Paul R. Rhomberg1,*
1 The JONES Group/JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317; 2 Tufts University School of Medicine, Boston, MA, USA
Received 17 September 2002; returned 8 October 2002; revised 10 October 2002; accepted 22 October 2002
 |
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 MIC50/90 (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.
Keywords: antimicrobial activity, peptide deformylase inhibitor, NVP-PDF386
 |
Introduction
|
---|
The continued evaluation of bacterial resistances to contemporary antimicrobial agents via modifications of targets requires the rapid search for agents with novel modes of action. Among the promising groups of candidate agents, the inhibitors of peptide deformylase (PDF) have emerged as potent agents with activity directed toward resistant Gram-positive species.13 The PDF was first described over 30 years ago and one inhibitor, actinonin, has been studied in some detail.4 More recently, other novel PDF inhibitors have been synthesized that demonstrate activity (usually bacteriostatic) against staphylococci, Enterococcus faecalis, Bacillus spp. and some Escherichia coli.2,5 Owing to the unique enzyme target of these inhibitors, no evidence of cross-resistance has been noted, making the PDF inhibitors attractive alternatives for the therapy of emerging antimicrobial-resistant Gram-positive infections.3,5
This report summarizes the antimicrobial potency and spectrum screening studies of NVP-PDF386 (VRC4887), a new PDF inhibitor. All tests were carried out by reference dilution methods6 and the organism sample included resistant subsets derived from international surveillance studies.
 |
Materials and methods
|
---|
A total of 1264 recent (20012002) clinical isolates were selected to over-represent key resistance mechanisms (higher frequency than expected in routine clinical practice) as a spectrum screen and to explore the potential for cross-resistance. The organisms included Staphylococcus aureus [104 strains; 53 methicillin-resistant (MRSA)], coagulase-negative staphylococci (CoNS; 49 strains), Streptococcus spp. (320 strains), enterococci (104 strains), Haemophilus influenzae (308 strains), Moraxella catarrhalis (103 strains), Enterobacteriaceae (112 strains), non-fermentative Gram-negative bacilli (107 strains) and anaerobes.
A total of 19 comparator agents were tested from 11 antimicrobial classes, including: vancomycin, teicoplanin, quinupristin/dalfopristin, linezolid, ampicillin, co-amoxiclav, penicillin, oxacillin, erythromycin, azithromycin, clarithromycin, clindamycin, ciprofloxacin, levofloxacin, chloramphenicol, tetracycline, gentamicin, streptomycin and trimethoprim/sulfamethoxazole.
NVP-PDF386 (VRC4887) laboratory standard powder was obtained from Novartis Pharmaceuticals (Summit, NJ, USA), diluted into broth and incorporated into microdilution trays for susceptibility testing using the NCCLS susceptibility testing methods and interpretative criteria.6,7 All testing was carried out in cation-adjusted MuellerHinton broth, except for Haemophilus spp. (Haemophilus Test Medium) and streptococci (MuellerHinton broth supplemented with 35% lysed horse blood). Concurrent quality control was performed with S. aureus ATCC 29213, E. faecalis ATCC 29212, Streptococcus pneumoniae ATCC 49619 and H. influenzae ATCC 49247.
 |
Results
|
---|
Table 1 compares the NVP-PDF386 (VRC4887) activity with that of selected agents against four key pathogens. NVP-PDF386 (VRC4887) showed excellent potency and spectrum against S. aureus (MIC90 1 mg/L) that was equal to vancomycin (MIC90 1 mg/L), was less active than the streptogramin (MIC90 0.5 mg/L) and two-fold more potent than teicoplanin and linezolid (MIC90 2 mg/L). The activity of NVP-PDF386 (VRC4887) against Enterococcus spp. was approximately two-fold less than that observed for S. aureus strains (49.0% MRSA), and two-fold more active against the S. pneumoniae strains (62% penicillin non-susceptible). All enterococcal and pneumococcal strains were inhibited by
4 and
1 mg/L of NVP-PDF386 (VRC4887), respectively. This PDF inhibitor was the most potent agent tested against these two pathogens.
View this table:
[in this window]
[in a new window]
|
Table 1. Comparative antimicrobial activity screen of NVP-PDF386 (VRC4887), a peptide deformylase inhibitor, tested against four selected organism groups
|
|
In contrast, PDF inhibitor potency versus H. influenzae (40.0% ampicillin-resistant) was lower (MIC90 32 mg/L) and more comparable with that of clarithromycin (MIC90 16 mg/L). Several comparison agents such as the fluoroquinolones (MIC90
0.03 mg/L) showed excellent activity.
Table 2 summarizes the cumulative percentages of six additional bacterial groups inhibited by NVP-PDF386 (VRC4887). Coagulase-negative staphylococci showed a susceptibility like that described for NVP-PDF386 (VRC4887) against S. aureus. Similarly, the 150 strains of viridans group and ß-haemolytic streptococci had results equal to that of S. pneumoniae versus NVP-PDF386 (VRC4887). M. catarrhalis was very susceptible to the PDF inhibitor (MIC90
0.25 mg/L); however, a mixture of 19 other species of Gram-positive organisms (Table 2; 26 strains) showed 88% of strains inhibited by
4 mg/L. The most PDF-resistant strains were the Nocardia spp. isolates. Anaerobes were moderately susceptible to the PDF inhibitor with all strains inhibited by
4 mg/L NVP-PDF386 (VRC4887). The Enterobacteriaceae and non-fermentative Gram-negative bacilli were resistant to NVP-PDF386 (VRC4887) (Table 2) with an MIC50/90 of >8 mg/L.
View this table:
[in this window]
[in a new window]
|
Table 2. Summary of antimicrobial activity at individual MIC values of NVP-PDF386 (VRC4887) tested against 11 organism groups
|
|
The isolates selected for use in this study were chosen to over-represent the key resistance mechanisms found in the individual bacterial species (resistance mechanisms in our sample are at a higher frequency than observed in contemporary clinical practice). Multidrug-resistant phenotypes among various species did not show increased MIC values of NVP-PDF386 (VRC4887). No differences in the MIC distribution of NVP-PDF386 (VRC4887) were observed between methicillin-susceptible (MSSA) and -resistant S. aureus (MRSA), methicillin-susceptible (MS-CoNS) and -resistant (MR-CoNS) CoNS, penicillin-susceptible and non-susceptible streptococci, and macrolide-susceptible and -resistant Gram-positive strains.
 |
Discussion
|
---|
Several PDF inhibitors have been studied in vitro, each having primary activity against Gram-positive organisms and some Gram-negative coccobacilli such as M. catarrhalis and H. influenzae.3,8 Although PDF inhibitory activity has generally been classified as bacteriostatic, some reports have demonstrated bactericidal action against staphylococci, some enterococci, Bacillus subtilis and even E. coli.2,5 Like other PDF inhibitors such as BB-83698, BB-83815, VRC4232, VRC4307 and Ro 66-6976,1,2,8 the novel NVP-PDF386 (VRC4887) has potency against S. aureus, CoNS, Enterococcus spp., streptococci, M. catarrhalis and selected anaerobes, with all MIC values
4 mg/L. This activity compared favourably with linezolid, quinupristin/dalfopristin and the glycopeptides (Table 1).
The activity of NVP-PDF386 (VRC4887) was lower for isolates of H. influenzae (MIC50/90 8/32 mg/L); however, pending bioavailability studies may indicate an expanded use of the PDF inhibitor for community-acquired respiratory tract infections, not limited to a role in therapy for resistant Gram-positive pathogens.2,3 Mutational rates to resistance for PDF inhibitors have been reported over the range of 107 to 109 for both Gram-positive and -negative species.1,5 Again these rates were comparable to those obtained with other antimicrobial classes studied. Animal septicaemia models have proven the PDF inhibitors to be viable candidates for therapy of staphylococcal and enterococcal infections.2,8
The clinical isolates utilized in our study were selected to significantly test key resistance mechanisms within individual bacterial species, and the in vitro results indicate that further studies of NVP-PDF386 (VRC4887) use in the treatment of infections caused by multi-resistant Gram-positive cocci are warranted. Further modification of PDF structures could expand the spectrum of activity to include key Gram-negative pathogens.9
 |
Acknowledgements
|
---|
The authors acknowledge the support of an education/research grant from Novartis Pharmaceuticals.
 |
Footnotes
|
---|
* Corresponding author. Tel: +1-319-665-3370; Fax: +1-319-665-3371; E-mail: paul-rhomberg{at}jmilabs.com 
 |
References
|
---|
1
.
Apfel, C. M., Locher, H., Evers, S., Takács, B., Hubschwerlen, C., Pirson, W. et al. (2001). Peptide deformylase as an antimicrobial drug target: target validation and resistance development. Antimicrobial Agents and Chemotherapy 45, 105864.[Abstract/Free Full Text]
2
.
Clements, J. M., Beckett, R. P., Brown, A., Catlin, G., Lobell, M., Palan, S. et al. (2001). Antibiotic activity and characterization of BB-3497, a novel peptide deformylase inhibitor. Antimicrobial Agents and Chemotherapy 45, 56370.[Abstract/Free Full Text]
3
.
Wise, R., Andrews, J. M. & Ashby, J. (2002). In vitro activities of peptide deformylase inhibitors against Gram-positive pathogens. Antimicrobial Agents and Chemotherapy 46, 11178.[Abstract/Free Full Text]
4
.
Giglione, C., Pierre, M. & Meinnel, T. (2000). Peptide deformylase as a target for new generation, broad spectrum antimicrobial agents. Molecular Microbiology 36, 1197205.[CrossRef][ISI][Medline]
5
.
Huntington, K. M., Yi, T., Wei, Y. & Pei, D. (2000). Synthesis and antibacterial activity of peptide deformylase inhibitors. Biochemistry 39, 454351.[CrossRef][ISI][Medline]
6
.
National Committee for Clinical Laboratory Standards. (2000). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow AerobicallyFifth Edition: Approved Standard M7-A5. NCCLS, Wayne, PA, USA.
7
.
National Committee for Clinical Laboratory Standards. (2002). Performance Standards for Antimicrobial Susceptibility TestingTwelfth Informational Supplement: M100-S12. NCCLS, Wayne, PA, USA.
8
.
Hackbarth, C. J., Chen, D. Z., Lewis, J. G., Clark, K., Mangold, J. B., Cramer, J. A. et al. (2002). N-Alkyl urea hydroxamic acids as a new class of peptide deformylase inhibitors with antibacterial activity. Antimicrobial Agents and Chemotherapy 46, 275264.[Abstract/Free Full Text]
9
.
Guilloteau, J. P., Mathieu, M., Giglione, C., Blanc, V., Dupuy, A., Chevrier, M. et al. (2002). The crystal structures of four peptide deformylases bound to the antibiotic actinonin reveal two distinct types: a platform for the structure-based design of antibacterial agents. Journal of Molecular Biology 320, 95162.[CrossRef][ISI][Medline]