Comparative Antimicrobial Characterization of LBM415 (NVP PDF-713), a New Peptide Deformylase Inhibitor of Clinical Importance

Abstract

LBM415 (NVP PDF-713) is the first member of the peptide deformylase (PDF) inhibitor class being developed for clinical trials as a parenteral and oral agent for treatment of community-acquired respiratory tract disease and serious infections caused by antimicrobial-resistant gram-positive cocci. In this study susceptibility testing results from 1,306 recent clinical isolates selected to overrepresent resistance trends among the species were summarized. All staphylococci (153 strains; MIC at which 90% of isolates were inhibited [MIC 90 ], 2 g/ml), Streptococcus pneumoniae (170 strains; MIC 90 , 1 g/ml), other streptococci (150 strains; MIC 90 , 1 g/ml), enterococci (104 strains; MIC 90 , 4 g/ml), Moraxella catarrhalis (103 strains; MIC 90 , 0.5 g/ml), and Legionella pneumophila (50 strains; MIC 90 , 0.12 g/ml) were inhibited at <8 g of LBM415/ml, as were 97% of Haemophilus influenzae isolates (300 strains; MIC 90 , 4 to 8 g/ml). Among other bacterial groups, 100% of gram-positive and -negative anaerobes, including 22 Bacteroides spp. strains (31 strains total; MIC 90 , 1 g/ml), were inhibited by <4 g/ml, whereas Enterobacteriaceae (112 strains) and most nonfermentative bacilli (107 strains) were not inhibited at readily achievable concentrations. The compound was found to have a dominantly bacteriostatic action, and spontaneous single-step mutational rates occurred at low levels (10 ؊6 to <10 ؊8 ). Drug interaction studies failed to identify any class-specific synergistic interactions, nor were antagonistic interactions observed. Variations in broth and agar MIC test conditions demonstrated that, whereas the agar-based method trended towards a 1-log 2 dilution-higher MIC than the broth method and was inoculum dependent, other variations in incubation environment, medium supplements, pH, or calcium concentration had little influence on LBM415 MIC results. Use of the efflux inhibitor phe-arg-␤-naphthylamide showed an average of 1 log 2 dilution decrease in H. influenzae MICs, demonstrating the contribution of efflux pumps in influencing susceptibility to PDF inhibitors. The in vitro activity of LBM415 against targeted bacterial species, including resistant subsets, and other laboratory characteristics of this novel compound demonstrate the potential of PDF inhibitors as a new class of antimicrobial agents.

Comparative Analysis of the Antibacterial Activity of a Novel Peptide Deformylase Inhibitor, GSK1322322

“…As a result, a considerable number of chemically diverse series of potent PDF inhibitors has been reported over the years, containing both peptidic and nonpeptidic scaffolds, with various antibacterial activities and in vivo efficacies in animal models of infection (20). Moreover, two pseudopeptidic PDF inhibitors, BB-83698 (21) and LBM415 (22), showed pharmacokinetic and toxicologic properties that supported their progression to phase I clinical trials. GSK1322322, a nonpeptidic PDF inhibitor from the hydrazide family that is structurally distinct from the previous molecules, has successfully demonstrated safety and efficacy in human proof-of-concept clinical studies (http: //www.clinicaltrials.gov).…”

The Crystal Structure of Mitochondrial (Type 1A) Peptide Deformylase Provides Clear Guidelines for the Design of Inhibitors Specific for the Bacterial Forms

“…Many actinonin derivatives have been synthesized and shown to display potent antibiotic activity (26). Phase I clinical studies were recently completed for two such potent peptide deformylase inhibitors derived from actinonin (27)(28)(29), which have now gone on to phase II and III trials. PDF-In therefore appear promising as a class of new antibiotics.…”

Novel Conformational States of Peptide Deformylase from Pathogenic Bacterium Leptospira interrogans

“…As a metalloprotease, the high degree of structure-function conservation makes rapid progress possible in the development of peptide deformylase inhibitors. Very recently, a new peptide deformylase inhibitor of clinical importance (LBM415) has been characterized (8). Moreover, a new human peptide deformylase (HsPDF) has been suggested to be involved in the deformylation and processing of mitochondrially encoded proteins and may provide a novel selective target for anticancer therapy based on the observation that inhibition of human peptide deformylase (HsPDF) by actinonin (a naturally occurring competitive inhibitor of PDF) also inhibits the proliferation of 16 human cancer cell lines (9).…”