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

Abstract

ABSTRACT GSK1322322 is a novel peptide deformylase (PDF) inhibitor being developed for the intravenous and oral treatment of acute bacterial skin and skin structure infections and hospitalized patients with community-acquired pneumonia. The activity of GSK1322322 was tested against a global collection of clinical isolates of Haemophilus influenzae ( n = 2,370), Moraxella catarrhalis ( n = 115), Streptococcus pneumoniae ( n = 947), Streptococcus pyogenes ( n = 617), and Staphylococcus aureus ( n = 940), including strains resistant to one or more marketed antibiotics. GSK1322322 had an MIC 90 of 1 μg/ml against M. catarrhalis and 4 μg/ml against H. influenzae , with 88.8% of β-lactamase-positive strains showing growth inhibition at that concentration. All S. pneumoniae strains were inhibited by ≤4 μg/ml of GSK1322322, with an MIC 90 of 2 μg/ml. Pre-existing resistance mechanisms did not affect its potency, as evidenced by the MIC 90 of 1 μg/ml for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae . GSK1322322 was very potent against S. pyogenes strains, with an MIC 90 of 0.5 μg/ml, irrespective of their macrolide resistance phenotype. This PDF inhibitor was also active against S. aureus strains regardless of their susceptibility to methicillin, macrolides, or levofloxacin, with an MIC 90 of 4 μg/ml in all cases. Time-kill studies showed that GSK1322322 had bactericidal activity against S. pneumoniae , H. influenzae , S. pyogenes , and S. aureus , demonstrating a ≥3-log 10 decrease in the number of CFU/ml at 4× MIC within 24 h in 29 of the 33 strains tested. Given the antibacterial potency demonstrated against this panel of organisms, GSK1322322 represents a valuable alternative therapy for the treatment of infectious diseases caused by drug-resistant pathogens.