title: Comparative analysis of the antibacterial activity of a novel peptide deformylase inhibitor, GSK1322322.
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.
authors.affiliation: Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: O'Dwyer
authors.forename: Meredith
authors.initials: M
authors.lastname: Hackel
authors.forename: Sarah
authors.initials: S
authors.lastname: Hightower
authors.forename: Daryl
authors.initials: D
authors.lastname: Hoban
authors.forename: Samuel
authors.initials: S
authors.lastname: Bouchillon
authors.forename: Donghui
authors.initials: D
authors.lastname: Qin
authors.forename: Kelly
authors.initials: K
authors.lastname: Aubart
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zalacain
authors.forename: Deborah
authors.initials: D
authors.lastname: Butler
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002986:Clinical Trials as Topic; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006193:Haemophilus influenzae / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D001936:Moraxella catarrhalis / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013211:Staphylococcus aureus / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013296:Streptococcus pneumoniae / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D013297:Streptococcus pyogenes / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D019086:Bridged Bicyclo Compounds, Heterocyclic; D004791:Enzyme Inhibitors; C583947:GSK1322322; D006877:Hydroxamic Acids; D000581:Amidohydrolases; C084507:peptide deformylase; D001618:beta-Lactamases