Giuseppe
Emeritus
[Source: Antimicrobial Agents and Chemotherapy, full text: (LINK). Abstract, edited.]
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Comparative Analysis of the Antibacterial Activity of a Novel Peptide Deformylase Inhibitor, GSK1322322
Karen O'Dwyer 1, Meredith Hackel 2, Sarah Hightower 1, Daryl Hoban 2, Samuel Bouchillon 2, Donghui Qin 1, Kelly Aubart 1, Magdalena Zalacain 1 and Deborah Butler 1,#
Author Affiliations: <SUP>1</SUP>Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA <SUP>2</SUP>International Health Management Associates, Inc., Schaumburg, IL, USA
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 community-acquired pneumonia. The activity of GSK1322322 was tested against a global collection of clinical isolates of Haemophilus influenzae (2370), Moraxella catarrhalis (115), Streptococcus pneumoniae (947), Streptococcus pyogenes (617), and Staphylococcus aureus (940), including strains resistant to one or more marketed antibiotics. GSK1322322 had an MIC<SUB>90</SUB> 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<SUB>90</SUB> of 2 μg/mL. Pre-existing resistance mechanisms did not affect its potency, as evidenced by the MIC<SUB>90</SUB> of 1 μg/mL for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae. GSK1322322 was very potent against S. pyogenes strains with an MIC<SUB>90</SUB> 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 MIC<SUB>90</SUB> values 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<SUB>10</SUB> decrease in CFU/mL at 4X MIC within 24 hours 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.
FOOTNOTES
#corresponding author, E-mail address, Deborah.L.Butler@gsk.com
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
-Karen O'Dwyer 1, Meredith Hackel 2, Sarah Hightower 1, Daryl Hoban 2, Samuel Bouchillon 2, Donghui Qin 1, Kelly Aubart 1, Magdalena Zalacain 1 and Deborah Butler 1,#
Author Affiliations: <SUP>1</SUP>Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, PA, USA <SUP>2</SUP>International Health Management Associates, Inc., Schaumburg, IL, USA
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 community-acquired pneumonia. The activity of GSK1322322 was tested against a global collection of clinical isolates of Haemophilus influenzae (2370), Moraxella catarrhalis (115), Streptococcus pneumoniae (947), Streptococcus pyogenes (617), and Staphylococcus aureus (940), including strains resistant to one or more marketed antibiotics. GSK1322322 had an MIC<SUB>90</SUB> 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<SUB>90</SUB> of 2 μg/mL. Pre-existing resistance mechanisms did not affect its potency, as evidenced by the MIC<SUB>90</SUB> of 1 μg/mL for penicillin, levofloxacin, and macrolide-resistant S. pneumoniae. GSK1322322 was very potent against S. pyogenes strains with an MIC<SUB>90</SUB> 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 MIC<SUB>90</SUB> values 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<SUB>10</SUB> decrease in CFU/mL at 4X MIC within 24 hours 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.
FOOTNOTES
#corresponding author, E-mail address, Deborah.L.Butler@gsk.com
Copyright ? 2013, American Society for Microbiology. All Rights Reserved.
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