Affiliation:
1. Antibacterial Discovery Performance Unit, Infectious Disease Therapeutic Area, GlaxoSmithKline, Collegeville, Pennsylvania, USA
2. International Health Management Associates, Inc., Schaumburg, Illinois, USA
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.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
33 articles.
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