JAC Advance Access published online on February 12, 2004
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkh108
© 2004 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Genesoft Pharmaceuticals,
7300 Shoreline Ct., South San Francisco, CA 94080, USA;
* Corresponding author. E-mail: kjohnson{at}genesoft.com.
Received 12 September 2003
; revised 3 December 2003
; accepted 8 December 2003
Objective: BB-81384, a novel peptide
deformylase (PDF) inhibitor, was characterized in terms of enzyme inhibition
profile, antibacterial activity, rodent pharmacokinetics and oral
efficacy in murine infection models. Methods: MICs were determined by standard NCCLS
broth microdilution. Selectivity of metalloenzyme inhibition was
determined with a limited panel of enzymes via standard biochemical
assays. Profiling of the pharmacokinetics and select tissue disposition
in mice was determined and compared with that of the macrolide,
azithromycin. In vivo murine efficacy studies using Streptococcus pneumoniae were conducted using a
peritonitis model, as well as lung and thigh burden models of infection. Results: BB-81384 selectively inhibited PDF
with an IC50 Conclusion: BB-81384, a novel PDF inhibitor
with good activity against S. pneumoniae in
vitro, was the first compound of this class to be profiled
for oral pharmacokinetics and tissue disposition and to demonstrate oral
anti-pneumococcal efficacy in mice.
Keywords: peptide deformylase, efficacy, pharmacokinetics
Oral anti-pneumococcal activity and pharmacokinetic
profiling of a novel peptide deformylase inhibitor
2 British Biotech plc, Watlington
Road, Oxford OX4 6LY, UK
10 nM and with
MICs < 0.5 mg/L against most S.
pneumoniae pathogens. Pharmacokinetic analysis revealed good
oral bioavailability and moderate clearance and volume of distribution.
BB-81384 partitioning to lung tissue was similar in terms of magnitude
and kinetics to that of the plasma compartment. Single-administration
oral efficacy in a mouse peritonitis model was evident with an ED50 of
30 mg/kg. BB-81384 reduced the bacterial load by 5
and 3 log units in organ-burden models of lung and thigh infection,
respectively.
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