Session: Poster Session: New Topoisomerase Inhibitors
Monday, October 27, 2008: 12:00 AM
Room: Hall C
Background: The pyrrolamides are a novel class of antibacterial agents that inhibit DNA gyrase resulting in inhibition of DNA synthesis and bacterial cell death. Herein, we describe the antibacterial activity and in vivo efficacy of representatives of the series. Methods: CSLI guidelines were used to determine the MICs, MIC90s, MBCs as well as killing kinetics. The frequency of spontaneous resistance was determined as the ratio of the number of colonies on compound-containing plates and the number of colonies on compound-free plates. Efficacy was evaluated against Streptococcus pneumoniae in a mouse pneumoniae model. Results: The MIC values of pyrrolamides against strains of Staphylococcus aureus, S. pneumoniae, Enterococcus faecium, Haemophilus influenzae and Moraxella catarrhalis were <=4 µg/ml. MIC90 values for selected compounds in 30 strain panels of the same species, including drug resistant strains, ranged from 0.063 to 8 µg/ml. Pyrrolamides were bactericidal against S. aureus and H. influenzae showing a 99.9% reduction in viable cells in 24 hours and had MBC values that were equal to their MIC values. The frequency of resistance development in S. aureus was <1 x 10-9 at 4x MIC. Efficacy was demonstrated against S. pneumoniae at 80 mg/kg qid causing a >4-log reduction in viable counts in the lung compared to the vehicle-treated control. Conclusions: 1) Pyrrolamides are a novel class of bacterial DNA gyrase inhibitors with potent in vitro activity against Gram-positive and selected Gram-negative pathogens, including MRSA, VRE and PRSP. 2) Representatives of the class are bactericidal, demonstrate a low frequency of spontaneous resistance and are efficacious against S. pneumoniae in vivo. 3) Pyrrolamides show promise as a novel class of antibacterial agents for the treatment of hospital and community-acquired infections.