Peptide deformylase is an essential bacterial enzyme and is being pursued as a target for designing novel antibiotics. This invention describes a new class of PDF inhibitors that have been designed, synthesized and tested for inhibition of PDF and in vitro antibacterial activities. The new inhibitors exhibit exceptional potency against PDF, with some having sub-nanomolar Ki values. These compounds showed excellent antibacterial activities against a host of Gram-positive bacteria (lowest MIC of 0.08 microgram/ml) and good to modest activity again Gram-negative bacteria. The inhibitors are selective to PDF and showed little inhibition to any of the matrix metalloproteases tested.
Bacteria specific inhibitor
- A PDF inhibitor should make a novel class of antibiotics.
- PDF is a new target and has been shown to be equally effective against pathogens that are resistant to current antibiotics and drug-sensitive microbes.
- No existing PDF inhibitors have been marketed as drugs; the best one is currently (June 2003) in Phase I trials.
- The cyclic inhibitors in this invention have improved potency, selectivity and in vivo stability over existing ones due to structural rigidity introduced by cyclization.
US Patent Application (10/899,207)
Provisional Patent Application (60/490,052)