ABSTRACT
A new class of PDF inhibitor with potent, broad spectrum antibacterial activity is described. Optimization of blood stability and potency provided compounds with improved pharmacokinetics that were suitable for in vivo experiments. Compound 5c, which has robust antibacterial activity, demonstrated efficacy in two respiratory tract infection models.
Subject(s)
Amides/chemical synthesis , Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Bacterial Proteins/antagonists & inhibitors , Proline/analogs & derivatives , Proline/chemical synthesis , Respiratory Tract Infections/drug therapy , Administration, Oral , Amides/pharmacology , Amidohydrolases/metabolism , Animals , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/metabolism , Crystallography, X-Ray , Disease Models, Animal , Haemophilus influenzae/drug effects , Haemophilus influenzae/growth & development , Humans , Injections, Intravenous , Microbial Sensitivity Tests , Models, Molecular , Proline/pharmacology , Rats , Respiratory Tract Infections/microbiology , Streptococcus pneumoniae/drug effects , Streptococcus pneumoniae/growth & development , Structure-Activity RelationshipABSTRACT
The synthesis and antibacterial activity of 3-methylenepyrrolidine formyl hydroxyamino derivatives are reported. The antibacterial activities of these derivatives were evaluated to discover SAR at P(1') and P(3') positions, and most of these derivatives exhibit better in vitro antibacterial activity than existing drugs against drug-resistant clinical isolates including MRSA, PRSP, and Haemophilus influenzae.
Subject(s)
Amidohydrolases/antagonists & inhibitors , Anti-Bacterial Agents/chemical synthesis , Enzyme Inhibitors/chemical synthesis , Pyrrolidines/chemistry , Amidohydrolases/metabolism , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Drug Design , Drug Resistance, Bacterial/drug effects , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Haemophilus influenzae/drug effects , Methicillin-Resistant Staphylococcus aureus/drug effects , Microbial Sensitivity Tests , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacologyABSTRACT
The in vitro activity of retapamulin was determined and compared to that of topical and community antibiotics. The MIC(90)s of retapamulin against Staphylococcus aureus and Streptococcus pyogenes were 0.12 microg/ml and 0.016 microg/ml, respectively. Retapamulin has a low propensity to select resistance and produces an in vitro postantibiotic effect.