Iclaprim. Antibacterial, dihydrofolate reductase inhibitor

The need for potent antibacterial agents with novel mechanisms of action remains a research priority. Dihydrofolate reductase (DHFR) is an enzyme essential for bacterial survival that is an excellent target for antibacterial drug development. Diaminopyrimidines such as trimethoprim (TMP) are inhibitors of DHFR which have been used clinically as monotherapy and in combination with other agents with relative success. However, TMP is weakly bactericidal and resistance has emerged due to frequent use. Researchers have therefore focused on the discovery of synthetic derivatives of benzyldiaminopyrimidines which exhibit improved potency and selectivity and can overcome resistance. Iclaprim is a novel diaminopyrimidine that has shown potent, expanded-spectrum activity against Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, vancomycin-intermediate and vancomycin-resistant S. aureus and macrolide-, quinolone- and TMP-resistant strains. Activity was also observed against Gram-positive and Gram-negative pathogens involved in respiratory tract infections and it proved effective in animal models of infection. Moreover, in a phase 11 trial, iclaprim was shown to be safe and effective as a treatment for complicated skin and soft tissue infections.