Actinonin and Analogs: Inhibitors of Bacterial Peptide Deformylase

The naturally occurring hydroxamic acid actinonin was isolated from species of actinomycetes and characterised as an antibiotic in the 1960s. More than 30 years later the antibacterial activity of actinonin was attributed to inhibition of the metallohydrolase peptide deformylase (PDF), an enzyme that performs an essential step in bacterial protein synthesis. To date, three PDF inhibitors have progressed into clinical trials and one compound, GSK1322322, is currently in Phase II for the treatment of respiratory tract infections and skin and soft tissue infections. This chapter provides an introduction to PDF as an antibacterial target and discusses PDF inhibitors described in the literature that are structurally related to actinonin. Structure–activity relationships, in vivo data, potential resistance mechanisms and recent developments in the area of PDF inhibition are presented.