Bacterial peptide deformylase inhibitors : A new class of antibacterial agents

Peptide deformylase (PDF) is a prokaryotic metalloenzyme that is essential for bacterial growth but is not required by mammalian cells. Thus, it represents a selective and promising target for the development of new antibacterial agents. Since deformylase inhibitors have yet to be used clinically as antibacterial drugs, compounds targeting this enzyme should avoid cross-resistance with currently used antibacterial agents. The PDF enzyme is a ferrous ion-containing metallohydrolase, but a nickel-containing surrogate is routinely used in the laboratory for testing inhibitors due to its better stability. Enzymes from several bacterial species have been cloned and both their three-dimensional structures and co-crystal structures with bound inhibitor have been determined. As a metallo enzyme, PDF lends itself to the well-precedented mechanism-based rational drug design approach. Using structural and mechanistic information together with high throughput screening, several types of potent PDF inhibitors have been identified. PDF inhibitors identified to date share a common structural feature of a “chelator + peptidomimetic” scaffold. Although compounds with many different chelators inhibit the cell free enzyme, only compounds containing hydroxamic acid or N-formyl hydroxylamine exhibit appreciable antibacterial activity. Several lead inhibitors have demonstrated in vivo efficacy and an excellent safety profile. Two PDF inhibitors, VIC-104959 (LBM415) and BB-83698, have progressed to Phase I clinical trials. In this review, different PDF inhibitors are compared and their biological activities are discussed. Structureactivity relationships have been established and the implications of this work in the design of future PDF inhibitors are considered.