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. Structure-activity relationships have been established and the implications of this work in the design of future PDF inhibitors are considered.
Jain
R
R
Vicuron Pharmaceuticals, 34790 Ardentech Court, Fremont, CA 94555, USA.
Chen
D
D
White
R J
RJ
Patel
D V
DV
Yuan
Z
Z
D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000900:Anti-Bacterial Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001424:Bacterial Infections / Q000188:drug therapy*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017321:Clinical Trials, Phase I as Topic; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D006090:Gram-Negative Bacteria / Q000187:drug effects / Q000201:enzymology*; D006094:Gram-Positive Bacteria / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D013329:Structure-Activity Relationship
D000900:Anti-Bacterial Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D000581:Amidohydrolases; C084507:peptide deformylase