Summary And Perspectives

The continuous increase of antibiotic resistance, including the emergence of multidrug resistance in common pathogens, has created an urgent need for antibiotics with novel mechanisms of action. PDF, an essential metallopro-tease that removes the N-formyl group of all newly synthesised bacterial polypeptides, is one of the best characterised and validated novel targets in the search for new agents to cover broad-spectrum community and hospital infections. Given the nature of the PDF substrate, it is not surprising to find that initial efforts focused on the design of peptide-like PDF inhibitors. This line of research was supported by the discovery that actinonin, a naturally occurring peptidic hydroxamic acid, inhibits PDF activity. Generally, these types of inhibitors show excellent potency against the enzyme and moderate antibacterial activity, but concerns persist regarding potential toxicity due to poor selectivity versus human metalloproteases. Also, hydroxamic acids are rather notorious for poor pharmacokinetic properties, although some pseu-dopeptidic hydroxamic acid PDF inhibitors containing a P2' proline residue have shown oral efficacy in animal models of infection. Some of the initially poor PK of the actinonin-like molecules seems to be resolved by the use of an N-formyl-N-hydroxylamine in place of a hydroxamate. Indeed, the two compounds that have entered clinical trials, BB-83698 (8) and LBM-415 (12), contain an N-formyl-N-hydroxylamine as the metal- chelator. The fact that these inhibitors have reached Phase I clinical trials is very encouraging, and although it seems they will not be further developed (possibly due to insufficient exposure), they showed no adverse effects in humans, providing an exciting result for this class of inhibitors.

Thus far, less serious attention seems to have been focused on alternative templates, and only one non-peptidic PDF inhibitor, benzamide SB 660618 (27), has been reported to demonstrate in vivo efficacy in an animal model of infection. However, non-peptidic inhibitors may potentially be superior drug candidates, as incorporation of good PK properties and selectivity against MMPs may be easier to achieve. With the abundance of PDF structural information available, the design of additional classes of non-peptidic inhibitors with suitable developability characteristics is likely to continue. Nevertheless, it is still relatively early in the search for clinically relevant PDF inhibitors, and the fact that two compounds have already reached Phase I clinical trials highlights the rapid progress made since PDF was identified as a valid antibacterial target in the late 1990s. Based upon the encouraging results obtained thus far, we believe it is only a matter of time before a novel PDF inhibitor is approved for clinical use.

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