New classes of antibiotics are urgently needed to counter increasing levels of pathogen resistance. Peptide
deformylase (PDF) was originally selected as a specific bacterial target, but a human homologue, the inhibition
of which causes cell death, was recently discovered. We developed a dual-screening strategy for selecting
highly effective compounds with low inhibition effect against human PDF. We selected a new scaffold in
vitro that discriminated between human and bacterial PDFs. Analyses of structure−activity relationships
identified potent antibiotics such as 2-(5-bromo-1H-indol-3-yl)-N-hydroxyacetamide (6b) with the same
mode of action in vivo as previously identified PDF inhibitors but without the apoptotic effects of these
inhibitors in human cells.
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