QPT-1 was discovered in a compound library by high-throughput screening and triage for substances with whole-cell antibacterial activity. This totally synthetic compound is an unusual barbituric acid derivative whose activity resides in the (؊)-enantiomer. QPT-1 had activity against a broad spectrum of pathogenic, antibioticresistant bacteria, was nontoxic to eukaryotic cells, and showed oral efficacy in a murine infection model, all before any medicinal chemistry optimization. Biochemical and genetic characterization showed that the QPT-1 targets the ␤ subunit of bacterial type II topoisomerases via a mechanism of inhibition distinct from the mechanisms of fluoroquinolones and novobiocin. Given these attributes, this compound represents a promising new class of antibacterial agents. The success of this reverse genomics effort demonstrates the utility of exploring strategies that are alternatives to target-based screens in antibacterial drug discovery.

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As part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold as potential novel anti-bacterial agents, we explored the synthesis of simple tyrosine-based systems. These were prepared via key intermediates containing internal allylglycine and allyltyrosine residues for subsequent ring closing metathesis reactions. Although the resulting anti-bacterial activity against Staphylococcus aureus was modest, this represents a novel and simple route to this class of compounds. One intermediate acyclic dipeptide precursor showed good activity against S. aureus with an MIC of 7.8 µg/mL. AbstractAs part of a program investigating cyclic peptides with an internal aromatic hydrophobic scaffold as

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