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c GSK2251052 is a broad-spectrum antibacterial inhibitor of leucyl tRNA-synthetase (LeuRS) that has been evaluated in phase II clinical trials. Here, we report the identification of a clinical isolate of Staphylococcus aureus that exhibits reduced susceptibility to GSK2251052 without prior exposure to the compound and demonstrate that this phenotype is attributable to a single amino acid polymorphism (P 329 ) within the editing domain of LeuRS.

The spread of drug-resistant malaria parasites urges the search for new antimalarial drugs. Malarial aspartic proteases - plasmepsins (Plms) - are differentially expressed in multiple stages of the Plasmodium parasite's lifecycle and are considered as attractive drug targets. We report the development of novel azole-based non-peptidomimetic plasmepsin inhibitors that have been designed by bioisosteric substitution of the amide moiety in the Actelion amino-piperazine inhibitors. The best triazole-based inhibitors show submicromolar potency toward Plm II, which is comparable to that of the parent Actelion compounds. The new inhibitors can be used as a starting point for the development of a resistance-free antimalarial drug targeting the non-digestive Plm IX or X, which are essential for the malaria parasite life cycle.

Method. -Hydroxylamine hydrochloride can be added to the CDI-activated carboxylic acids either in solid state (anhydrous method) or as aqueous solution. Both methods provide an operationally simple access to structurally different hydroxyamic acids and are suitable for parallel syntheses. N-Protected chiral amino acids are converted with high enantiomeric purity. -(USACHOVA, N.; LEITIS, G.; JIRGENSONS*, A.; KALVINSH, I.; Synth. Commun. 40 (2010) 6, 927-935,

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