Natural product derivatives with bactericidal activity against Gram-positive pathogens including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecalis

Abstract

We have shown that the intentional engineering of a natural product biosynthesis pathway is a useful way to generate stereochemically complex scaffolds for use in the generation of combinatorial libraries that capture the structural features of both natural products and synthetic compounds. Analysis of a prototype library based upon nonactic acid lead to the discovery of triazole-containing nonactic acid analogs, a new structural class of antibiotic that exhibits bactericidal activity against drug resistant, Gram-positive pathogens including Staphylococcus aureus and Enterococcus faecalis.

High-Throughput Screening Platform for Natural Product–Based Drug Discovery Against 3 Neglected Tropical Diseases: Human African Trypanosomiasis, Leishmaniasis, and Chagas Disease

“…Determination of IC 50 values showed all compounds to be active in the nanomolar range (Table 2). Several of these selected chemical entities have been previously reported to exhibit antibacterial, 21,22 antifungal, 23 or antitumor activity. [24][25][26] With respect to their antiparasitic activities, actinomycin D has been shown to produce an accumulation of RNA binding proteins in the nucleolus of T. cruzi and Leishmania mexicana, 27 and the treatment of infected mice with actinomycin D has been reported to induce some protection against T. cruzi.…”