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Publication Abstract from PubMed

We present the discovery and optimization of a novel series of bacterial topoisomerase inhibitors. Starting from a virtual screening hit, activity was optimized through a combination of structure-based design and physical property optimization. Synthesis of fewer than a dozen compounds was required to achieve inhibition of the growth of methicillin-resistant Staphyloccus aureus (MRSA) at compound concentrations of 1.56muM. These compounds simultaneously inhibit DNA gyrase and Topoisomerase IV at similar nanomolar concentrations, reducing the likelihood of the spontaneous occurrence of target-based mutations resulting in antibiotic resistance, an increasing threat in the treatment of serious infections.

Discovery of a novel azaindole class of antibacterial agents targeting the ATPase domains of DNA gyrase and Topoisomerase IV.,Manchester JI, Dussault DD, Rose JA, Boriack-Sjodin PA, Uria-Nickelsen M, Ioannidis G, Bist S, Fleming P, Hull KG Bioorg Med Chem Lett. 2012 Aug 1;22(15):5150-6. Epub 2012 Jun 19. PMID:22814212^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.