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Publication Abstract from PubMed

DNA gyrase is an essential enzyme in bacteria and its inhibition results in the disruption of DNA synthesis and subsequently cell death. The pyrrolamides are a novel class of antibacterial agents targeting DNA gyrase. These compounds were identified from a fragment-based lead generation (FBLG) approach using NMR screening to identify low molecular weight compounds that bind to the ATP pocket of DNA gyrase. A pyrrole hit with a binding constant of 1 mM formed the basis of the design and synthesis of a focused library of compounds that resulted in the rapid identification of a lead compound that inhibited DNA gyrase with an IC(50) value of 3 muM. The potency of the lead compound was further optimized utilizing iterative X-ray crystallography to yield DNA gyrase inhibitors that also displayed antibacterial activity. Spontaneous mutants were isolated in Staphylococcus aureus by plating on agar plates containing pyrrolamide 4 at the MIC. The resistant variants displayed 4- to 8-fold increased MIC values relative to the parent strain. DNA sequencing revealed two independent point mutations in the pyrrolamide binding region of the gyrB gene from these variants, supporting the hypothesis that the mode-of-action of these compounds was inhibition of DNA gyrase. Efficacy of a representative pyrrolamide was demonstrated against Streptococcus pneumoniae in a mouse lung infection model. These data demonstrate that the pyrrolamides are a novel class of DNA gyrase inhibitors with the potential to deliver future antibacterial agents targeting multiple clinical indications.

Pyrrolamide DNA Gyrase Inhibitors: Fragment-based NMR Screening to Antibacterial Agents.,Eakin AE, Green O, Hales N, Walkup GK, Bist S, Singh A, Mullen G, Bryant J, Embrey K, Gao N, Breeze A, Timms D, Andrews B, Uria-Nickelsen M, Demeritt J, Loch JT 3rd, Hull K, Blodgett A, Illingworth RN, Prince B, Boriack-Sjodin PA, Hauck S, Macpherson LJ, Ni H, Sherer B Antimicrob Agents Chemother. 2011 Dec 19. PMID:22183167^[1]

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