Antimicrobial resistance (AMR) is a global healthcare concern,1 a shortage of new therapies has led to a race to develop new treatments to fight 'superbugs'. DNA gyrase, a prokaryotic topoisomerase enzyme responsible for regulating the topological state of bacterial DNA,2 is only found in bacteria and thus is a rational drug target.3 Ciprofloxacin, a quinolone antibiotic, stabilises a DNA-gyrase-drug intermediate resulting in cell death.4 Ciprofloxacin's success is a paradigm for disrupting topoisomerase function; however enzyme mutations, alterations in efflux pumps and plasmid mediated resistance are diminishing the quinolones efficacy.5 Simocyclinone D8, (SD8) a natural product from Streptomyces, also targets DNA gyrase but with a novel mode of action,6 preventing binding of DNA with the gyrase enzyme. SD8 is bifunctional, containing a chlorinated dihydroxylated aminocoumarin, a tetraene linker, D-olivose sugar and angucyclic polyketide. Inspired by the structural diversity and distinct mechanism of action of SD8,7 we describe herein the synthesis of small molecules designed to mimic its mechanism of action and move towards the synthetic construction of both the natural product and designed analogues. We will also present biological assays for the activity of the compounds against DNA gyrase. Huttner, A.; Harbarth, S.; Carlet, J.; Cosgrove, S.; Goossens, H.; Holmes, A.; Jarlier, V.; Voss, A.; Pittet, D.; Antimicrob Resist Infect Control 2013 ; 2, 1-13Tse-Dinh, Y. C.; Infect Disord Drug Targets 2007 ; 7, 3-9Collin, F.; Karkare, S.; Maxwell, A.; Appl Microbiol Biotechnol 2011 ; 92, 479-97Drlica, K.; Zhao, X.; Microbiol Mol Biol Rev 1997 ; 61, 377-92Jacoby G. A.; Clin Infect Dis 2005 ; 4, 120-126Flatman, R. H.; Howells, A. J.; Heide, L.; Fiedler, H. P.; Antimicrob Agents Chemother 2005 ; 49, 1093-100Hearnshaw S. J.; Edwards, M. J.; Stevenson, C. E.; Lawson, D. M.; Maxwell, A.; J Mol Biol 2014;  http://dx.doi.org/10.1016/j.jmb.2014.02.017

Learning lessons from nature: Design and synthesis of DNA gyrase inhibitors based on the structure of Simocyclinone D8

248th National Meeting (2014)

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