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000220438 1001_ $$0P:(DE-HGF)0$$aKling, A.$$b0
000220438 245__ $$aTargeting DnaN for tuberculosis therapy using novel griselimycins
000220438 260__ $$aWashington, DC [u.a.]$$bAmerican Association for the Advancement of Science16205$$c2015
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000220438 500__ $$a(c) AAAS. Post referee full text in progress. Embargo for full text 6 months from 06.06.15.
000220438 520__ $$aThe discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.
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000220438 7001_ $$0P:(DE-H253)PIP1019884$$aLukat, P.$$b1
000220438 7001_ $$0P:(DE-HGF)0$$aAlmeida, D. V.$$b2
000220438 7001_ $$0P:(DE-HGF)0$$aBauer, A.$$b3
000220438 7001_ $$0P:(DE-HGF)0$$aFontaine, E.$$b4
000220438 7001_ $$0P:(DE-HGF)0$$aSordello, S.$$b5
000220438 7001_ $$0P:(DE-HGF)0$$aZaburannyi, N.$$b6
000220438 7001_ $$0P:(DE-HGF)0$$aHerrmann, J.$$b7
000220438 7001_ $$0P:(DE-HGF)0$$aWenzel, S. C.$$b8
000220438 7001_ $$0P:(DE-HGF)0$$aKonig, C.$$b9
000220438 7001_ $$0P:(DE-HGF)0$$aAmmerman, N. C.$$b10
000220438 7001_ $$0P:(DE-HGF)0$$aBarrio, M. B.$$b11
000220438 7001_ $$0P:(DE-HGF)0$$aBorchers, K.$$b12
000220438 7001_ $$0P:(DE-HGF)0$$aBordon-Pallier, F.$$b13
000220438 7001_ $$0P:(DE-HGF)0$$aBronstrup, M.$$b14
000220438 7001_ $$0P:(DE-HGF)0$$aCourtemanche, G.$$b15
000220438 7001_ $$0P:(DE-HGF)0$$aGerlitz, M.$$b16
000220438 7001_ $$0P:(DE-HGF)0$$aGeslin, M.$$b17
000220438 7001_ $$0P:(DE-HGF)0$$aHammann, P.$$b18
000220438 7001_ $$0P:(DE-HGF)0$$aHeinz, D. W.$$b19
000220438 7001_ $$0P:(DE-HGF)0$$aHoffmann, H.$$b20
000220438 7001_ $$0P:(DE-HGF)0$$aKlieber, S.$$b21
000220438 7001_ $$0P:(DE-HGF)0$$aKohlmann, M.$$b22
000220438 7001_ $$0P:(DE-HGF)0$$aKurz, M.$$b23
000220438 7001_ $$0P:(DE-HGF)0$$aLair, C.$$b24
000220438 7001_ $$0P:(DE-HGF)0$$aMatter, H.$$b25
000220438 7001_ $$0P:(DE-HGF)0$$aNuermberger, E.$$b26
000220438 7001_ $$0P:(DE-HGF)0$$aTyagi, S.$$b27
000220438 7001_ $$0P:(DE-HGF)0$$aFraisse, L.$$b28
000220438 7001_ $$0P:(DE-HGF)0$$aGrosset, J. H.$$b29
000220438 7001_ $$0P:(DE-HGF)0$$aLagrange, S.$$b30
000220438 7001_ $$0P:(DE-HGF)0$$aMuller, R.$$b31$$eCorresponding author
000220438 773__ $$0PERI:(DE-600)2066996-3$$a10.1126/science.aaa4690$$gVol. 348, no. 6239, p. 1106 - 1112$$n6239$$p1106 - 1112$$tScience$$v348$$x1095-9203$$y2015
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