TY  - JOUR
AU  - Kling, A.
AU  - Lukat, P.
AU  - Almeida, D. V.
AU  - Bauer, A.
AU  - Fontaine, E.
AU  - Sordello, S.
AU  - Zaburannyi, N.
AU  - Herrmann, J.
AU  - Wenzel, S. C.
AU  - Konig, C.
AU  - Ammerman, N. C.
AU  - Barrio, M. B.
AU  - Borchers, K.
AU  - Bordon-Pallier, F.
AU  - Bronstrup, M.
AU  - Courtemanche, G.
AU  - Gerlitz, M.
AU  - Geslin, M.
AU  - Hammann, P.
AU  - Heinz, D. W.
AU  - Hoffmann, H.
AU  - Klieber, S.
AU  - Kohlmann, M.
AU  - Kurz, M.
AU  - Lair, C.
AU  - Matter, H.
AU  - Nuermberger, E.
AU  - Tyagi, S.
AU  - Fraisse, L.
AU  - Grosset, J. H.
AU  - Lagrange, S.
AU  - Muller, R.
TI  - Targeting DnaN for tuberculosis therapy using novel griselimycins
JO  - Science
VL  - 348
IS  - 6239
SN  - 1095-9203
CY  - Washington, DC [u.a.]
PB  - American Association for the Advancement of Science16205
M1  - PUBDB-2015-02248
SP  - 1106 - 1112
PY  - 2015
N1  - (c) AAAS. Post referee full text in progress. Embargo for full text 6 months from 06.06.15.
AB  - The 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000355590500040
C6  - pmid:26045430
DO  - DOI:10.1126/science.aaa4690
UR  - https://bib-pubdb1.desy.de/record/220438
ER  -