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Science. 2015 Jun 5;348(6239):1106-12. doi: 10.1126/science.aaa4690.

Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins.

Author information

1
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany.
2
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
3
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban 4001, South Africa.
4
Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
5
Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
6
Sanofi-Aventis R&D, Strategy, Science Policy & External Innovation (S&I), 75008 Paris, France.
7
Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany. Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
8
Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 65926 Frankfurt, Germany.
9
German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
10
Sanofi-Aventis R&D, Disposition Safety and Animal Research, 34184 Montpellier, France.
11
Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
12
Department of Microbial Natural Products, Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Helmholtz Centre for Infection Research and Pharmaceutical Biotechnology, Saarland University, 66123 Saarbrücken, Germany. German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. rolf.mueller@helmholtz-hzi.de.

Abstract

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.

PMID:
26045430
DOI:
10.1126/science.aaa4690
[Indexed for MEDLINE]

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