Targeting DnaN for tuberculosis therapy using novel griselimycins

Angela Kling, Peer Lukat, Deepak V. Almeida, Armin Bauer, Evelyne Fontaine, Sylvie Sordello, Nestor Zaburannyi, Jennifer Herrmann, Silke C. Wenzel, Claudia König, Nicole C. Ammerman, María Belén Barrio, Kai Borchers, Florence Bordon-Pallier, Mark Brönstrup, Gilles Courtemanche, Martin Gerlitz, Michel Geslin, Peter Hammann, Dirk W. HeinzHolger Hoffmann, Sylvie Klieber, Markus Kohlmann, Michael Kurz, Christine Lair, Hans Matter, Eric Nuermberger, Sandeep Tyagi, Laurent Fraisse, Jacques H. Grosset, Sophie Lagrange, Rolf Müller

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1106-1112
Number of pages7
JournalScience
Volume348
Issue number6239
DOIs
StatePublished - Jun 5 2015

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ASJC Scopus subject areas

  • General

Cite this

Kling, A., Lukat, P., Almeida, D. V., Bauer, A., Fontaine, E., Sordello, S., Zaburannyi, N., Herrmann, J., Wenzel, S. C., König, C., Ammerman, N. C., Barrio, M. B., Borchers, K., Bordon-Pallier, F., Brönstrup, M., Courtemanche, G., Gerlitz, M., Geslin, M., Hammann, P., ... Müller, R. (2015). Targeting DnaN for tuberculosis therapy using novel griselimycins. Science, 348(6239), 1106-1112. https://doi.org/10.1126/science.aaa4690