Science
[Research Article] 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 K?nig, Nicole C. Ammerman, María Belén Barrio, Kai Borchers, Florence Bordon-Pallier, Mark Br?nstrup, Gilles Courtemanche, Martin Gerlitz, Michel Geslin, Peter Hammann, Dirk W. Heinz, Holger Hoffmann, Sylvie Klieber, Markus Kohlmann, Michael Kurz, Christine Lair, Hans Matter, Eric Nuermberger, Sandeep Tyagi, Laurent Fraisse, Jacques H. Grosset, Sophie Lagrange, Rolf Müller.
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.