title: Antibiotics. Targeting DnaN for tuberculosis therapy using novel griselimycins.
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.
authors.affiliation: 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.
authors.forename: Angela
authors.initials: A
authors.lastname: Kling
authors.affiliation: 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.
authors.forename: Peer
authors.initials: P
authors.lastname: Lukat
authors.affiliation: 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.
authors.forename: Deepak V
authors.initials: DV
authors.lastname: Almeida
authors.affiliation: Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Bauer
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Fontaine
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Sordello
authors.affiliation: 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.
authors.forename: Nestor
authors.initials: N
authors.lastname: Zaburannyi
authors.affiliation: 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.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Herrmann
authors.affiliation: 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.
authors.forename: Silke C
authors.initials: SC
authors.lastname: Wenzel
authors.affiliation: Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: König
authors.affiliation: 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.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Ammerman
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
authors.forename: María Belén
authors.initials: MB
authors.lastname: Barrio
authors.affiliation: Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Kai
authors.initials: K
authors.lastname: Borchers
authors.affiliation: Sanofi-Aventis R&D, Strategy, Science Policy & External Innovation (S&I), 75008 Paris, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Bordon-Pallier
authors.affiliation: Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany. Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Mark
authors.initials: M
authors.lastname: Brönstrup
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
authors.forename: Gilles
authors.initials: G
authors.lastname: Courtemanche
authors.affiliation: Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Gerlitz
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
authors.forename: Michel
authors.initials: M
authors.lastname: Geslin
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 65926 Frankfurt, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Hammann
authors.affiliation: German Centre for Infection Research (DZIF), Partner Site Hannover-Braunschweig, Hannover, Germany. Helmholtz Centre for Infection Research (HZI), 38124 Braunschweig, Germany.
authors.forename: Dirk W
authors.initials: DW
authors.lastname: Heinz
authors.affiliation: Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Holger
authors.initials: H
authors.lastname: Hoffmann
authors.affiliation: Sanofi-Aventis R&D, Disposition Safety and Animal Research, 34184 Montpellier, France.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Klieber
authors.affiliation: Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Kohlmann
authors.affiliation: Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Kurz
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Lair
authors.affiliation: Sanofi-Aventis R&D, LGCR/Chemistry, Industriepark Höchst, 65926 Frankfurt am Main, Germany.
authors.forename: Hans
authors.initials: H
authors.lastname: Matter
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Nuermberger
authors.affiliation: Center for Tuberculosis Research, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Tyagi
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Fraisse
authors.affiliation: 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.
authors.forename: Jacques H
authors.initials: JH
authors.lastname: Grosset
authors.affiliation: Sanofi-Aventis R&D, Infectious Diseases Therapeutic Strategic Unit, 31036 Toulouse, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lagrange
authors.affiliation: 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.
authors.forename: Rolf
authors.initials: R
authors.lastname: Müller
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors*; D045744:Cell Line, Tumor; D018360:Crystallography, X-Ray; D004259:DNA-Directed DNA Polymerase; D004195:Disease Models, Animal; D015195:Drug Design; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D058990:Molecular Targeted Therapy; D020102:Mycobacterium smegmatis / Q000187:drug effects / Q000201:enzymology; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D017433:Protein Structure, Secondary; D013302:Streptomyces / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy* / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D010456:Peptides, Cyclic; C000599096:cyclohexylgriselimycin; C000599094:griselimycin; C000599095:methylgriselimycin; D004259:DNA-Directed DNA Polymerase; C083980:dnaN protein, Bacteria