Targeting DnaN for tuberculosis therapy using novel griselimycins

被引：255

作者：

Kling, Angela ^{[1
,2
]}

Lukat, Peer ^{[1
,2
,3
]}

Almeida, Deepak V. ^{[4
,5
]}

Bauer, Armin ^{[6
]}

Fontaine, Evelyne ^{[7
]}

Sordello, Sylvie ^{[7
]}

Zaburannyi, Nestor ^{[1
,2
]}

Herrmann, Jennifer ^{[1
,2
]}

Wenzel, Silke C. ^{[1
,2
]}

Koenig, Claudia ^{[6
]}

Ammerman, Nicole C. ^{[4
,5
]}

Barrio, Maria Belen ^{[7
]}

Borchers, Kai ^{[6
]}

Bordon-Pallier, Florence ^{[8
]}

Broenstrup, Mark ^{[3
,6
]}

Courtemanche, Gilles ^{[7
]}

Gerlitz, Martin ^{[6
]}

Geslin, Michel ^{[7
]}

Hammann, Peter ^{[9
]}

Heinz, Dirk W. ^{[2
,3
]}

Hoffmann, Holger ^{[6
]}

Klieber, Sylvie ^{[10
]}

Kohlmann, Markus ^{[6
]}

Kurz, Michael ^{[6
]}

Lair, Christine ^{[7
]}

Matter, Hans ^{[6
]}

Nuermberger, Eric ^{[4
]}

Tyagi, Sandeep ^{[4
]}

Fraisse, Laurent ^{[7
]}

Grosset, Jacques H. ^{[4
,5
]}

Lagrange, Sophie ^{[7
]}

Mueller, Rolf ^{[1
,2
]}

机构：

[1] Univ Saarland, Helmholtz Ctr Infect Res & Pharmaceut Biotechnol, Helmholtz Inst Pharmaceut Res Saarland HIPS, Dept Microbial Nat Prod, D-66123 Saarbrucken, Germany

[2] German Ctr Infect Res DZIF, Partner Site Hannover Braunschweig, Hannover, Germany

[3] Helmholtz Ctr Infect Res HZI, D-38124 Braunschweig, Germany

[4] Johns Hopkins Univ, Ctr TB Res, Sch Med, Baltimore, MD 21231 USA

[5] KwaZulu Natal Res Inst TB & HIV K RITH, ZA-4001 Durban, South Africa

[6] Sanofi Aventis R&D, LGCR Chem, D-65926 Frankfurt, Germany

[7] Sanofi Aventis R&D, Infect Dis Therapeut Strateg Unit, F-31036 Toulouse, France

[8] Sanofi Aventis R&D, Strategy Sci Policy & External Innovat S&I, F-75008 Paris, France

[9] Sanofi Aventis R&D, Infect Dis Therapeut Strateg Unit, D-65926 Frankfurt, Germany

[10] Sanofi Aventis R&D, Disposit Safety & Anim Res, F-34184 Montpellier, France

来源：

SCIENCE | 2015年 / 348卷 / 6239期

关键词：

BACTERIAL SLIDING CLAMP; MYCOBACTERIUM-SMEGMATIS; REPLICATION; ORIGIN; MODEL;

D O I：

10.1126/science.aaa4690

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：1106 / 1112

页数：7

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