Chimeric peptidomimetic antibiotics against Gram-negative bacteria

被引：234

作者：

Luther, Anatol ^{[1
]}

Urfer, Matthias ^{[2
]}

Zahn, Michael ^{[3
]}

Mueller, Maik ^{[4
,5
]}

Wang, Shuang-Yan ^{[2
]}

Mondal, Milon ^{[2
]}

Vitale, Alessandra ^{[6
]}

Hartmann, Jean-Baptiste ^{[3
]}

Sharpe, Timothy ^{[3
]}

Lo Monte, Fabio ^{[2
]}

Kocherla, Harsha ^{[2
]}

Cline, Elizabeth ^{[2
]}

Pessi, Gabriella ^{[6
]}

Rath, Parthasarathi ^{[3
]}

Modaresi, Seyed Majed ^{[3
]}

Chiquet, Petra ^{[1
]}

Stiegeler, Sarah ^{[1
]}

Verbree, Carolin ^{[1
]}

Remus, Tobias ^{[1
]}

Schmitt, Michel ^{[1
]}

Kolopp, Caroline ^{[1
]}

Westwood, Marie-Anne ^{[1
]}

Desjonqueres, Nicolas ^{[1
]}

Brabet, Emile ^{[1
]}

Hell, Sophie ^{[1
]}

LePoupon, Karen ^{[1
]}

Vermeulen, Annie ^{[1
]}

Jaisson, Regis ^{[1
]}

Rithie, Virginie ^{[1
]}

Upert, Gregory ^{[1
]}

Lederer, Alexander ^{[1
]}

Zbinden, Peter ^{[1
]}

Wach, Achim ^{[1
]}

Moehle, Kerstin ^{[2
]}

Zerbe, Katja ^{[2
]}

Locher, Hans H. ^{[1
]}

Bernardini, Francesca ^{[1
]}

Dale, Glenn E. ^{[1
]}

Eberl, Leo ^{[6
]}

Wollscheid, Bernd ^{[4
,5
]}

Hiller, Sebastian ^{[3
]}

Robinson, John A. ^{[2
]}

Obrecht, Daniel ^{[1
]}

机构：

[1] Polyphor AG, Allschwil, Switzerland

[2] Univ Zurich, Dept Chem, Zurich, Switzerland

[3] Univ Basel, Biozentrum, Basel, Switzerland

[4] Swiss Fed Inst Technol, Inst Mol Syst Biol, Zurich, Switzerland

[5] Swiss Fed Inst Technol, Dept Hlth Sci & Technol, Zurich, Switzerland

[6] Univ Zurich, Dept Plant & Microbial Biol, Zurich, Switzerland

来源：

NATURE | 2019年 / 576卷 / 7787期

基金：

瑞士国家科学基金会; 英国惠康基金;

关键词：

2-COMPONENT REGULATORY SYSTEM; OUTER-MEMBRANE; POLYMYXIN-B; LIPOPOLYSACCHARIDE TRANSPORT; COLISTIN RESISTANCE; LAST-LINE; COMPLEX; BAMA;

D O I：

10.1038/s41586-019-1665-6

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：

There is an urgent need for new antibiotics against Gram-negative pathogens that are resistant to carbapenem and third-generation cephalosporins, against which antibiotics of last resort have lost most of their efficacy. Here we describe a class of synthetic antibiotics inspired by scaffolds derived from natural products. These chimeric antibiotics contain a beta-hairpin peptide macrocycle linked to the macrocycle found in the polymyxin and colistin family of natural products. They are bactericidal and have a mechanism of action that involves binding to both lipopolysaccharide and the main component (BamA) of the beta-barrel folding complex (BAM) that is required for the folding and insertion of beta-barrel proteins into the outer membrane of Gram-negative bacteria. Extensively optimized derivatives show potent activity against multidrug-resistant pathogens, including all of the Gram-negative members of the ESKAPE pathogens(1). These derivatives also show favourable drug properties and overcome colistin resistance, both in vitro and in vivo. The lead candidate is currently in preclinical toxicology studies that-if successful-will allow progress into clinical studies that have the potential to address life-threatening infections by the Gram-negative pathogens, and thus to resolve a considerable unmet medical need.

引用

页码：452 / +

页数：22

共 31 条

[1] Molecular mechanisms of polymyxin resistance: knowns and unknowns [J].