A new antibiotic selectively kills Gram-negative pathogens

被引：486

作者：

Imai, Yu ^{[1
]}

Meyer, Kirsten J. ^{[1
]}

Iinishi, Akira ^{[1
]}

Favre-Godal, Quentin ^{[1
]}

Green, Robert ^{[1
]}

Manuse, Sylvie ^{[1
]}

Caboni, Mariaelena ^{[1
]}

Mori, Miho ^{[1
]}

Niles, Samantha ^{[1
]}

Ghiglieri, Meghan ^{[1
]}

Honrao, Chandrashekhar ^{[2
]}

Ma, Xiaoyu ^{[2
]}

Guo, Jason J. ^{[2
,3
]}

Makriyannis, Alexandros ^{[2
]}

Linares-Otoya, Luis ^{[4
]}

Boehringer, Nils ^{[4
]}

Wuisan, Zerlina G. ^{[4
]}

Kaur, Hundeep ^{[5
]}

Wu, Runrun ^{[6
,7
]}

Mateus, Andre ^{[8
]}

Typas, Athanasios ^{[8
]}

Savitski, Mikhail M. ^{[8
]}

Espinoza, Josh L. ^{[9
,10
]}

O'Rourke, Aubrie ^{[9
,10
]}

Nelson, Karen E. ^{[9
,10
,11
,12
]}

Hiller, Sebastian ^{[5
]}

Noinaj, Nicholas ^{[6
,7
]}

Schaeberle, Till F. ^{[4
,13
,14
]}

D'Onofrio, Anthony ^{[1
]}

Lewis, Kim ^{[1
]}

机构：

[1] Northeastern Univ, Dept Biol, Antimicrobial Discovery Ctr, Boston, MA 02115 USA

[2] Northeastern Univ, Dept Pharmaceut Sci, Ctr Drug Discovery, Boston, MA 02115 USA

[3] Northeastern Univ, Dept Chem & Chem Biol, Barnett Inst Chem & Biol Anal, Boston, MA 02115 USA

[4] Justus Liebig Univ Giessen, Inst Insect Biotechnol, Giessen, Germany

[5] Univ Basel, Biozentrum, Basel, Switzerland

[6] Purdue Univ, Purdue Inst Inflammat Immunol & Infect Dis, W Lafayette, IN 47907 USA

[7] Purdue Univ, Dept Biol Sci, Markey Ctr Struct Biol, W Lafayette, IN 47907 USA

[8] European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany

[9] J Craig Venter Inst, Dept Human Biol, La Jolla, CA USA

[10] J Craig Venter Inst, Dept Genom Med, La Jolla, CA USA

[11] J Craig Venter Inst, Dept Human Biol, Rockville, MD USA

[12] J Craig Venter Inst, Dept Genom Med, Rockville, MD USA

[13] Fraunhofer Inst Mol Biol & Appl Ecol, Dept Bioresources, Giessen, Germany

[14] German Ctr Infect Res DZIF, Partner Site Giessen Marburg Langen, Giessen, Germany

来源：

NATURE | 2019年 / 576卷 / 7787期

基金：

瑞士国家科学基金会;

关键词：

ESCHERICHIA-COLI; SPECTRUM; IDENTIFICATION; RECONSTITUTION; BIOSYNTHESIS; RESISTANCE; PHYLOGENY; DISCOVERY; RHABDITIS; BACTERIA;

D O I：

10.1038/s41586-019-1791-1

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 current need for novel antibiotics is especially acute for drug-resistant Gram-negative pathogens(1,2). These microorganisms have a highly restrictive permeability barrier, which limits the penetration of most compounds(3,4). As a result, the last class of antibiotics that acted against Gram-negative bacteria was developed in the 1960s(2). We reason that useful compounds can be found in bacteria that share similar requirements for antibiotics with humans, and focus on Photorhabdus symbionts of entomopathogenic nematode microbiomes. Here we report a new antibiotic that we name darobactin, which was obtained using a screen of Photorhabdus isolates. Darobactin is coded by a silent operon with little production under laboratory conditions, and is ribosomally synthesized. Darobactin has an unusual structure with two fused rings that form post-translationally. The compound is active against important Gram-negative pathogens both in vitro and in animal models of infection. Mutants that are resistant to darobactin map to BamA, an essential chaperone and translocator that folds outer membrane proteins. Our study suggests that bacterial symbionts of animals contain antibiotics that are particularly suitable for development into therapeutics.

引用

页码：459 / +

页数：25

共 54 条

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