Optimized arylomycins are a new class of Gram-negative antibiotics

被引：267

作者：

Smith, Peter A. ^{[1
]}

Koehler, Michael F. T. ^{[2
]}

Girgis, Hany S. ^{[1
]}

Yan, Donghong ^{[3
]}

Chen, Yongsheng ^{[4
]}

Chen, Yuan ^{[5
]}

Crawford, James J. ^{[2
]}

Durk, Matthew R. ^{[5
]}

Higuchi, Robert I. ^{[6
,11
]}

Kang, Jing ^{[3
]}

Murray, Jeremy ^{[7
]}

Paraselli, Prasuna ^{[6
,12
]}

Park, Summer ^{[3
]}

Phung, Wilson ^{[8
]}

Quinn, John G. ^{[9
]}

Roberts, Tucker C. ^{[6
,13
]}

Rouge, Lionel ^{[7
]}

Schwarz, Jacob B. ^{[2
,14
]}

Skippington, Elizabeth ^{[10
]}

Wai, John ^{[4
]}

Xu, Min ^{[3
]}

Yu, Zhiyong ^{[4
]}

Zhang, Hua ^{[3
]}

Tan, Man-Wah ^{[1
]}

Heise, Christopher E. ^{[1
,9
]}

机构：

[1] Genentech Inc, Dept Infect Dis, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Discovery Chem, San Francisco, CA USA

[3] Genentech Inc, Dept Translat Immunol, San Francisco, CA USA

[4] Wuxi AppTec, Dept Chem, Shanghai, Peoples R China

[5] Genentech Inc, Dept Drug Metab & Pharmacokinet, San Francisco, CA USA

[6] RQx Pharmaceut, La Jolla, CA USA

[7] Genentech Inc, Dept Struct Biol, San Francisco, CA USA

[8] Genentech Inc, Dept Microchem Prote, San Francisco, CA USA

[9] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[10] Genentech Inc, Dept Bioinformat & Computat Biol, San Francisco, CA USA

[11] Retrovirox, San Diego, CA USA

[12] Vertex, San Diego, CA USA

[13] Aduro Biotech, Berkeley, CA USA

[14] FLX Bio, San Francisco, CA USA

来源：

NATURE | 2018年 / 561卷 / 7722期

关键词：

OUTER-MEMBRANE PERMEABILITY; I SIGNAL PEPTIDASES; ANTIBACTERIAL DISCOVERY; SPECTRUM; CHALLENGES; INHIBITORS; PATHOGENS; BACTERIA; TARGET; BROAD;

D O I：

10.1038/s41586-018-0483-6

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：

Multidrug-resistant bacteria are spreading at alarming rates, and despite extensive efforts no new class of antibiotic with activity against Gram-negative bacteria has been approved in over fifty years. Natural products and their derivatives have a key role in combating Gram-negative pathogens. Here we report chemical optimization of the arylomycins-a class of natural products with weak activity and limited spectrum-to obtain G0775, a molecule with potent, broad-spectrum activity against Gram-negative bacteria. G0775 inhibits the essential bacterial type I signal peptidase, a new antibiotic target, through an unprecedented molecular mechanism. It circumvents existing antibiotic resistance mechanisms and retains activity against contemporary multidrug-resistant Gram-negative clinical isolates in vitro and in several in vivo infection models. These findings demonstrate that optimized arylomycin analogues such as G0775 could translate into new therapies to address the growing threat of multidrug-resistant Gram-negative infections.

引用

页码：189 / +

页数：16

共 31 条

[1] Trends and Exceptions of Physical Properties on Antibacterial Activity for Gram-Positive and Gram-Negative Pathogens [J].

Brown, Dean G. ;

May-Dracka, Tricia L. ;

Gagnon, Moriah M. ;

Tommasi, Ruben .

JOURNAL OF MEDICINAL CHEMISTRY, 2014, 57 (23) :10144-10161

[2] Lipopeptide substrates for SpsB, the Staphylococcus aureus type I signal peptidase:: design, conformation and conversion to α-ketoamide inhibitors [J].

Bruton, G ;

Huxley, A ;

O'Hanlon, P ;

Orlek, B ;

Eggleston, D ;

Humphries, J ;

Readshaw, S ;

West, A ;

Ashman, S ;

Brown, M ;

Moore, K ;

Pope, A ;

O'Dwyer, K ;

Wang, L .

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 2003, 38 (04) :351-356

[3]

Castanheira M, 2017, ANTIMICROB AGENTS CH, V61, DOI [10.1128/AAC.00567-17, 10.1128/aac.00567-17]

[4] ACHN-490, a Neoglycoside with Potent In Vitro Activity against Multidrug-Resistant Klebsiella pneumoniae Isolates [J].

Endimiani, Andrea ;

Hujer, Kristine M. ;

Hujer, Andrea M. ;

Armstrong, Eliana S. ;

Choudhary, Yuvraj ;

Aggen, James B. ;

Bonomo, Robert A. .

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, 2009, 53 (10) :4504-4507

[5] ANTIBIOTIC UPTAKE INTO GRAM-NEGATIVE BACTERIA [J].

HANCOCK, REW ;

BELL, A .

EUROPEAN JOURNAL OF CLINICAL MICROBIOLOGY & INFECTIOUS DISEASES, 1988, 7 (06) :713-720

[6] Structure-activity relationships of globomycin analogues as antibiotics [J].

Kiho, T ;

Nakayama, M ;

Yasuda, K ;

Miyakoshi, S ;

Inukai, M ;

Kogen, H .

BIOORGANIC & MEDICINAL CHEMISTRY, 2004, 12 (02) :337-361

[7] Novel lipoglycopeptides as inhibitors of bacterial signal peptidase I [J].

Kulanthaivel, P ;

Kreuzman, AJ ;

Strege, MA ;

Belvo, MD ;

Smitka, TA ;

Clemens, M ;

Swartling, JR ;

Minton, KL ;

Zheng, F ;

Angleton, EL ;

Mullen, D ;

Jungheim, LN ;

Klimkowski, VJ ;

Nicas, TI ;

Thompson, RC ;

Peng, SB .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (35) :36250-36258

[8] Efforts toward broadening the spectrum of arylomycin antibiotic activity [J].

Liu, Jian ;

Smith, Peter A. ;

Steed, Danielle Barrios ;

Romesberg, Floyd .

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, 2013, 23 (20) :5654-5659

[9] Synthesis and Characterization of the Arylomycin Lipoglycopeptide Antibiotics and the Crystallographic Analysis of Their Complex with Signal Peptidase [J].

Liu, Jian ;

Luo, Chuanyun ;

Smith, Peter A. ;

Chin, Jodie K. ;

Page, Malcolm G. P. ;

Paetzel, Mark ;

Romesberg, Floyd E. .

JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 2011, 133 (44) :17869-17877

[10] Proteolytic processing of Escherichia coli twin-arginine signal peptides by LepB [J].

Luke, Iris ;

Handford, Jennifer I. ;

Palmer, Tracy ;

Sargent, Frank .

ARCHIVES OF MICROBIOLOGY, 2009, 191 (12) :919-925

← 1 2 3 4 →