Design of Next Generation Polymyxins with Lower Toxicity: The Discovery of SPR206

被引：65

作者：

Brown, Pamela ^{[1
,2
]}

Abbott, Elizabeth ^{[1
]}

Abdulle, Omar ^{[1
]}

Boakes, Steven ^{[1
]}

Coleman, Scott ^{[2
]}

Divan, Naomi ^{[1
]}

Duperchy, Esther ^{[1
]}

Moss, Stephen ^{[3
]}

Rivers, Dean ^{[1
]}

Simonovic, Mona ^{[1
]}

Singh, Jaspal ^{[1
]}

Stanway, Steven ^{[3
]}

Wilson, Antoinette ^{[3
]}

Dawson, Michael J. ^{[1
,2
]}

机构：

[1] Cantab Antiinfect Ltd, BioPk,Broadwater Rd, Welwyn Garden City AL7 3AX, Herts, England

[2] Spero Therapeut Inc, 675 Massachusetts Ave,14th Floor, Cambridge, MA 02139 USA

[3] Eurofins Selcia Drug Discovery UK, Fyfield Business & Res Pk,Fyfield Rd, Ongar CMS 0GS, Essex, England

来源：

ACS INFECTIOUS DISEASES | 2019年 / 5卷 / 10期

基金：

美国国家卫生研究院; “创新英国”项目;

关键词：

polymyxin; antimicrobial resistance; multidrug-resistant bacteria; nephrotoxicity; antibacterials; Gram-negative; 3 POSITIVE CHARGES; DERIVATIVES; ANALOGS; NEPHROTOXICITY;

D O I：

10.1021/acsinfecdis.9b00217

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Polymyxins are an important class of antibiotics for the treatment of bacterial infections due to multidrug resistant Gram-negative pathogens. However, their clinical utility is limited by nephrotoxicity. Here, we report a series of promising next generation polymyxin nonapeptides identified on the basis of our understanding of the relationship of structure with activity, cytotoxicity, and kidney compartment accumulation. We demonstrate that nonapeptides with an amine-containing N-terminal moiety of specific regio- and stereochemistry possess superior in vitro activity, together with lower cytotoxicity compared to polymyxin B. We further demonstrate that compounds with a beta-branched aminobutyrate N-terminus with an aryl substituent offer a promising combination of low cytotoxicity and kidney exposure, leading to low toxicity in the mouse. From this series, SPR206 has been selected as a development candidate.

引用

页码：1645 / 1656

页数：23

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