期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 103, 期 47, 页码 17897-17902出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0606795103
关键词
antimicrobials; chaperone-usher pathway; pilicide; urinary tract infection
资金
- Medical Research Council [G0100442] Funding Source: Medline
- NIAID NIH HHS [R37 AI029549, U54 AI057160, R01 AI48689-05, R01 AI048689] Funding Source: Medline
- NICHD NIH HHS [K12-HD00850, K12 HD000850] Funding Source: Medline
- MRC [G0100442] Funding Source: UKRI
- Medical Research Council [G0100442] Funding Source: researchfish
A chemical synthesis platform with broad applications and flexibility was rationally designed to inhibit biogenesis of adhesive pili assembled by the chaperone-usher pathway in Gram-negative pathogens. The activity of a family of bicyclic 2-pyridones, termed pilicides, was evaluated in two different pilus biogenesis systems in uropathogenic Escherichia coli. Hemagglutination mediated by either type 1 or P pili, adherence to bladder cells, and biofilm formation mediated by type I pili were all reduced by approximate to 90% in laboratory and clinical E. coli strains. The structure of the pilicide bound to the P pilus chaperone PapD revealed that the pilicide bound to the surface of the chaperone known to interact with the usher, the outer-membrane assembly platform where pili are assembled. Point mutations in the pilicide-binding site dramatically reduced pilus formation but did not block the ability of PapD to bind subunits and mediate their folding. Surface plasmon resonance experiments confirmed that the pilicide interfered with the binding of chaperone-subunit complexes to the usher. These pilicides thus target key virulence factors in pathogenic bacteria and represent a promising proof of concept for developing drugs that function by targeting virulence factors.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据