High-throughput identification of chemical inhibitors of E. coli Group 2 capsule biogenesis as anti-virulence agents.
High-throughput identification of chemical inhibitors of E. coli Group 2 capsule biogenesis as anti-virulence agents.
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DOI：
10.1371/journal.pone.0011642
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发表时间：
2010-07-19
期刊：
影响因子：
3.7
通讯作者：
Seed PC
中科院分区：
文献类型：
--
作者：
Goller CC;Seed PC
作为尿路感染(UTIs)的主要原因，大肠埃希菌对抗生素的耐药性不断上升，这使得分子发病机制研究成为一个新的焦点，旨在寻找新的治疗靶点。抗毒力药物作为化疗药物在疾病期间具有吸引力，但在良性共生期间不一定能削弱微生物，从而减少对有益微生物群落的压力，减少耐药性的出现。我们和其他人已经证明，在泌尿系感染和更具侵袭性的疾病中，大肠杆菌的K抗原衣壳是一个卓越的毒力决定因素。在引起尿路感染的大肠杆菌的主要K抗原包膜类型中，组装和输出成分高度保守，不同于许多共生大肠杆菌的包膜生物发生机制，使这些具有吸引力的治疗靶点。我们对抗囊小分子进行了筛选，并确定了一种名为“C7”的试剂，它可以阻止K1和K5胶囊的产生，这两种胶囊是第2-3组胶囊中无关的多糖类型。这就是概念的证明，这个筛选可以用更大的化学库来鉴定胶囊生物发生的第二代小分子抑制剂。这些抑制剂将有助于更好地了解胶囊的生物发生，并可能代表一类新的治疗方法。
Rising antibiotic resistance among Escherichia coli, the leading cause of urinary tract infections (UTIs), has placed a new focus on molecular pathogenesis studies, aiming to identify new therapeutic targets. Anti-virulence agents are attractive as chemotherapeutics to attenuate an organism during disease but not necessarily during benign commensalism, thus decreasing the stress on beneficial microbial communities and lessening the emergence of resistance. We and others have demonstrated that the K antigen capsule of E. coli is a preeminent virulence determinant during UTI and more invasive diseases. Components of assembly and export are highly conserved among the major K antigen capsular types associated with UTI-causing E. coli and are distinct from the capsule biogenesis machinery of many commensal E. coli, making these attractive therapeutic targets. We conducted a screen for anti-capsular small molecules and identified an agent designated “C7” that blocks the production of K1 and K5 capsules, unrelated polysaccharide types among the Group 2–3 capsules. Herein lies proof-of-concept that this screen may be implemented with larger chemical libraries to identify second-generation small-molecule inhibitors of capsule biogenesis. These inhibitors will lead to a better understanding of capsule biogenesis and may represent a new class of therapeutics.
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影响因子：
4
作者：
Foxman, B
通讯作者：
Foxman, B
影响因子：
3.2
作者：
Clarke, BR;Esumeh, F;Roberts, IS
通讯作者：
Roberts, IS
影响因子：
120.7
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Stamm, WE
影响因子：
3.1
作者：
HEDGES, S;ANDERSON, P;SVANBORG, C
通讯作者：
SVANBORG, C
影响因子：
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作者：
Gupta, K;Hooton, TM;Stamm, WE
通讯作者：
Stamm, WE