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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Inhibitor of streptokinase gene expression improves survival after group A streptococcus infection in mice
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Inhibitor of streptokinase gene expression improves survival after group A streptococcus infection in mice

机译：链激酶基因表达抑制剂可改善小鼠A组链球菌感染后的存活率

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摘要

The widespread occurrence of antibiotic resistance among human pathogens is a major public health problem. Conventional antibiotics typically target bacterial killing or growth inhibition, resulting in strong selection for the development of antibiotic resistance. Alternative therapeutic approaches targeting microbial pathoge-nicity without inhibiting growth might minimize selection for resistant organisms. Compounds inhibiting gene expression of streptokinase (SK), a critical group A streptococcal (GAS) virulence factor, were identified through a high-throughput, growth-based screen on a library of 55,000 small molecules. The lead compound [Center for Chemical Genomics 2979 (CCG-2979)] and an analog (CCG-102487) were confirmed to also inhibit the production of active SK protein. Microarray analysis of GAS grown in the presence of CCG-102487 showed down-regulation of a number of important virulence factors in addition to SK, suggesting disruption of a general virulence gene regulatory network. CCG-2979 and CCG-102487 both enhanced granulocyte phagocytosis and killing of GAS in an in vitro assay, and CCG-2979 also protected mice from GAS-induced mortality in vivo. These data suggest that the class of compounds represented by CCG-2979 may be of therapeutic value for the treatment of GAS and potentially other Gram-positive infections in humans.
机译：人类病原体中抗生素耐药性的广泛发生是主要的公共卫生问题。常规抗生素通常针对细菌杀灭或生长抑制，从而导致对抗生素抗性发展的强烈选择。在不抑制生长的情况下，针对微生物病原体的替代治疗方法可能会最小化对耐药生物的选择。通过在55,000个小分子文库中进行的基于生长的高通量筛选，鉴定了抑制链激酶（SK）（一种关键的A组链球菌（GAS）毒力因子）基因表达的化合物。证实了先导化合物[化学基因组学中心2979（CCG-2979）]和类似物（CCG-102487）也抑制了活性SK蛋白的产生。在CCG-102487存在下生长的GAS的微阵列分析显示，除SK外，许多重要的毒力因子也被下调，这提示了一般毒力基因调控网络的破坏。 CCG-2979和CCG-102487在体外测定中均增强了粒细胞的吞噬作用和GAS的杀灭作用，而CCG-2979还保护小鼠免受GAS诱导的体内死亡。这些数据表明，CCG-2979代表的一类化合物可能具有治疗GAS和人类潜在的其他革兰氏阳性感染的治疗价值。

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    Hongmin Sun; Yuanxi Xu; Izabela Sitkiewicz; Yibao Ma; Xixi Wang; Bryan D. Yestrepsky; Yuping Huang; Martian C. Lapadatescu; Martha J. Larsen; Scott D. Larsen; James M. Musser; David Ginsburg;

  • 作者单位

    Department of Internal Medicine, University of Missouri Hospital and Clinics, Columbia, MO 65212;

    Department of Internal Medicine, University of Missouri Hospital and Clinics, Columbia, MO 65212;

    Department of Epidemiology and Clinical Microbiology, National Medicines Institute, Chelmska 30/34 00-725, Warsaw, Poland;

    Department of Internal Medicine, University of Missouri Hospital and Clinics, Columbia, MO 65212;

    Howard Hughes Medical Institute, Life Sciences Institute, Departments of Internal Medicine, Human Genetics, and Pediatrics, University of Michigan, Ann Arbor, Ml 48109;

    Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Ml 48109;

    Life Sciences Institute, Wuhan University, Wuhan 430072, Hubei, China;

    Department of Internal Medicine, University of Missouri Hospital and Clinics, Columbia, MO 65212;

    Center for Chemical Genomics, Life Sciences Institute, University of Michigan, Ann Arbor, Ml 48109;

    Vahlteich Medicinal Chemistry Core, College of Pharmacy, University of Michigan, Ann Arbor, Ml 48109;

    Center for Molecular and Translational Human Infectious Diseases Research, Methodist Hospital Research Institute and Department of Pathology, Houston, TX 77030;

    Howard Hughes Medical Institute, Life Sciences Institute, Departments of Internal Medicine, Human Genetics, and Pediatrics, University of Michigan, Ann Arbor, Ml 48109;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
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  • 关键词

    fibrinolysis; plasminogen; streptococcus pyogenes;

    机译：纤维蛋白溶解纤溶酶原化脓性链球菌;

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