HIV药物奈非纳韦或可有效抑制耐药性细菌感染

  随着抗生素耐药性的不断上升，科学家们正在努力寻找新型方法来抵御耐药性细菌的感染，而引发链球菌性咽喉炎以及很多严重疾病的病原体都属于耐药性细菌的行列，而研究人员也一直在寻找新型的工具来帮助抵御这些病原体。

  近日一篇发表在国际杂志ACS Chemical Biology上的研究报告中，来自美国国家过敏和传染病研究所的研究人员就发现一种用于治疗HIV的药物或许可以帮助抵御耐药性细菌的感染。

  文章中研究者Douglas A. Mitchell表示，每年化脓性链球菌都会引发6亿人患病及50万人死亡，而该菌致病的主要因子就是可以产生一种名为链球菌溶血素-S（SLS）的毒素；如果研究者可以有效阻断细菌产生SLS，那么或许就可以有效抑制化脓性链球菌的繁殖，进而也会减缓该菌引发的抗生素耐药性的扩散，然而目前研究人员并不清楚化脓性链球菌如何分泌产生SLS，而本文的研究人员也希望通过研究填补这一研究空白。

  研究者发现，一种用于治疗HIV的名为奈非纳韦的药物或许就是制胜的法宝，该药物的作用靶点为HIV表面的一种蛋白，众所周知该药物可以阻断HIV患者机体的关键酶类，而这种酶类对于化脓性链球菌产生SLS非常关键；于是研究者制造了许多奈非纳韦样的化合物，其在实验室检测中可以有效阻断化脓性链球菌产生SLS，因此这种用于治疗HIV的药物或许就可以帮助抑制致命性化脓性链球菌的繁殖及耐药性的产生。

  研究者表示后期他们还将通过更为深入的研究来揭示化脓性链球菌产生SLS的分子机制，从而为开发更多有效控制该菌引发疾病的疗法提供希望和思路，相关研究由美国国立卫生研究院提供资助。（转化医学网360zhyx.com）
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转化医学网推荐的原文摘要：

HIV Protease Inhibitors Block Streptolysin S Production
ACS Chem. Biol DOI: 10.1021/cb500843r
Tucker Maxson †, Caitlin D. Deane †‡, Evelyn M. Molloy ‡, Courtney L. Cox ‡§, Andrew L. Markley ∥, Shaun W. Lee ⊥, and Douglas A. Mitchell *†‡§
Streptolysin S (SLS) is a post-translationally modified peptide cytolysin that is produced by the human pathogen Streptococcus pyogenes. SLS belongs to a large family of azole-containing natural products that are biosynthesized via an evolutionarily conserved pathway. SLS is an important virulence factor during S. pyogenes infections, but despite an extensive history of study, further investigations are needed to clarify several steps of its biosynthesis. To this end, chemical inhibitors of SLS biosynthesis would be valuable tools to interrogate the various maturation steps of both SLS and biosynthetically related natural products. Such chemical inhibitors could also potentially serve as antivirulence therapeutics, which in theory may alleviate the spread of antibiotic resistance. In this work, we demonstrate that FDA-approved HIV protease inhibitors, especially nelfinavir, block a key proteolytic processing step during SLS production. This inhibition was demonstrated in live S. pyogenes cells and through in vitro protease inhibition assays. A panel of 57 nelfinavir analogs was synthesized, leading to a series of compounds with improved anti-SLS activity while illuminating structure–activity relationships. Nelfinavir was also found to inhibit the maturation of other azole-containing natural products, namely those involved in listeriolysin S, clostridiolysin S, and plantazolicin production. The use of nelfinavir analogs as inhibitors of SLS production has allowed us to begin examining the proteolysis event in SLS maturation and will aid in further investigations of the biosynthesis of SLS and related natural products.