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    • A Structure-Function-Inhibition Analysis of the Pseudomonas Aeruginosa Type III Secretion Needle Protein PscF

    Donald T. Moir,Nicholas O. Bowlin,Bryan J. Berube, Jaden Yabut,Debra M. Mills,Giang T. Nguyen,Zachary D. Aron,John D. Williams,Joan Mecsas,Alan R. Hauser,Terry L. Bowlin

    Journal of bacteriology（2020）SCI 3区

    Microbiotix Inc | Northwestern Univ | Tufts Univ

    Cited 3|Views41
    Abstract
    P. aeruginosa effector toxin translocation into host innate immune cells is critical for the establishment and dissemination of P. aeruginosa infections. The medical need for new anti- P. aeruginosa agents is evident by the fact that P. aeruginosa ventilator-associated pneumonia is associated with a high mortality rate (40 to 69%) and recurs in >30% of patients, even with standard-of-care antibiotic therapy. The results described here confirm roles for the PscF needle in T3SS secretion and translocation and suggest that it affects regulation, possibly by interaction with T3SS regulatory proteins. The results also support a model of direct interaction of the needle with PhA and suggest that, with further development, members of the PhA series may prove useful as drugs for P. aeruginosa infection.
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    P. aeruginosa,phenoxyacetamides,translocation,type III needle protein,type III secretion
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    【要点】：本论文通过分析Pseudomonas aeruginosa的Type III Secretion System (T3SS)的针状蛋白PscF的结构、功能和抑制作用，揭示了PscF在T3SS毒素穿膜过程中的关键角色，以及其与新型抑制剂PhA的相互作用机制。
    

    【方法】：研究者通过评估pscF基因的71个单突变体，这些突变体改变了编码蛋白的49个氨基酸残基，以研究其对T3SS表型的影响。
    

    【实验】：实验使用了一个包含多种PscF亚基的T3SS针状结构，该结构对人类细胞中效应毒素的穿膜至关重要。研究者对pscF基因的71个单突变体进行了评估，这些突变体改变了编码蛋白的49个氨基酸残基，以研究其对T3SS表型的影响。其中37%的突变体消除了分泌，而63%的突变体保持了分泌。14个密码子的突变体对PhA具有一定抵抗力，而不会消除分泌。这些突变体主要位于PscF的α-螺旋结构的C端25%。PhA耐药突变体对两种不同化学骨架的T3SS抑制剂没有交叉耐药性。两个突变体导致了持续的T3SS分泌。在野生型（WT）、持续分泌或PhA耐药的情况下，pscF基因在其天然位点是显性的，但在非天然位点表达的pscF等位基因和其他突变体混合时，观察到了混合表型。一些PhA耐药突变体显示出降低的穿膜效率，但随PhA剂量的增加有所改善，这表明PhA可以与这些耐药针状蛋白结合。总的来说，这些结果表明PhA抑制剂与T3SS针状蛋白有直接相互作用，可能通过阻断其构象变化来发挥作用，并且PscF在T3SS的调控、分泌和穿膜过程中发挥重要作用。这些研究结果为开发新的抗P. aeruginosa药物提供了可能，这对治疗与P. aeruginosa相关的高度致命性肺炎具有重要意义。
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