ABSTRACT

Pseudomonas aeruginosa

is an opportunistic pathogen and a major cause of corneal infections worldwide. The bacterium secretes several toxins through its type III secretion system (T3SS) to subvert host immune responses. In addition, it is armed with intrinsic as well as acquired antibiotic resistance mechanisms that make treatment a significant challenge and new therapeutic interventions are needed. Type III secretion inhibitors have been studied as an alternative or in accompaniment to traditional antibiotics to inhibit virulence of bacteria. In this study, INP0341, a T3SS inhibitor, inhibited cytotoxicity by P. aeruginosa toward human corneal epithelial cells (HCEC) at 100 μM without affecting bacterial growth in the liquid media. An increased expression of antimicrobial peptides and reactive oxygen species generation was also observed in cells exposed to P. aeruginosa in the presence of INP0341. Furthermore, INP0341 efficiently attenuated corneal infection by P. aeruginosa in an experimental model of murine keratitis as evident from corneal opacity, clinical score and bacterial load. Thus, INP0341 appears to be a promising candidate to treat corneal infection caused by P. aeruginosa and can be further considered as an alternative therapeutic intervention.

中文翻译：

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在角膜炎的小鼠模型中，水杨叉酰基酰肼INP0341减轻了铜绿假单胞菌感染。

摘要

铜绿假单胞菌

是一种机会病原体，是全球角膜感染的主要原因。该细菌通过其III型分泌系统（T3SS）分泌多种毒素，从而破坏宿主的免疫反应。此外，它还具有内在的和获得性的抗生素抗性机制，这使治疗成为一项重大挑战，需要采取新的治疗干预措施。已经研究了III型分泌抑制剂作为传统抗生素的替代品或替代品，以抑制细菌的毒性。在这项研究中，T3SS抑制剂INP0341抑制铜绿假单胞菌的细胞毒性以100μM的浓度注入人角膜上皮细胞（HCEC），而不会影响液体培养基中的细菌生长。在INP0341存在下，暴露于铜绿假单胞菌的细胞中也观察到了抗菌肽表达的增加和活性氧的产生。此外，从角膜混浊度，临床评分和细菌载量来看，INP0341在鼠类角膜炎的实验模型中有效减轻了铜绿假单胞菌对角膜的感染。因此，INP0341似乎是治疗由铜绿假单胞菌引起的角膜感染的有前途的候选者，并且可以进一步考虑作为替代性治疗干预措施。