Attenuation of <i>Pseudomonas aeruginosa</i> infection by INP0341, a salicylidene acylhydrazide, in a murine model of keratitis
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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 <i>P. aeruginosa</i> 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 <i>P. aeruginosa</i> in the presence of INP0341. Furthermore, INP0341 efficiently attenuated corneal infection by <i>P. aeruginosa</i> 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 <i>P. aeruginosa</i> and can be further considered as an alternative therapeutic intervention.
该菌为机会致病菌，亦是全球范围内角膜感染的主要病原菌。其可通过三型分泌系统（Type III Secretion System, T3SS）分泌多种毒素，以逃逸宿主免疫应答。此外，该菌兼具固有与获得性耐药机制，使得临床治疗面临严峻挑战，亟需开发新型治疗干预手段。三型分泌系统抑制剂作为传统抗生素的替代方案或联合用药，用于抑制细菌毒力，已得到广泛研究。本研究中，三型分泌系统抑制剂INP0341在100μM浓度下，可抑制铜绿假单胞菌（*P. aeruginosa*）对人角膜上皮细胞（Human Corneal Epithelial Cells, HCEC）的细胞毒性，且不会影响液体培养基中细菌的生长。在经INP0341处理且暴露于铜绿假单胞菌的细胞中，观测到抗菌肽表达上调与活性氧生成增加。进一步实验表明，在小鼠角膜炎模型中，INP0341可有效减弱铜绿假单胞菌引发的角膜感染，该效果可通过角膜混浊度、临床评分与细菌载量得到验证。综上，INP0341是治疗铜绿假单胞菌相关性角膜感染的极具潜力的候选药物，可作为新型治疗干预手段进行后续开发与应用。
