Attenuation of Pseudomonas aeruginosa infection by INP0341, a salicylidene acylhydrazide, in a murine model of keratitis

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.

KEYWORDS:

• Antimicrobial peptides
• type III secretion system
• Pseudomonas aeruginosa
• reactive oxygen species
• corneal epithelial cells
• INP0341

Acknowledgments

We are thankful to Ophthalmic Pathology Laboratory, LVPEI for the help with tissue sections. Authors acknowledge Dr. Rajesh Karunanithi for animal studies and Apurwa Samarth for technical help. We sincerely thank Prof. Sheila MacNeil for English revision of the paper. The support of Hyderabad Eye Research Foundation is also acknowledged.

Disclosure statement

No potential conflict of interest was reported by the authors.

Supplementary material

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Additional information

Funding

This work was supported partially by a grant from SERB, Govt. of India, [EMR/2016/001514] to S.R and a student fellowship from University Grants Commission, Govt. of India was given to P.S.