Designed Host Defense Peptides for the Treatment of Bacterial Keratitis

• Published in: Investigative ophthalmology & visual science 2017-12, Vol.58 (14), p.6273-6281
• Main Authors: Clemens, L Edward, Jaynes, Jesse, Lim, Edward, Kolar, Satya S, Reins, Rose Y, Baidouri, Hasna, Hanlon, Samuel, McDermott, Alison M, Woodburn, Kathryn W
• Format: Article
• Language: English
• Subjects: Animals; Biofilms - drug effects; Cornea; Cornea - microbiology; Culture Media, Serum-Free; Disease Models, Animal; Dose-Response Relationship, Drug; Eye Infections, Bacterial - drug therapy; Eye Infections, Bacterial - microbiology; Keratitis - drug therapy; Keratitis - microbiology; Mice, Inbred C57BL; Microbial Sensitivity Tests; Organotechnetium Compounds - administration & dosage; Peptides, Cyclic - administration & dosage; Pseudomonas aeruginosa - drug effects; Pseudomonas aeruginosa - isolation & purification; Pseudomonas Infections - drug therapy; Pseudomonas Infections - microbiology
• ISSN: 1552-5783; 0146-0404; 1552-5783
• DOI: 10.1167/iovs.17-22243

To limit corneal damage and potential loss of vision, bacterial keratitis must be treated aggressively. Innovation in antimicrobials is required due to the need for empirical treatment and the rapid emergence of bacterial resistance. Designed host defense peptides (dHDPs) are synthetic analogues of naturally occurring HDPs, which provide defense against invading pathogens. This study investigates the use of novel dHDPs for the treatment of bacterial keratitis. The minimum inhibitory concentrations (MICs) were determined for dHDPs on both Gram-positive and -negative bacteria. The minimum biofilm eradication concentrations (MBEC) and in vitro time-kill assays were determined. The most active dHDP, RP444, was evaluated for propensity to induce drug resistance and therapeutic benefit in a murine Pseudomonas aeruginosa keratitis model. Designed HDPs were bactericidal with MICs ranging from 2 to >64 μg/mL and MBEC ranging from 6 to 750 μg/mL. In time-kill assays, dHDPs were able to rapidly reduce bacterial counts upon contact with as little as 2 μg/mL. RP444 did not induce resistance after repeated exposure of P. aeruginosa to subinhibitory concentrations. RP444 demonstrated significant efficacy in a murine model of bacterial keratitis as evidenced by a significant dose-dependent decrease in ocular clinical scores, a significantly reduced bacterial load, and substantially decreased inflammatory cell infiltrates. Innovative dHDPs demonstrated potent antimicrobial activity, possess a limited potential for development of resistance, and reduced the severity of murine P. aeruginosa keratitis. These studies demonstrate that a novel dHDP may have potential to treat patients with sight-threatening bacterial keratitis.