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OP-4 Development of novel human-derived hybrid host defense peptides for infectious keratitis
  1. Darren Shu Jeng Ting1,
  2. Rajamani Lakshminarayanan2,
  3. Imran Mohammed3,
  4. Harminder Dua4
  1. 1Institute of Inflammation and Ageing, University of Birmingham, Edgbaston, UK
  2. 2Singapore Eye Research Institute, Singapore
  3. 3Cardiff University, Cardiff, UK
  4. 4University of Nottingham, Nottingham, UK


*Correspondence, Darren Shu Jeng Ting:

Background/Aim Infectious keratitis (IK) is a major cause of corneal blindness worldwide. This study aimed to develop potent human-derived hybrid host defense peptides (HyHDPs) with broad-spectrum antimicrobial activities for IK.

Methods HyHDPs were rationally designed through combination of human cathelicidin (LL-37) and human-beta-defensins (HBDs), and with guidance from molecular dynamics (MD) simulations. Efficacy of HyHDPs was determined against a range of bacteria, fungi and Acanthamoeba. Risk of antimicrobial resistance (AMR) was evaluated using multipassage AMR assay. Pre-clinical murine studies were performed to examine the in vivo efficacy and safety of HyHDPs in methicillin-resistant S. aureus (MRSA)-related keratitis.

Results Hybridisation of LL-37 and HBD-2 led to the development of HDP23, which demonstrated good efficacy against S. aureus and MRSA [minimum inhibitory concentration (MIC)=12.5–25.0 µm/ml], but not against fungi or Acanthamoeba. MD simulations provided atomistic insights into the key membrane-active residues and accelerated the discovery of HDP56. Compared to HDP23, HDP56 exhibited 4–32 times improved efficacy against S. aureus, MRSA, Pseudomonas aeruginosa, and Fusarium solani (MIC=3.1–6.3 µm/ml). At 100 µm/ml, HDP56 exhibited good anti-Acanthamoeba trophozoites efficacy (99.8%) and anti-encystation efficacy (80.9%). S. aureus did not develop any AMR against HDP56 after 15 treatment passages/days but developed significant AMR (32 times increase in MIC) against levofloxacin after 13 passages/days. Pre-clinical murine studies demonstrated strong efficacy and safety of HDP56 (0.5 mg/ml) in treating MRSA-related keratitis (93% reduction in bacteria, which was equally effective to levofloxacin (5 mg/ml).

Conclusion Rational hybridisation of HDPs, with guidance from MD simulations, has enabled the development of a novel HDP-based therapy for IK.

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