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Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis

Ting, Darren Shu Jeng; Leng, Eunice Tze; Mayandi, Venkatesh; Busoy, Joanna M. F.; Aung, Thet Tun; Periayah, Mercy Halleluyah; Nubile, Mario; Mastropasqua, Leonardo; Said, Dalia G.; Htoon, Hla M.; Barathi, Veluchamy Amutha; Beuerman, Roger W.; Lakshminarayanan, Rajamani; Mohammed, Imran; Dua, Harminder S.

Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis Thumbnail


Darren Shu Jeng Ting

Eunice Tze Leng

Venkatesh Mayandi

Joanna M. F. Busoy

Thet Tun Aung

Mercy Halleluyah Periayah

Mario Nubile

Leonardo Mastropasqua

Dalia G. Said

Hla M. Htoon

Veluchamy Amutha Barathi

Roger W. Beuerman

Rajamani Lakshminarayanan

Imran Mohammed

Professor of Ophthalmology and Visual Sciences


Bacterial keratitis (BK) is a major cause of corneal blindness globally. This study aimed to develop a novel class of antimicrobial therapy, based on human-derived hybrid host defense peptides (HyHDPs), for treating BK. HyHDPs were rationally designed through combination of functional amino acids in parent HDPs, including LL-37 and human beta-defensin (HBD)-1 to -3. Minimal inhibitory concentrations (MICs) and time-kill kinetics assay were performed to determine the concentration- and time-dependent antimicrobial activity and cytotoxicity was evaluated against human corneal epithelial cells and erythrocytes. In vivo safety and efficacy of the most promising peptide was examined in the corneal wound healing and Staphylococcus aureus (ATCC SA29213) keratitis murine models, respectively. A second-generation HyHDP (CaD23), based on rational hybridization of the middle residues of LL-37 and C-terminal of HBD-2, was developed and was shown to demonstrate good efficacy against methicillin-sensitive and methicillin-resistant S. aureus [MIC = 12.5–25.0μg/ml (5.2–10.4μM)] and S. epidermidis [MIC = 12.5μg/ml (5.2μM)], and moderate efficacy against P. aeruginosa [MIC = 25-50μg/ml (10.4–20.8μM)]. CaD23 (at 25μg/ml or 2× MIC) killed all the bacteria within 30min, which was 8 times faster than amikacin (25μg/ml or 20× MIC). After 10 consecutive passages, S. aureus (ATCC SA29213) did not develop any antimicrobial resistance (AMR) against CaD23 whereas it developed significant AMR (i.e. a 32-fold increase in MIC) against amikacin, a commonly used treatment for BK. Pre-clinical murine studies showed that CaD23 (0.5mg/ml) achieved a median reduction of S. aureus bioburden by 94% (or 1.2 log10 CFU/ml) while not impeding corneal epithelial wound healing. In conclusion, rational hybridization of human-derived HDPs has led to generation of a potentially efficacious and safe topical antimicrobial agent for treating Gram-positive BK, with no/minimal risk of developing AMR.

Journal Article Type Article
Acceptance Date Aug 24, 2021
Online Publication Date Sep 15, 2021
Publication Date Sep 15, 2021
Deposit Date Sep 3, 2021
Publicly Available Date Sep 17, 2021
Journal Scientific Reports
Electronic ISSN 2045-2322
Publisher Springer Science and Business Media LLC
Peer Reviewed Peer Reviewed
Volume 11
Article Number 18304
Keywords Multidisciplinary
Public URL
Publisher URL


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