Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis
Abstract 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...
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Nature Portfolio
2021
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oai:doaj.org-article:b8964e8c144045dd99c424d45d86d9a42021-12-02T18:49:53ZHybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis10.1038/s41598-021-97821-32045-2322https://doaj.org/article/b8964e8c144045dd99c424d45d86d9a42021-09-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-97821-3https://doaj.org/toc/2045-2322Abstract 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 = 12.5–25.0 μg/ml (5.2–10.4 μM)] and S. epidermidis [MIC = 12.5 μg/ml (5.2 μM)], and moderate efficacy against P. aeruginosa [MIC = 25-50 μg/ml (10.4–20.8 μM)]. CaD23 (at 25 μg/ml or 2× MIC) killed all the bacteria within 30 min, which was 8 times faster than amikacin (25 μg/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 (0.5 mg/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.Darren Shu Jeng TingEunice Tze Leng GohVenkatesh MayandiJoanna M. F. BusoyThet Tun AungMercy Halleluyah PeriayahMario NubileLeonardo MastropasquaDalia G. SaidHla M. HtoonVeluchamy Amutha BarathiRoger W. BeuermanRajamani LakshminarayananImran MohammedHarminder S. DuaNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-14 (2021) |
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Medicine R Science Q Darren Shu Jeng Ting Eunice Tze Leng Goh 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 Harminder S. Dua Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis |
| description |
Abstract 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 = 12.5–25.0 μg/ml (5.2–10.4 μM)] and S. epidermidis [MIC = 12.5 μg/ml (5.2 μM)], and moderate efficacy against P. aeruginosa [MIC = 25-50 μg/ml (10.4–20.8 μM)]. CaD23 (at 25 μg/ml or 2× MIC) killed all the bacteria within 30 min, which was 8 times faster than amikacin (25 μg/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 (0.5 mg/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. |
| format |
article |
| author |
Darren Shu Jeng Ting Eunice Tze Leng Goh 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 Harminder S. Dua |
| author_facet |
Darren Shu Jeng Ting Eunice Tze Leng Goh 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 Harminder S. Dua |
| author_sort |
Darren Shu Jeng Ting |
| title |
Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis |
| title_short |
Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis |
| title_full |
Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis |
| title_fullStr |
Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis |
| title_full_unstemmed |
Hybrid derivative of cathelicidin and human beta defensin-2 against Gram-positive bacteria: A novel approach for the treatment of bacterial keratitis |
| title_sort |
hybrid derivative of cathelicidin and human beta defensin-2 against gram-positive bacteria: a novel approach for the treatment of bacterial keratitis |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/b8964e8c144045dd99c424d45d86d9a4 |
| work_keys_str_mv |
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