Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing
Many antibiotics are ineffective in killing Gram-negative bacteria due to the permeability barrier of the outer-membrane LPS. Infections caused by multi-drug-resistant Gram-negative pathogens require new antibiotics, which are often difficult to develop. Antibiotic potentiators disrupt outer-membran...
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MDPI AG
2022-12-01
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| Series: | International Journal of Molecular Sciences |
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| author | Sheetal Sinha Vidhya Bharathi Dhanabal Veronica Lavanya Manivannen Floriana Cappiello Suet-Mien Tan Surajit Bhattacharjya |
| author_facet | Sheetal Sinha Vidhya Bharathi Dhanabal Veronica Lavanya Manivannen Floriana Cappiello Suet-Mien Tan Surajit Bhattacharjya |
| author_sort | Sheetal Sinha |
| collection | DOAJ |
| description | Many antibiotics are ineffective in killing Gram-negative bacteria due to the permeability barrier of the outer-membrane LPS. Infections caused by multi-drug-resistant Gram-negative pathogens require new antibiotics, which are often difficult to develop. Antibiotic potentiators disrupt outer-membrane LPS and can assist the entry of large-scaffold antibiotics to the bacterial targets. In this work, we designed a backbone-cyclized ultra-short, six-amino-acid-long (WKRKRY) peptide, termed cWY6 from LPS binding motif of β-boomerang bactericidal peptides. The cWY6 peptide does not exhibit any antimicrobial activity; however, it is able to permeabilize the LPS outer membrane. Our results demonstrate the antibiotic potentiator activity in the designed cWY6 peptide for several conventional antibiotics (vancomycin, rifampicin, erythromycin, novobiocin and azithromycin). Remarkably, the short cWY6 peptide exhibits wound-healing activity in in vitro assays. NMR, computational docking and biophysical studies describe the atomic-resolution structure of the peptide in complex with LPS and mode of action in disrupting the outer membrane. The dual activities of cWY6 peptide hold high promise for further translation to therapeutics. |
| first_indexed | 2024-03-11T09:59:46Z |
| format | Article |
| id | doaj.art-54cc04de6a824d07864e0acf87ee6415 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T09:59:46Z |
| publishDate | 2022-12-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-54cc04de6a824d07864e0acf87ee64152023-11-16T15:30:50ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-12-0124126310.3390/ijms24010263Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound HealingSheetal Sinha0Vidhya Bharathi Dhanabal1Veronica Lavanya Manivannen2Floriana Cappiello3Suet-Mien Tan4Surajit Bhattacharjya5School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeDepartment of Biochemical Sciences, Laboratory Affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00185 Rome, ItalySchool of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeSchool of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore 637551, SingaporeMany antibiotics are ineffective in killing Gram-negative bacteria due to the permeability barrier of the outer-membrane LPS. Infections caused by multi-drug-resistant Gram-negative pathogens require new antibiotics, which are often difficult to develop. Antibiotic potentiators disrupt outer-membrane LPS and can assist the entry of large-scaffold antibiotics to the bacterial targets. In this work, we designed a backbone-cyclized ultra-short, six-amino-acid-long (WKRKRY) peptide, termed cWY6 from LPS binding motif of β-boomerang bactericidal peptides. The cWY6 peptide does not exhibit any antimicrobial activity; however, it is able to permeabilize the LPS outer membrane. Our results demonstrate the antibiotic potentiator activity in the designed cWY6 peptide for several conventional antibiotics (vancomycin, rifampicin, erythromycin, novobiocin and azithromycin). Remarkably, the short cWY6 peptide exhibits wound-healing activity in in vitro assays. NMR, computational docking and biophysical studies describe the atomic-resolution structure of the peptide in complex with LPS and mode of action in disrupting the outer membrane. The dual activities of cWY6 peptide hold high promise for further translation to therapeutics.https://www.mdpi.com/1422-0067/24/1/263antibiotic potentiatorMDR Gram-negative bacteriacyclic peptidelipopolysaccharide (LPS) |
| spellingShingle | Sheetal Sinha Vidhya Bharathi Dhanabal Veronica Lavanya Manivannen Floriana Cappiello Suet-Mien Tan Surajit Bhattacharjya Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing International Journal of Molecular Sciences antibiotic potentiator MDR Gram-negative bacteria cyclic peptide lipopolysaccharide (LPS) |
| title | Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing |
| title_full | Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing |
| title_fullStr | Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing |
| title_full_unstemmed | Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing |
| title_short | Ultra-Short Cyclized β-Boomerang Peptides: Structures, Interactions with Lipopolysaccharide, Antibiotic Potentiator and Wound Healing |
| title_sort | ultra short cyclized β boomerang peptides structures interactions with lipopolysaccharide antibiotic potentiator and wound healing |
| topic | antibiotic potentiator MDR Gram-negative bacteria cyclic peptide lipopolysaccharide (LPS) |
| url | https://www.mdpi.com/1422-0067/24/1/263 |
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