Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap
Host defense antimicrobial peptides (AMPs) are a promising source of antibiotics for the treatment of multiple-drug-resistant pathogens. Lipopolysaccharide (LPS), the major component of the outer leaflet of the outer membrane of Gram-negative bacteria, functions as a permeability barrier against a v...
| Main Authors: | , |
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| Format: | Journal Article |
| Language: | English |
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2015
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| Online Access: | https://hdl.handle.net/10356/106719 http://hdl.handle.net/10220/25116 |
| _version_ | 1811677784031887360 |
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| author | Mohanram, Harini Bhattacharjya, Surajit |
| author2 | School of Biological Sciences |
| author_facet | School of Biological Sciences Mohanram, Harini Bhattacharjya, Surajit |
| author_sort | Mohanram, Harini |
| collection | NTU |
| description | Host defense antimicrobial peptides (AMPs) are a promising source of antibiotics for the treatment of multiple-drug-resistant pathogens. Lipopolysaccharide (LPS), the major component of the outer leaflet of the outer membrane of Gram-negative bacteria, functions as a permeability barrier against a variety of molecules, including AMPs. Further, LPS or endotoxin is the causative agent of sepsis killing 100,000 people per year in the United States alone. LPS can restrict the activity of AMPs inducing aggregations at the outer membrane, as observed for frog AMPs, temporins, and also in model AMPs. Aggregated AMPs, "trapped" by the outer membrane, are unable to traverse the cell wall, causing their inactivation. In this work, we show that these inactive AMPs can overcome LPS-induced aggregations while conjugated with a short LPS binding β-boomerang peptide motif and become highly bactericidal. The generated hybrid peptides exhibit activity against Gram-negative and Gram-positive bacteria in high-salt conditions and detoxify endotoxin. Structural and biophysical studies establish the mechanism of action of these peptides in LPS outer membrane. Most importantly, this study provides a new concept for the development of a potent broad-spectrum antibiotic with efficient outer membrane disruption as the mode of action. |
| first_indexed | 2024-10-01T02:42:52Z |
| format | Journal Article |
| id | ntu-10356/106719 |
| institution | Nanyang Technological University |
| language | English |
| last_indexed | 2024-10-01T02:42:52Z |
| publishDate | 2015 |
| record_format | dspace |
| spelling | ntu-10356/1067192023-02-28T17:05:20Z Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap Mohanram, Harini Bhattacharjya, Surajit School of Biological Sciences DRNTU::Science::Biological sciences::Microbiology Host defense antimicrobial peptides (AMPs) are a promising source of antibiotics for the treatment of multiple-drug-resistant pathogens. Lipopolysaccharide (LPS), the major component of the outer leaflet of the outer membrane of Gram-negative bacteria, functions as a permeability barrier against a variety of molecules, including AMPs. Further, LPS or endotoxin is the causative agent of sepsis killing 100,000 people per year in the United States alone. LPS can restrict the activity of AMPs inducing aggregations at the outer membrane, as observed for frog AMPs, temporins, and also in model AMPs. Aggregated AMPs, "trapped" by the outer membrane, are unable to traverse the cell wall, causing their inactivation. In this work, we show that these inactive AMPs can overcome LPS-induced aggregations while conjugated with a short LPS binding β-boomerang peptide motif and become highly bactericidal. The generated hybrid peptides exhibit activity against Gram-negative and Gram-positive bacteria in high-salt conditions and detoxify endotoxin. Structural and biophysical studies establish the mechanism of action of these peptides in LPS outer membrane. Most importantly, this study provides a new concept for the development of a potent broad-spectrum antibiotic with efficient outer membrane disruption as the mode of action. Accepted version 2015-02-26T06:45:32Z 2019-12-06T22:16:51Z 2015-02-26T06:45:32Z 2019-12-06T22:16:51Z 2014 2014 Journal Article Mohanram, H., & Bhattacharjya, S. (2014). Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap. Antimicrobial agents and chemotherapy, 58(4), 1987-1996. 0066-4804 https://hdl.handle.net/10356/106719 http://hdl.handle.net/10220/25116 10.1128/AAC.02321-13 24419338 en Antimicrobial agents and chemotherapy © 2014 American Society for Microbiology. This is the author created version of a work that has been peer reviewed and accepted for publication by Antimicrobial Agents and Chemotherapy, American Society for Microbiology. It incorporates referee’s comments but changes resulting from the publishing process, such as copyediting, structural formatting, may not be reflected in this document. The published version is available at: [http://dx.doi.org/10.1128/AAC.02321-13]. 36 p. application/pdf |
| spellingShingle | DRNTU::Science::Biological sciences::Microbiology Mohanram, Harini Bhattacharjya, Surajit Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap |
| title | Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap |
| title_full | Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap |
| title_fullStr | Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap |
| title_full_unstemmed | Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap |
| title_short | Resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap |
| title_sort | resurrecting inactive antimicrobial peptides from the lipopolysaccharide trap |
| topic | DRNTU::Science::Biological sciences::Microbiology |
| url | https://hdl.handle.net/10356/106719 http://hdl.handle.net/10220/25116 |
| work_keys_str_mv | AT mohanramharini resurrectinginactiveantimicrobialpeptidesfromthelipopolysaccharidetrap AT bhattacharjyasurajit resurrectinginactiveantimicrobialpeptidesfromthelipopolysaccharidetrap |