Turn-engineering tunes the conformational rigidity of β-hairpin AMPs in achieving membrane selectivity and killing drug-resistant ESKAPE pathogens
Naturally occurring β-hairpin antimicrobial peptides (AMPs) exhibit potent membranolytic activity against bacterial and mammalian cells, limiting their therapeutic development due to the lack of selectivity. This study demonstrates that the reverse turn in these AMPs can be used to dictate their molecular rigidity, which drives their membranolytic action. By fine-tuning the rigidity at the reverse turn by incorporating a moderately rigid β-II' turn-inducing motif through <i>N</i>-methylation of the amide bond, we achieved selectivity in targeting the bacterial membrane over human red blood cells. The selectivity results from the hairpin-nucleation efficiency of the engineered β-turn within these linear AMPs devoid of disulfide bridges and their interaction with the neutral mammalian and negatively charged bacterial membrane. Such fine-tuning of the structure at the β-turn allowed us to develop molecules derived from naturally occurring toxic AMPs, which displayed selective killing of drug-resistant bacterial pathogens over mammalian cells with <i>in vivo</i> efficacy.
Authors
- Jayanta Chatterjee (ORCID: https://orcid.org/0000-0002-4124-7339)
- Ranjana Pathania (ORCID: https://orcid.org/0000-0002-7965-8176)
- Mahak Saini (ORCID: https://orcid.org/0000-0002-6247-6851)
- Priyanka Lahiri (ORCID: https://orcid.org/0000-0002-6971-1500)
- Pritam Biswas (ORCID: https://orcid.org/0000-0001-6111-3015)
- Amit K. Baidya (ORCID: https://orcid.org/0000-0002-2472-3719)
- Govardhan Reddy (ORCID: https://orcid.org/0000-0002-9013-8040)
- Sk Abdul Mohid (ORCID: https://orcid.org/0000-0002-6574-0179)
- Aparna Asok
- Anirban Bhunia (ORCID: https://orcid.org/0000-0002-8752-2842)
- Manish Agrawal (ORCID: https://orcid.org/0000-0002-1456-2923)
- S. Priyadarshini (ORCID: https://orcid.org/0000-0002-3712-9620)
- Raju S Rajmani
- Vishnu S M Ammineni
Institutions
- Bose Institute (IN)
- Indian Institute of Technology Roorkee (IN)
- Indian Institute of Science Bangalore (IN)
Publication Details
- Journal
- Chemical Science
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1039/d5sc06810j
- Primary Topic
- Antimicrobial Peptides and Activities
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Indian Institute of Science
- Department of Biotechnology, Ministry of Science and Technology, India
- Department of Science and Technology, Ministry of Science and Technology, India
- Indian Council of Medical Research
- Science and Engineering Research Board