Rational Substitution of ϵ-Lysine for α-Lysine Enhances the Cell and Membrane Selectivity of Pore-Forming Melittin

Venkatesh Mayandi, Qingxiao Xi, Eunice Tze Leng Goh, Siew Kwan Koh, Thomas Yong Jie Toh, Veluchamy Amutha Barathi, Mobashar Hussain Urf Turabe Fazil, Madhavi Latha Somaraju Chalasani, Jayasudha Varadarajan, Darren Shu Jeng Ting, Roger W. Beuerman, Lai Wah Chan, Rupesh Agrawal, Timothy Mark Sebastian Barkham, Lei Zhou, Navin Kumar Verma, Rajamani Lakshminarayanan

Research output: Journal article publicationJournal articleAcademic researchpeer-review

19 Citations (Scopus)


Here, we present a rational approach that enhances the membrane selectivity of a prolific pore-forming peptide, melittin, based on experimental observations that the cationic polymer, ϵ-polylysine, disrupts bacterial membranes with greater affinity over mammalian cells when compared to poly-l-lysine and poly-d-lysine. We systematically replaced three α-lysine residues in melittin with ϵ-lysine residues and identified key residues that are important for cytotoxicity. We then assessed the antimicrobial properties of the modified peptides which carry two or three ϵ-lysyl residues. Two modified melittin peptides displayed rapid bactericidal properties against antibiotic-resistant strains, low innate resistance development by pathogenic bacteria, remained nonimmunogenic for T lymphocytes, and increased bioavailability in tear fluids. In proof-of-concept in vivo experiments, one of the peptides was noncytotoxic for ocular surfaces and had comparable antimicrobial efficacy to that of fluoroquinolone antibiotics. The results uncover a simple and potential strategy that can enhance the membrane selectivity of cytolytic peptides by ϵ-lysylation.

Original languageEnglish
Pages (from-to)3522-3537
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number7
Publication statusPublished - 9 Apr 2020
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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