Short and Robust Anti-Infective Lipopeptides Engineered Based on the Minimal Antimicrobial Peptide KR12 of Human LL-37

Jayaram Lakshmaiah Narayana, Radha Golla, Biswajit Mishra, Xiuqing Wang, Tamara Lushnikova, Yingxia Zhang, Atul Verma, Vikas Kumar, Jingwei Xie, Guangshun Wang

Research output: Contribution to journalArticlepeer-review

Abstract

This study aims to push the frontier of the engineering of human cathelicidin LL-37, a critical antimicrobial innate immune peptide that wards off invading pathogens. By sequential truncation of the smallest antibacterial peptide (KR12) of LL-37 and conjugation with fatty acids, with varying chain lengths, a library of lipopeptides is generated. These peptides are subjected to antibacterial activity and hemolytic assays. Candidates (including both forms made of l- and d-amino acids) with the optimal cell selectivity are subsequently fed to the second layer of in vitro filters, including salts, pH, serum, and media. These practices lead to the identification of a miniature LL-37 like peptide (d-form) with selectivity, stability, and robust antimicrobial activity in vitro against both Gram-positive and negative bacteria. Proteomic studies reveal far fewer serum proteins that bind to the d-form than the l-form peptide. C10-KR8d targets bacterial membranes to become helical, making it difficult for bacteria to develop resistance in a multiple passage experiment. In vivo, C10-KR8d is able to reduce bacterial burden of methicillin-resistant Staphylococcus aureus (MRSA) USA300 LAC in neutropenic mice. In addition, this designer peptide prevents bacterial biofilm formation in a catheter-associated mouse model. Meanwhile, C10-KR8d also recruits cytokines to the vicinity of catheters to clear infection. Thus, based on the antimicrobial region of LL-37, this study succeeds in identifying the smallest anti-infective peptide C10-KR8d with both robust antimicrobial, antibiofilm, and immune modulation activities.

Original languageEnglish (US)
Pages (from-to)1795-1808
Number of pages14
JournalACS infectious diseases
Volume7
Issue number6
DOIs
StatePublished - Jun 11 2021

Keywords

  • bacterial resistance
  • human cathelicidin
  • in vitro filtering
  • in vivo efficacy
  • peptide library
  • proteomics

ASJC Scopus subject areas

  • Infectious Diseases

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