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Constructing Cyclic Peptides Using an On-Tether Sulfonium Center
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Published on: September 28, 2022

Design of a cyclic peptide targeting intracellular Staphylococcus aureus

Álvaro Mourenza1,2, Jesús Llano-Verdeja3, Pablo Castañera3

  • 1Grupo EXPRELA, Instituto de Investigación Biomédica de A Coruña (INIBIC), As Xubias, A Coruña, Spain. alvaro.mourenza@udc.es.

Molecular Biomedicine
|July 29, 2026
PubMed

Insights

Engineered cyclic peptides (MCo-KTR2) show enhanced stability and cellular uptake, improving treatment of intracellular Methicillin-resistant Staphylococcus aureus (MRSA) infections. This strategy offers a promising scaffold for developing new antimicrobial therapies.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Drug Discovery

Background:

  • Methicillin-resistant Staphylococcus aureus (MRSA) poses a significant clinical challenge, especially intracellular infections, due to difficulties in antimicrobial drug delivery.
  • Existing antimicrobial agents struggle to achieve the necessary stability, host-cell penetration, and bacterial target engagement for intracellular pathogens.

Purpose of the Study:

  • To engineer a novel cyclic peptide, MCo-KTR2, by grafting an antimicrobial peptide (KTR) onto a cyclotide scaffold (MCoTI-I).
  • To evaluate MCo-KTR2's potential as an intracellular antimicrobial agent against MRSA, focusing on stability, cellular uptake, and efficacy.

Main Methods:

  • Molecular docking and dynamics simulations to predict interactions with MRSA's penicillin-binding protein PBP2a.
  • Site-directed mutagenesis and fluorescence polarization assays to identify key binding residues.
  • In vitro assays to assess serum stability, cellular uptake, intracellular activity, cytotoxicity, and haemolytic activity.
  • Combination studies with other antimicrobial agents (Visomitin, vancomycin, gentamicin).

Main Results:

  • MCo-KTR2 demonstrated a >30-fold increase in serum stability and enhanced cellular uptake compared to linear KTR.
  • The engineered peptide colocalized with intracellular MRSA and showed improved activity against intracellular bacteria.
  • MCo-KTR2 exhibited no detectable cytotoxicity or haemolytic activity.
  • Combination therapies enhanced MCo-KTR2's antibacterial efficacy.

Conclusions:

  • Cyclotide grafting is an effective strategy for enhancing peptide stability and intracellular delivery of antimicrobial agents.
  • MCo-KTR2 shows promise as a scaffold for developing novel therapeutics against intracellular MRSA infections.
  • Further optimization of MCo-KTR2 could lead to improved treatments for challenging bacterial infections.
Keywords:
Antimicrobial peptidesCyclotidesDocking and molecular dynamicsIntracellular infectionsMRSA

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