A Self-Assembling Peptide with Nanoparticle-to-Fibril Transformation Exhibits Multimodal Antimicrobial Activity...

Area of Science:

• Biochemistry
• Microbiology
• Materials Science

Background:

• Quorum sensing (QS) is vital for bacterial virulence, biofilm formation, and antibiotic resistance, presenting a key target for antimicrobial strategies.
• Multidrug-resistant pathogens pose a significant threat, necessitating novel therapeutic approaches beyond traditional antibiotics.

Purpose of the Study:

• To design and evaluate self-assembling peptides (SAPs) as a novel therapeutic strategy against multidrug-resistant pathogens.
• To investigate the mechanism of action of a lead peptide, SAP2-PEG, focusing on its ability to disrupt bacterial membranes and inhibit QS.

Main Methods:

• Design of amphiphilic self-assembling peptides (SAPs) with specific monomeric units.
• Characterization of peptide self-assembly into nanoparticles and fibrillar networks.
• Assessment of antimicrobial activity against nosocomial pathogens and disruption of polymicrobial biofilms.
• Transcriptome analysis to elucidate QS inhibition mechanisms in Pseudomonas aeruginosa and Staphylococcus aureus.
• In vivo efficacy studies in murine models of lung and systemic infections.

Main Results:

• SAP2-PEG spontaneously forms nanoparticles and transforms into fibrillar networks under membrane-mimicking conditions.
• The peptide demonstrates potent antimicrobial activity against critical nosocomial pathogens at low micromolar concentrations.
• SAP2-PEG effectively disrupts both pre-formed and nascent polymicrobial biofilms in wound and catheter infection models.
• Transcriptome analysis confirmed that SAP2-PEG inhibits QS by downregulating key regulatory genes (las, rh1, agr).
• In vivo studies showed significant reduction in P. aeruginosa lung infections and S. aureus systemic infections.

Conclusions:

• SAP2-PEG is a promising therapeutic candidate that combines direct antimicrobial effects with QS inhibition.
• This dual mechanism of action offers a novel strategy for combating challenging biofilm-associated infections caused by multidrug-resistant pathogens.
• The findings support the potential of self-assembling peptides as a new class of antimicrobial agents.