Introduction
The studies presented in this issue collectively underscore the growing potential of novel peptides as foundations for next-generation antibacterial agents—especially in the context of rising antibiotic resistance. Increasingly, new antimicrobial peptides (AMPs) are being identified from parasitic organisms and animal venoms. For example, mesco-2, a newly identified AMP from the parasitic flatworm Mesocestoides corti, and a series of chimeric mastoparan analogs derived from the venom peptide of Paravespula lewisii, are reviewed in detail in this issue.
Mesco-2: A potent, selective antimicrobial peptide
Through genomic screening of three candidate sequences (mesco-1, -2, -3), mesco-2 emerged as a highly cationic and amphipathic peptide—features typical of AMPs [6]. It exhibited strong activity against Gram-negative (E. coli, K. pneumoniae, A. baumannii, P. aeruginosa) and Gram-positive (S. aureus) pathogens, with MIC values in the submicromolar to low-micromolar range. Mechanistic studies using fluorescence microscopy, flow cytometry, and AFM confirmed that mesco-2 disrupts bacterial membranes while sparing eukaryotic cells. Structural analysis showed that the peptide adopts an unusual curved α-helical conformation upon binding to anionic membranes, with the CRGIGRG motif playing a central structural role. Cytotoxicity was observed only at concentrations substantially higher than antimicrobial levels, indicating good selectivity and safety.
Chimeric mastoparan analogs with reduced toxicity
Mastoparan (INLKALAALAKKIL) is a well-known antimicrobial peptide, but its clinical application is limited by hemolysis and mast-cell degranulation. To overcome these drawbacks, researchers designed a range of chimeric mastoparan variants with improved safety profiles and high antimicrobial activity. These included:
- retro-inverted analogs
- chimeras with RNA III inhibiting peptide (RIP), which suppresses toxin synthesis in S. aureus
- hybrids with galanin fragments and CPPs such as transportan (TP) and TP10
- conjugates incorporating benzimidazole derivatives
MIC testing against S. aureus, E. coli, and P. aeruginosa demonstrated that several chimeras achieved favorable activity–toxicity profiles.
Blap-6: A promising antifungal peptide
Another article presents Blap-6, a 17-residue antifungal peptide (KRCRFRTYRWGFPRRRF) isolated from the hemolymph of Blaps rhynchopetera. Blap-6 shows potent inhibitory activity against Cryptococcus neoformans (MIC = 0.81 μM), outperforming fluconazole by a factor of 6–8. TEM confirmed membrane-disruptive action, and the peptide was effective at preventing and destabilizing fungal biofilms. Blap-6 exhibited low hemolytic activity and minimal cytotoxicity, making it a strong candidate for further development. Its αβ structural motif and enrichment in arginine and tryptophan contribute to its amphiphilicity and potency.
cWY6: A multifunctional ultrashort cyclic peptide
The cyclic hexapeptide cWY6 (WKRKRY) demonstrated a unique combination of properties—potentiating antibiotics against Gram-negative bacteria and promoting wound healing. By binding LPS and disrupting the outer membrane, cWY6 enhances the efficacy of poorly permeable antibiotics (vancomycin, rifampin, novobiocin, erythromycin). In some cases, MIC values were reduced more than 120-fold. The peptide also accelerated fibroblast and keratinocyte migration in wound-healing assays, with very low cytotoxicity. Its stability, short length, and dual action make it a compelling therapeutic candidate.
Polymyxin B polymer conjugates
To address polymyxin B toxicity, researchers developed polymer–PMX B conjugates with improved biocompatibility and controlled release. Conjugation significantly reduced cytotoxicity while maintaining antimicrobial activity. The PMAG–PMX B conjugate showed the highest activity (MIC = 4 μg/mL) and demonstrated pH-responsive antibiotic release, making it especially promising for infection-site targeting.
Hybrid peptides based on amyloidogenic regions of S. aureus S1 protein
Another study describes hybrid AMPs incorporating CPP fragments (TAT peptide) and amyloidogenic motifs from domains of the S1 ribosomal protein of S. aureus. Peptides R23F, R23DI, and R23EI exhibited broad-spectrum activity against Gram-positive and Gram-negative pathogens, including MRSA. Their mechanism likely involves intracellular penetration followed by coaggregation with bacterial proteins, disrupting essential cellular processes. These peptides show strong potential against multidrug-resistant strains.
Membrane penetration mechanisms via molecular dynamics (MD)
The final article examines AMP penetration through lipid bilayers using steered MD simulations of 15 peptides (656 trajectories) in POPC membranes. Key findings include:
- peak membrane reaction force occurs at initial bilayer entry
- peptides with higher instability indices showed lower resistance (correlation > 0.9)
- addition of TAT peptides improved permeability in some cases
- center-of-mass pulling introduces more drag due to compaction
- pulling speed did not significantly impact results
However, the work does not fully elucidate the mechanism of spontaneous AMP penetration.
Conclusions
In summary, these studies highlight the strong potential of novel antimicrobial peptides from diverse biological sources, along with the importance of enhancing their stability and exploring synergistic effects. However, despite promising in vitro results, most peptides still lack in vivo validation, resistance studies, and pharmacokinetic data. More detailed mechanistic research and broader testing are essential before these candidates can be considered for clinical development.
Source: Galzitskaya, O.V. Creation of New Antimicrobial Peptides 3: Research Promises and Shortcomings. Int. J. Mol. Sci. 2025, 26, 11992. https://doi.org/10.3390/ijms262411992
