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Designing New Chimeric Proline-Rich Antimicrobial Peptides to Enhance Efficacy Toward the ESKAPE+E: Beyond Sequence
Adriana Di Stasi1, Luigi de Pascale1, Martino Morici2
1Department of Life Sciences, University of Trieste, 34127 Trieste, Italy.
Abstract:
Proline-rich antimicrobial peptides (PrAMPs) primarily exert their antimicrobial effects intracellularly, inhibiting protein synthesis. B7-005, a synthetic 16-amino acid PrAMP, has a broader antimicrobial spectrum compared to native counterparts, despite shorter PrAMPs typically exhibiting reduced activity. This study aimed to enhance B7-005's potency by extending it with 6 or 11 amino acids derived from the C-terminal sequences of cetacean Tur1A and Lip1 PrAMPs, as well as bovine Bac7(1-35). Six chimeric derivatives were evaluated for antimicrobial and bactericidal potency, cytotoxicity, bacterial membrane permeabilization, and in vitro inhibition of protein synthesis. Extending B7-005 with sequences from other PrAMPs increased its activity against most ESKAPE+E pathogens, reducing minimum inhibitory concentration (MIC) values by 2- to 8-fold, with notable differences among bacterial species, without increasing cytotoxicity toward the A549 cell line. All chimeras retained the ability to inhibit protein synthesis in Escherichia coli and to modestly perturb the E. coli membranes like B7-005. These novel chimeric PrAMPs, particularly the 22-mer derivatives, hold promise for developing new antimicrobial agents. The study also highlights variability in bacterial responses to PrAMPs and underscores how minor sequence differences can significantly impact efficacy against specific microorganisms. PrAMPs thus represent a valuable scaffold to rationally design derivatives targeting high-priority pathogens.
Insights
Synthetic proline-rich antimicrobial peptides (PrAMPs) were modified to create chimeric derivatives. These novel PrAMPs show enhanced potency against pathogens without increased toxicity, offering new antimicrobial agent potential.
Area of Science:
- Antimicrobial peptide research
- Drug discovery and development
- Molecular biology
Background:
- Proline-rich antimicrobial peptides (PrAMPs) are key intracellular effectors inhibiting protein synthesis.
- Synthetic PrAMP B7-005 exhibits a broad spectrum but can be improved.
- Shorter PrAMPs often have reduced activity, necessitating optimization strategies.
Purpose of the Study:
- To enhance the antimicrobial potency of the synthetic PrAMP B7-005.
- To create chimeric PrAMPs by extending B7-005 with sequences from other PrAMPs.
- To evaluate these novel derivatives for antimicrobial activity, cytotoxicity, and mechanism of action.
Main Methods:
- Synthesis of six chimeric PrAMP derivatives by extending B7-005.
- Assessment of antimicrobial and bactericidal potency against ESKAPE+E pathogens.
- Evaluation of cytotoxicity in A549 cells and bacterial membrane permeabilization.
- In vitro analysis of protein synthesis inhibition in Escherichia coli.
Main Results:
- Chimeric PrAMPs demonstrated 2- to 8-fold increased activity against most tested pathogens.
- Enhanced activity varied among bacterial species, with no increase in cytotoxicity.
- All derivatives maintained protein synthesis inhibition and modest membrane perturbation.
- 22-mer derivatives showed particular promise.
Conclusions:
- Chimeric PrAMPs derived from B7-005 represent a promising strategy for developing novel antimicrobial agents.
- Rational design of PrAMP derivatives can target high-priority pathogens effectively.
- Bacterial responses to PrAMPs are variable, highlighting the importance of sequence optimization.
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