Proline-Modified (RW)n Peptides: Enhancing the Antimicrobial Efficacy and Selectivity against Multidrug-Resistant
Anderson Sunda-Meya1, Nsoki Phambu2
1Department of Physics, Xavier University of Louisiana, New Orleans, Louisiana 70125, United States.
Abstract:
The growing threat of multidrug-resistant (MDR) bacteria necessitates the development of novel antimicrobial agents. This study investigates the potential of proline-modified (RW)n peptides as a platform for combating MDR pathogens with minimal toxicity. We synthesized and evaluated (RW)n peptides (n = 4, 6, and 8) with and without central proline residues against five clinically relevant bacterial strains, including ESKAPE pathogens. Antimicrobial activity, cytotoxicity, and synergistic effects with conventional antibiotics were assessed. Proline incorporation significantly enhanced the peptide selectivity and broadened the spectrum of activity, particularly against Gram-negative bacteria. RW6P and RW8P demonstrated exceptional efficacy (MICs ≤ 0.25 μg/mL) against methicillin-resistant Staphylococcus aureus and Escherichia coli with minimal toxicity to human cells. Notably, RW8P restored ampicillin susceptibility in Pseudomonas aeruginosa (MIC < 0.25 μg/mL) without dose-dependent toxicity. Exceptionally, RW6-2P demonstrated efficacy against all Gram-positive and Gram-negative bacteria, except Klebsiella pneumoniae (Kp), without toxicity. Furthermore, several Gram-negative isolates were rendered susceptible to vancomycin when combined with these peptides, addressing a key limitation of glycopeptide antibiotics. Gram-negative Klebsiella pneumoniae (Kp) was rendered susceptible to vancomycin when combined with RW4P and RW6-2P. RW4P and RW6-2P, with and without antibiotics, have shown selectivity. This study presents proline-modified (RW)n peptides as promising candidates for developing broad-spectrum antimicrobials with enhanced selectivity and the potential to revitalize existing antibiotics against MDR pathogens.
Insights
Proline-modified peptides show promise against multidrug-resistant bacteria. These novel agents exhibit broad-spectrum activity and can restore antibiotic susceptibility, offering new hope against challenging infections.
Area of Science:
- Antimicrobial drug discovery
- Peptide therapeutics
- Bacterial resistance mechanisms
Background:
- Multidrug-resistant (MDR) bacteria pose a significant global health threat.
- Existing antibiotics are becoming less effective against resistant strains.
- Novel antimicrobial strategies are urgently needed.
Purpose of the Study:
- To investigate proline-modified (RW)n peptides as potential antimicrobial agents.
- To evaluate their efficacy against clinically relevant MDR pathogens.
- To assess their toxicity and synergistic potential with conventional antibiotics.
Main Methods:
- Synthesis and evaluation of (RW)n peptides with and without proline.
- Testing against five bacterial strains, including ESKAPE pathogens.
- Assessing antimicrobial activity, cytotoxicity, and synergistic effects.
Main Results:
- Proline incorporation enhanced peptide selectivity and activity against Gram-negative bacteria.
- RW6P and RW8P showed high efficacy against MRSA and E. coli with low toxicity.
- RW8P restored ampicillin susceptibility in P. aeruginosa.
- RW6-2P demonstrated broad efficacy, except against K. pneumoniae.
- Peptides restored vancomycin susceptibility in Gram-negative bacteria.
Conclusions:
- Proline-modified (RW)n peptides are promising broad-spectrum antimicrobials.
- These peptides offer enhanced selectivity and minimal toxicity.
- They have the potential to revitalize existing antibiotics against MDR pathogens.
