Abstract
Multidrug resistance against conventional antibiotics poses an important threat to human health. In this context, antimicrobial peptides (AMPs) have been extensively studied for their antibacterial activity and promising results have been shown so far. However, AMPs tend to be rather vulnerable to protease degradation, which offsets their therapeutic appeal. Here, we demonstrate how replacing functional residues in the antimicrobial region of human RNase 3—also named eosinophil cationic protein—by non-natural amino acids increases stability in human serum. These changes were also shown to reduce the hemolytic effect of the peptides in general terms, whereas the antimicrobial activity was reasonably preserved. Digestion profiles enabled us to design new peptides with superior stability and lower toxicity that could become relevant candidates to reach clinical stages.
Highlights
The increasing spread of antibiotic-resistant bacteria is putting our health system at risk.[1−3] Misuse and abuse of antibiotic prescriptions in humans and the extended use in animal feeding are leading causes of antibiotic resistance.[4]
These results suggest that Arg replacement protects all susceptible peptide bonds except one
The replacement of original residues in peptides by nonproteinogenic or D-amino acids has been extensively studied over recent years to enhance antimicrobial peptides (AMPs) viability for clinical use.[38]
Summary
The increasing spread of antibiotic-resistant bacteria is putting our health system at risk.[1−3] Misuse and abuse of antibiotic prescriptions in humans and the extended use in animal feeding are leading causes of antibiotic resistance.[4]. Following Arg replacement with non-proteinogenic surrogates (Figure 1), we created a highly stable fragment with a half-life above 6 h in the presence of human serum These peptide analogs have similar antimicrobial activity against Gram-negative bacterial strains, including clinical isolates, but low toxicity compared to the original peptide. Aeruginosa and S. typhimurium, the concentrations required to inhibit bacterial growth were, on average, higher compared to the original peptide Such behavior may be related to a higher net charge requirement to disrupt the cell membrane, as Orn is less basic than Arg.[32] For E. coli and A. baumannii, MIC values for analogs were similar, or even better, than the reference peptide and, in general terms, 7 was substantially more active than 6 (Table 5). The hydrophobic patch extends to D-Pro[2] in the case of 6 and 7
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