Abstract
The branched M33 antimicrobial peptide was previously shown to be very active against Gram-negative bacterial pathogens, including multidrug-resistant strains. In an attempt to produce back-up molecules, we synthesized an M33 peptide isomer consisting of D-aminoacids (M33-D). This isomeric version showed 4 to 16-fold higher activity against Gram-positive pathogens, including Staphylococcus aureus and Staphylococcus epidermidis, than the original peptide, while retaining strong activity against Gram-negative bacteria. The antimicrobial activity of both peptides was influenced by their differential sensitivity to bacterial proteases. The better activity shown by M33-D against S. aureus compared to M33-L was confirmed in biofilm eradication experiments where M33-L showed 12% activity with respect to M33-D, and in vivo models where Balb-c mice infected with S. aureus showed 100% and 0% survival when treated with M33-D and M33-L, respectively. M33-D appears to be an interesting candidate for the development of novel broad-spectrum antimicrobials active against bacterial pathogens of clinical importance.
Highlights
Antimicrobial resistance (AMR) is not a recent phenomenon, but it is a critical health issue today
Certain drawbacks have limited the development of AMPs as drugs for bacterial infections: i) toxicity to eukaryotic cells, that may lead to nephrotoxicity, neurotoxicity and neuromuscular blockade [4,5]; ii) selection of resistant strains that may be cross-resistant to human-neutrophil-defensin-1, a key component of the innate immune response to infection [6]; iii) the fact that natural AMPs are generally very short peptides attacked by circulating proteolytic enzymes, making their half-life too short to be active against bacteria in vivo
MIC Determination MICs of M33-L and M33 peptide isomer consisting of D-aminoacids (M33-D) were determined against strains of different bacterial species, including major Gram-negative and Gram-positive pathogens (Table 1)
Summary
Antimicrobial resistance (AMR) is not a recent phenomenon, but it is a critical health issue today. Antimicrobial peptides (AMPs) are seen with great interest for the development of new agents against bacterial infections, because most of them show strong bactericidal activity against multidrug-resistant (MDR) bacterial pathogens, and may contribute to innate immunity by modulating dendritic cell differentiation and maturation, angiogenesis and chemokine production [2]. These features are attractive and many natural host defense peptides (HDPs) or artificial AMPs are currently under experimentation for drug development [3]. Researchers and industry have been seeking new AMPs of natural and nonnatural origin, with low toxicity and the longer half-life necessary for drug development
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