Antimicrobial peptides (AMPs) have been described as excellent candidates to overcome antibiotic resistance. Frequently, AMPs exhibit a wide therapeutic window, with low cytotoxicity and broad-spectrum antimicrobial activity against a variety of pathogens. In addition, some AMPs are also able to modulate the immune response, decreasing potential harmful effects such as sepsis. Despite these benefits, only a few formulations have successfully reached clinics. A common flaw in the druggability of AMPs is their poor pharmacokinetics, common to several peptide drugs, as they may be degraded by a myriad of proteases inside the organism. The combination of AMPs with carrier nanoparticles to improve delivery may enhance their half-life, decreasing the dosage and thus, reducing production costs and eventual toxicity. Here, we present the most recent advances in lipid and metal nanodevices for AMP delivery, with a special focus on metal nanoparticles and liposome formulations.
Discovering antibiotic molecules able to hold the growing spread of antimicrobial resistance is one of the most urgent endeavors that public health must tackle. The case of Gram-negative bacterial pathogens is of special concern, as they are intrinsically resistant to many antibiotics, due to an outer membrane that constitutes an effective permeability barrier. Antimicrobial peptides (AMPs) have been pointed out as potential alternatives to conventional antibiotics, as their main mechanism of action is membrane disruption, arguably less prone to elicit resistance in pathogens. Here, we investigate the in vitro activity and selectivity of EcDBS1R4, a bioinspired AMP. To this purpose, we have used bacterial cells and model membrane systems mimicking both the inner and the outer membranes of Escherichia coli, and a variety of optical spectroscopic methodologies. EcDBS1R4 is effective against the Gram-negative E. coli, ineffective against the Gram-positive Staphylococcus aureus and noncytotoxic for human cells. EcDBS1R4 does not form stable pores in E. coli, as the peptide does not dissipate its membrane potential, suggesting an unusual mechanism of action. Interestingly, EcDBS1R4 promotes a hemi-fusion of vesicles mimicking the inner membrane of E. coli. This fusogenic ability of EcDBS1R4 requires the presence of phospholipids with a negative curvature and a negative charge. This finding suggests that EcDBS1R4 promotes a large lipid spatial reorganization able to reshape membrane curvature, with interesting biological implications herein discussed.
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