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Anne-Claire Groo,1 Nada Matougui,2 Anita Umerska,2,3 Patrick Saulnier2,4 1Normandie Univ, UNICAEN, CERMN - EA 4258, FR CNRS 3038 INC3M, SF 4206 ICORE, Caen, France; 2Micro & Nanomédecines Translationelles-MINT, UNIV Angers, INSERM U1066, CNRS UMR 6021, UBL Universite Bretagne Loire, Angers, France; 3Université de Lorraine, CITHEFOR, Nancy, France; 4Angers University Hospital, Angers, France Introduction: Resistance to traditional antibiotics is an increasingly serious problem. Antimicrobial peptides (AMPs) have emerged as a new therapeutic class with great potential against infectious diseases, as they are less prone to induce resistance. Nanotechnology-based delivery strategies can improve the efficiency and stability of AMPs, particularly against proteolytic degradation. Lipid nanocapsules (LNCs) are a new generation of biomimetic nanocarriers and were used in this study to deliver peptides.Methods: AMP-loaded reverse micelles (RM) were developed and incorpo­rated into LNCs by the phase inversion process and the antimicrobial activity of the AMPs-loaded LNC was evaluated by the minimum inhibitory concentration method. We studied the activity of AMP solutions and AMP-loaded LNCs against Gram-positive and Gram-negative bacterial strains and then evaluated the encapsulation of a new cationic AMP called AP138. Finally, we analyzed the effect of enzymatic attack on AP138 and AP138-RM-LNCs after incubation with trypsin.Results: AP138 was efficiently encapsulated in the LNCs (encapsulation efficiency = 97.8% at a drug loading of 0.151%), resulting in protection against degradation by proteases and the preservation of antimicrobial activity against Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus.Conclusion: This study shows that RM-LNCs are an excellent candidate system to deliver AMPs. Keywords: nanoparticles, nanomedicine, antibacterial, AMP, methicillin-resistant Staphylococcus aureus, infection

Anita Umerska,1 Viviane Cassisa,2 Guillaume Bastiat,1 Nada Matougui,1 Hassan Nehme,1 Florence Manero,3 Matthieu Eveillard,4 Patrick Saulnier1 1MINT, UNIV Angers, INSERM 1066, CNRS 6021, Université Bretagne Loire, Angers, Cedex, France; 2Laboratoire de bactériologie, CHU Angers, France; 3SCIAM (Service Commun d’Imagerie et d’Analyses Microscopiques), Angers, France; 4Equipe ATIP AVENIR, CRCINA, Inserm, Université de Nantes, Université d’Angers, Angers, France Abstract: Development of effective antibacterial agents for the treatment of infections caused by Gram-positive bacteria resistant to existing antibiotics, such as methicillin-resistant Staphylococcus aureus (MRSA), is an area of intensive research. In this work, the antibacterial efficacy of two antimicrobial peptides derived from plectasin, AP114 and AP138, used alone and in combination with monolaurin-lipid nanocapsules (ML-LNCs) was evaluated. Several interesting findings emerged from the present study. First, ML-LNCs and both plectasin derivatives showed potent activity against all 14 tested strains of S. aureus, independent of their resistance phenotype. Both peptides displayed a considerable adsorption (33%–62%) onto ML-LNCs without having an important impact on the particle properties such as size. The combinations of peptide with ML-LNC displayed synergistic effect against S. aureus, as confirmed by two methods: checkerboard and time-kill assays. This synergistic interaction enables a dose reduction and consequently decreases the risk of toxicity and has the potential of minimizing the development of resistance. Together, these results suggest that ML-LNCs loaded with a plectasin derivative may be a very promising drug delivery system for further development as a novel antibacterial agent against S. aureus, including MRSA. Keywords: nanoparticles, antimicrobial peptides, glycerol monolaurate, synergy, antibiotic resistan