ABSTRACT

Antibiotic resistance developed by bacterial and fungal pathogens is one of the current major health problems in the world; hence, the development of newer antimicrobial therapies based on novel antimicrobial molecules that diminish this resistance is urgently required. Antimicrobial peptides or, in a wider concept, host defense peptides (HDPs), a diverse set of peptides that are evolutionarily conserved to combat or enhance immunity to infections in all forms of life, could be a reassuring and complementary solution to this health emergency. Many antimicrobial peptides could combine antimicrobial activity with immunomodulatory and anti-inammatory activities. Although bacteria and fungi have resistance mechanisms against these peptides, their multifunctionality can evade such resistance. HDPs exhibit a broad spectrum of activity against a wide range of microorganisms. Different mechanisms of action have been proposed for these molecules, which indicate that many of them could have more than one antimicrobial target at the cellular level. Many of

5.1 Introduction .................................................................................................. 132 5.2 Host Defense Peptides .................................................................................. 133 5.3 Mechanism of Action of HDPs ..................................................................... 134 5.4 HDP Therapeutics ......................................................................................... 135 5.5 Nanoparticles ................................................................................................ 137 5.6 Nanoparticle Preparation, Functionalization, and Bioconjugation ............... 138 5.7 Antimicrobial Properties of Nanoparticles ................................................... 142 5.8 Conclusions ................................................................................................... 143 Acknowledgments .................................................................................................. 143 References .............................................................................................................. 144

them interact with plasma membrane (pore formation, physical and functional disorganization, or simply transit to localize intracellular targets). One of the main difculties for the utilization of HDPs for microbial control is peptide inactivation by proteinases, which is a real resistance mechanism shared by multiple human pathogens. Also, inactivation in the presence of salts, serum, or microbial components is an additional cause of no in vivo activity. The preventive action of HDPs is controversial not only for its effectiveness itself but also from a cost-benet point of view. The potential immunomodulatory effect of HDP is promising. The combination of new peptides with novel delivery techniques is another approach that could become effective for such peptides. Despite the success in preclinical models, the clinical results of these molecules have not been good enough to approve them for medical use. Alternatives to increase the stability, efcacy, and biodistribution of HDPs are required. Different nanosystems have been demonstrated to develop medical applications. Nanoparticles (1-100 nm) of different materials are characterized by large surface-to-volume ratio, with a large fraction of their atoms located at the surface with unsaturated coordination bonds. Nanoparticles basically are obtained by bottom-up procedures and by top-down routes. They can be functionalized by the incorporation, through acid-base reactions or coordination interactions, of molecular species to allow their conjugation to biomolecules or to provide functional properties. The antimicrobial activity of different types of nanoparticles has been demonstrated when metals exhibit antibacterial properties in their bulk. The antimicrobial effect of these metals increases at nanoscale dimensions. Conjugation of HDPs with nanoparticles could increase the antimicrobial activity of the combined parts. Nanoparticles could be a perfect carrier for HDPs because of their multifunctional activities.