Novel antimicrobial peptides for therapeutic applications: design, synthesis, characterization, and evaluation of their biological and biophysical activity

Programa de Doctorat en Química Orgànica ; After decades of exorbitant antibiotic misuse and overuse in human medicine, agriculture and livestock industry, multidrug resistant bacteria (MDR) have become a major medical concern. In this regard, the design of new, safe, and effective antimicrobials, particularly against Gram-negative bacteria is an urgent need. Polymyxins are antimicrobial lipopeptides, highly active and selective against Gram- negative bacteria which were discovered in 1947, but their use was abandoned in the 1970s due to nephro- and neurotoxicity issues. In the last decades, polymyxins have been rescued as last line therapy in hospitals due to the antibiotic crisis. In that regard, 31 new polymyxin-based compounds were designed, synthesized, and characterized during this work. Furthermore, their biological activity and mechanism of action were evaluated using diverse microbiological and biophysical assays. Finally, two compounds were selected as promising candidates for further development, they presented comparable in vitro and in vivo potency to that displayed by natural polymyxin and outstandingly low nephrotoxic effects in vivo. On the other hand, the ability to form pores on bacterial membranes of BP100 was studied. BP100 is an 11-residue antimicrobial peptide derived from the well-known cecropin A and melittin. By studying a series of BP100 analogues with different lengths ranging from 4 to 24 amino acids, it was possible to determine its potential mechanism of action, which consists in a dynamic carpet mechanism, where BP100 gets inserted dynamically into the membrane, perturbating the bilayer, increasing the membrane permeability and ultimately producing the cell death. ; Després de dècades d'excessiu ús d'antibiòtics en la medicina humana, l'agricultura i la indústria ramadera, els bacteris multiresistents (resistents a molts o tots els antibiòtics convencionals) s'han convertit en un important problema de salut pública de primer ordre a escala mundial. En aquest sentit, és de gran ...