نبذة مختصرة : Programa de Doctorat en Química Orgànica ; Following the laws of evolution, bacteria are capable of slowly but inexorably acquiring resistance to antibiotic compounds that we have been using for decades. Therefore, bacteria that seemed harmless to most people (such as E. coli or P. aeruginosa) have become dangerous agents capable of alarming resilience. Furthermore, due to the ease in which bacteria develop new antibiotic resistances, or even share them across multiple species, the development of new compounds is no longer profitable for most pharma companies, which makes them not to prioritize this research field. These facts result in the non-existent development of new families of antibiotics, which supposes the risk of a future in which bacteria cannot be controlled without medication. In this context, many research groups have started working in the development of new antibiotics with more efficacy or less toxic effects than the ones that already exist. In this thesis, we focus on the study of an antimicrobial lipopeptide with effect against Gram-negative bacteria, colistin, and how to alter its composition or peptide sequence can potentially mean the development of new antimicrobial analogues that show a greater therapeutic profile. To do that, we used solid phase synthesis to generate the peptide analogues and we tested them for antimicrobial activity both in vitro and in vivo, and analysed their biophysical properties when exposing synthetic and natural membranes to them. Among other modifications, we can highlight the length of the fat chain of the lipopeptide, even with the substitution of the residues in position 6 and 7 without changing the net load. As a result of our research, we demonstrated that the solid phase synthesis of peptides is a consistent method for producing pure composts that allows industrial scale. Regarding the obtained peptide analogues, we confirm that their antibiotic action had a similar mechanism to the natural colistin. We also observed the differences between the activity of ...
No Comments.