Peptide-based approaches for the race against resistant bacteria
[eng] Antimicrobial resistance to almost all available antibiotics is on the top ten list of global public health challenges of the World Health Organization. Each year, the deaths due to AMR infections achieve the alarming numbers of 35000 in the European Economic Area (EEA) and 700000 worldwide. T...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2024 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/218477 |
| Acceso en línea: | https://hdl.handle.net/2445/218477 http://hdl.handle.net/10803/693558 |
| Access Level: | acceso embargado |
| Palabra clave: | Antibiòtics Pèptids Bacteris Ciclodextrines Resistència als medicaments Antibiotics Peptides Bacteria Cyclodextrins Drug resistance |
| Sumario: | [eng] Antimicrobial resistance to almost all available antibiotics is on the top ten list of global public health challenges of the World Health Organization. Each year, the deaths due to AMR infections achieve the alarming numbers of 35000 in the European Economic Area (EEA) and 700000 worldwide. This problem is due to the high capacity of bacteria to multiply and mutate quickly, caused mainly by the indiscriminate use of broad-spectrum antibiotics or the excessive use of antibiotics in the veterinary and food industries. The development of new antibiotics with novel mechanisms of action faces significant challenges, both scientifically and economically. As a result, the number of antibiotics approved by the Food and Drug Administration or the European Medicines Agency has drastically decreased in recent years. This thesis presents the design, synthesis, characterization and evaluation of the in vitro activity of 18 analogues of polymyxin B and 9 analogues of murepavadin, two cyclic antimicrobial peptides. The analogues incorporate a disulfide bond in the macrocycle, aimed at maintaining the in vitro activity against bacteria, while facilitating peptide proteolysis compared to an amide bond, potentially reducing renal toxicity. The analogues have been synthesized by solid-phase peptide synthesis (SPPS) following an Fmoc/tBu protection scheme. In addition, the mode of action of two polymyxin analogues has been studied using model membranes and biophysical techniques. Finally, polymyxin B and murepavadin have also been combined with cyclodextrins, and the formation of inclusion complexes has been studied by ITC, DSC, TGA, MS, UV-Vis and NMR techniques. |
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