Discovery, evaluation and optimization of new antimicrobials against multidrug resistant bacteria
[eng] Antimicrobial resistance is a global problem, reducing the effectiveness of drugs used to treat infections caused by microorganisms. In 2019, antibiotic resistance is estimated to have caused 1.27 million deaths related to bacterial infections. The World Health Organization has stressed the im...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2023 |
| País: | España |
| Institución: | Universidad de Barcelona |
| Repositorio: | Dipòsit Digital de la UB |
| OAI Identifier: | oai:diposit.ub.edu:2445/223382 |
| Acceso en línea: | https://hdl.handle.net/2445/223382 http://hdl.handle.net/10803/695277 |
| Access Level: | acceso abierto |
| Palabra clave: | Microbiologia mèdica Bacteriologia mèdica Malalties infeccioses Medical microbiology Medical bacteriology Communicable diseases |
| Sumario: | [eng] Antimicrobial resistance is a global problem, reducing the effectiveness of drugs used to treat infections caused by microorganisms. In 2019, antibiotic resistance is estimated to have caused 1.27 million deaths related to bacterial infections. The World Health Organization has stressed the importance of addressing this problem and looking for new antibiotics effective against multidrug-resistant bacteria. Antimicrobial peptides are molecules of the defense system of different organisms that they use to protect themselves from pathogens. They have antimicrobial properties and have been shown to be effective against multidrug-resistant bacteria. In this doctoral thesis project, antimicrobial peptides have been designed, optimized and developed, as well as antimicrobial peptides with photoswitchable structures. It is hypothesized that the design and optimization of these peptides by means of different strategies will produce structures with good antibacterial activity and low toxicity. In addition, the creation of a photoswitchable peptide that allows the control of antimicrobial activity in the environment and reduces the development of resistance is proposed. Specific objectives include the optimization of peptides derived from CAP-18 and optimization of a cyclic peptide based on protegrin-1 and called PLP-3, the evaluation of antimicrobial activity and toxicity, and the study of its effect on bacterial cells of all engineered peptides. It also seeks to analyze the antimicrobial activity of photochangeable analogues of thyrocidine A and their toxicity. The results show that the peptides derived from CAP-18 have a potent antimicrobial activity against multidrug-resistant strains of A. baumannii and P. aeruginosa, with a low toxicity and bactericidal effect. By viewing samples of these bacterial species under the action of CAP-18 derivatives, it is observed that these bacterial cells suffer damage to their membrane, consequent to an antimicrobial mechanism of action of membrane disruption. PLP-3 also demonstrates high antimicrobial activity against multidrug-resistant strains of A. baumannii, K. pneumoniae and P. aeruginosa, low toxicity at clinically relevant concentrations for pathogen inhibition and membrane permeabilization of A. baumannii and P. aeruginosa strains. The designed photoswitchable derivatives have effective antimicrobial activity against resistant bacteria, and their activity is precisely modulated by irradiation with red light and natural light, leading to their inactivation. These results suggest that photoswitchable antibiotics based on antimicrobial fungi could be a promising strategy for the development of new antimicrobial agents addressing the problem of the emergence of antibiotic resistance in environmental bacteria. These advances contribute to the development of new antibiotics effective against multidrug-resistant bacteria and address the problem of the spread of antimicrobial resistance. |
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