Publicação
Towards the development of antimicrobial peptides active against bacterial biofilms
| datacite.subject.fos | Ciências Médicas::Ciências da Saúde | pt_PT |
| dc.contributor.advisor | Veiga, Ana Salomé Rocha do Nascimento | |
| dc.contributor.author | Dias, Susana Filipa Almeida | |
| dc.date.accessioned | 2024-03-22T18:14:30Z | |
| dc.date.embargo | 2027-06 | |
| dc.date.issued | 2023-05 | |
| dc.date.submitted | 2023-03 | |
| dc.description.abstract | Antibiotic-resistant bacteria are rapidly emerging, and the number of available therapeutic options to fight them is decreasing. In addition, as a surviving strategy, bacteria can aggregate and form biofilms, a multicellular community embedded in a self-produced matrix of extracellular polymeric substances (EPS), which contributes significantly to the reduced susceptibility of bacteria towards conventional antibiotics and innate host defenses. It has been estimated that biofilms are responsible for most infections in tissues and are also recurrent colonizers of biomedical devices. Hence, the identification of novel antimicrobial agents capable to fight infections caused by resistant bacteria and bacterial biofilms is urgently needed. Antimicrobial peptides (AMPs) have been proposed as promising therapeutic alternatives to conventional antibiotics due to their broad-spectrum activity, fast-killing kinetics, and distinct mechanisms of action. In general, AMPs selectively target and kill bacteria through membrane-disruptive mechanisms, thus their activity is independent of the cellular metabolism. This feature confers AMPs the ability to act on dormant populations, which are frequently found in biofilms and are particularly difficult to target by conventional antibiotics. Taking advantage of the fact that viral proteins are an underexplored source of bioactive peptides with antimicrobial properties and based on the knowledge that cell-penetrating peptides (CPPs) can act as AMPs, the present work identified one viral-derived peptide, vCPP2319, active against bacteria in the planktonic and biofilm forms. The peptide was able to effectively kill bacteria through a mechanism of action involving bacterial membrane permeabilization. Nonetheless, vCPP2319 had a limited effect on the biofilm EPS matrix itself. Thus, biofilm treatment with vCPP2319 and a matrix-degrading enzyme, α-amylase, was studied. This combination did not improve the antibacterial action of the peptide. Given the knowledge that cyclization of bioactive peptides is a promising approach for improving peptides’ stability and bioactivity, the antibiofilm activity of the cyclic peptide, [G1K,K8R]cGm, was investigated against S. aureus biofilms. The peptide was able to kill biofilm-embedded cells in a concentration-dependent manner. Mechanistic studies showed that [G1K,K8R]cGm causes morphological changes on bacterial cells and permeabilizes their membranes with a half time of 65 min. Also, we tested an analogue of [G1K,K8R]cGm without disulfide bonds, and a linear unfolded analogue, and found both to be inactive. This finding suggests that the three dimensional structure of [G1K,K8R]cGm and its stabilization by disulfide bonds are essential for its antibacterial and antibiofilm activities. Overall, this study demonstrates the potential of viral proteins as rich sources of new bioactive peptides with antibacterial and antibiofilm properties. In addition, peptide backbone cyclization proved to be valuable strategy to enhance AMPs activity against preformed biofilms. | pt_PT |
| dc.identifier.tid | 101517700 | pt_PT |
| dc.identifier.uri | http://hdl.handle.net/10451/63711 | |
| dc.language.iso | eng | pt_PT |
| dc.relation | Towards the development of antimicrobial peptides active against bacterial biofilms | |
| dc.subject | Biofilmes bacterianos | pt_PT |
| dc.subject | Péptidos antimicrobianos | pt_PT |
| dc.subject | Combinação de diferentes terapias | pt_PT |
| dc.subject | Ciclização de sequências peptídicas | pt_PT |
| dc.subject | Bacterial biofilms | pt_PT |
| dc.subject | Antimicrobial peptides | pt_PT |
| dc.subject | Combination therapy | pt_PT |
| dc.subject | Backbone cyclization | pt_PT |
| dc.title | Towards the development of antimicrobial peptides active against bacterial biofilms | pt_PT |
| dc.type | doctoral thesis | |
| dspace.entity.type | Publication | |
| oaire.awardTitle | Towards the development of antimicrobial peptides active against bacterial biofilms | |
| oaire.awardURI | info:eu-repo/grantAgreement/FCT//PD%2FBD%2F114425%2F2016/PT | |
| project.funder.identifier | http://doi.org/10.13039/501100001871 | |
| project.funder.name | Fundação para a Ciência e a Tecnologia | |
| rcaap.rights | embargoedAccess | pt_PT |
| rcaap.type | doctoralThesis | pt_PT |
| relation.isProjectOfPublication | f6c12e94-efb9-477d-bc04-074b9283400e | |
| relation.isProjectOfPublication.latestForDiscovery | f6c12e94-efb9-477d-bc04-074b9283400e | |
| thesis.degree.name | Tese de doutoramento, Ciências Biomédicas (Biofísica), Universidade de Lisboa, Faculdade de Medicina, 2023 | pt_PT |