ITQB: MMPR - PhD Theses
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- Towards therapeutic applications of carbon monoxide releasing moleculesPublication . Mendes, Sofia S.; Saraiva, Lígia; Prudêncio, Miguel"The misuse of antimicrobial drugs over the past decades has led to an increased number of Multi-Drug-Resistant (MDR) pathogens, from bacteria, funghi to parasites. Pathogenic bacteria, such as, Methicillinresistant Staphylococcus aureus (MRSA) and MDR Escherichia coli pose a serious threat to society, as several outbreaks have occurred over the past decades. Fungal infections that can lead to pneumonia and meningitis are also highly drug resistant. The World Health Organization’s (WHO) priority pathogen list includes fungal species like Candida albicans, Candida glabrata and Aspergillus fumigatus. Malaria is responsible for 600 thousand deaths per year, and due to the lack of a effective vaccine and the increasing cases of Plasmodium MDR species, millions of lives are threatened by this parasite. Carbon monoxide releasing molecules (CORMs) that release CO in a controlled manner, have been shown to be effective against a wide range of pathogens, including E. coli, S. aureus and Plasmodium spp. The work presented in this thesis aimed to elucidate the mechanism of action of CORMs and their possible use as antimicrobial agents(...)"
- Di iron Proteins with Cell Repair Functions in PathogensPublication . Silva, Liliana; Saraiva, Lígia; Romão, Célia"Repair of Iron Centres (RIC) proteins are a family of di-iron hemerythrin-like proteins widely spread among pathogens, such as Escherichia coli and Staphylococcus aureus. RICs restore the activity of stress damaged iron-sulfur (Fe-S) containing proteins, such as those acting in the tricarboxylic acid cycle, namely aconitase and fumarase. Moreover, E. coli RIC (herein designed as YtfE) is able to provide iron for the assembly of Fe-S clusters in apo- and scaffold proteins.(...)"
- Staphylococcus aureus: the paths and crosstalks that lead to hemePublication . Videira, Marco A.M; Saraiva, Lígia; Lobo, SusanaTetrapyrroles are biological molecules widespread through all living organisms and necessary for fundamental cellular processes. Within the wide range of known tetrapyrroles, heme and siroheme are prosthetic groups in proteins responsible for important functions such as gas transport and storage, electron transport, cellular signaling, cellular detoxification as well as for reduction of sulfite and nitrite. Both molecules are synthesized from a last common tetrapyrrole precursor, namely uroporphyrinogen III, forming heme via four enzymatic steps know as the classical heme biosynthesis pathway and generating siroheme via an independent route. In some organisms such as sulfate and nitrate reducing bacteria, heme is alternatively synthesized through the siroheme-dependent pathway. (...)
- Defences of Helicobacter species against host antimicrobialsPublication . Parente, Adelina Margarida Lima Pereira Rodrigues; Saraiva, Lígia; Justino, MartaBacteria of the genus Helicobacter are related to gastrointestinal and hepatic disease in humans. Helicobacter pylori infects the gastric mucosa of a large percentage of the human population and has been reported to cause gastric ulcer and stomach cancer. Other Helicobacter related species, such as the enterohepatic Helicobacter pullorum, although firstly discovered in chickens are now known to be associated with human digestive disorders such as gastroenteritis, inflammatory bowel disease, hepatobiliary disease and hepatic cancer.(...)
- Novel insights into the action of antimicrobial agents against human pathogensPublication . Tavares, Ana Filipa Nogueira; Saraiva, LígiaNowadays, the growing increase of antibiotic resistance represents a global public health concern. Hence, it is crucial to understand the mode of action of antimicrobial agents and to develop new strategies to control bacterial infections. The work presented in this thesis contributes with new insights into the mechanisms that underpin the action of antimicrobial agents against pathogenic bacteria through: (i) the study of a putative nitroreductase of Staphylococcus aureus and its involvement in nitrofurans activation; (ii) elucidation of the mechanisms that sustain the antibacterial activity of the recently discovered Carbon Monoxide‐Releasing Molecules (CO‐RMs); and (iii) evaluation of the bactericidal effect of CO‐RMs on Helicobacter pylori.(...)
- Desulfovibrio vulgaris defenses against oxidative and nitrosative stressesPublication . Figueiredo, Mafalda Cristina de Oliveira; Saraiva, Lígia MThe work presented in this dissertation aimed to unravel the defense mechanisms of the anaerobic sulfate reducing bacterium Desulfovibrio (D.) vulgaris Hildenborough against oxidative and nitrosative stresses. Desulfovibrio spp. are usually found in anaerobic niches in soil, marine and fresh waters and sediments, but also in zones periodically exposed to oxygen. Ecologically, Desulfovibrio spp.(...)
- The role of Di-iron proteins in pathogen resistancePublication . Baptista, Joana Morais; Saraiva, Lígia M.Reactive oxygen and nitrogen species (ROS and RNS) are produced by phagocytic cells of the human immune system to attack invading pathogens due to their ability to damage DNA and the metal centres of proteins. In order to survive inside the host, bacteria activate genes that encode detoxifier enzymes, like the Escherichia coli nitric oxide-reductase flavodiiron protein, also known as flavorubredoxin (FlRd), and repairing proteins, such as the E. coli YtfE di-iron protein involved in the recovery of damaged Fe-S centres. Using E. coli and Staphylococcus aureus, the work presented in this thesis aimed at unravelling: i) the role of E. coli FlRd in bacteria exposed to a combination of oxidative and nitrosative stresses, ii) the identification and characterisation of S. aureus YtfE homologue, iii) the study of E. coli YtfE mechanisms that allow the repair of damaged Fe-S clusters, and iv) the identification of proteins that interact with E. coli YtfE. To analyse the role of E. coli FlRd in cells submitted to both hydrogen peroxide and nitric oxide, the transcription and expression of norV was explored by means of β-galactosidase and immunoblotting assays, respectively. Under these conditions, it was observed that the norV transcription and expression were hindered. To identify if the lack of norV expression was related to its regulator, the NorR transcription factor, the gene was cloned and expressed, and the protein was purified and the binding of nitric oxide to NorR in the presence of hydrogen peroxide was studied. EPR experiments revealed that upon incubation of NorR with nitric oxide and hydrogen peroxide the oxidation promoted by H2O2 of the monoiron centre of NorR impairs the ligation of nitric oxide.(...)
- Unravelling novel modes of antimicrobial actionPublication . Nobre, Lígia S.; Saraiva, Lígia M.The work presented in this thesis aimed at unravelling novel modes of antimicrobial action through: i) the study of Staphylococcus aureus defences against nitric oxide, an antimicrobial weapon of the innate immune system, namely by performing the biochemical characterisation of S. aureus NO-detoxifying flavohaemoglobin and analysing the conditions under which the enzyme is operative; ii) the identification of the mechanisms beyond the antibacterial activity of azole antibiotics towards S. aureus that were shown to include the increase of endogenous reactive oxygen species triggered by the binding of imidazoles to flavohaemoglobin; and iii) the discovery of a novel type of bactericides, the carbon monoxide-releasing molecules, and identification of its potential cellular targets via analysis of the transcriptional response of Escherichia coli to CORM-2, a carbon monoxide-releasing molecule known to mimic the physiological function of carbon monoxide.(...)
- Anaerobic bacteria: an investigation of metabolic important enzymes: a novel type of oxygen reductase and enzymes of the tetrapyrrole biosynthesisPublication . Lobo, Susana André; Saraiva, Lígia M.; Teixeira, MiguelDesulfovibrio desulfuricans was the first species of a sulphatereducing bacterium to be isolated, in 1895. Since that time, many questions were raised in the scientific community regarding the metabolic and ecological aspects of these bacteria. At present, there is still a myriad of open questions remaining to be answered to enlarge our knowledge of the metabolic pathways operative in these bacteria that have implications in the sulfur cycle, in biocorrosion, namely in sewers and in oil and gas systems, and in bioremediation of several toxic metals. The work presented in this dissertation aimed at contributing with new insights of enzymes involved in two different metabolic systems on Desulfovibrio species, namely enzymes that play a role in the response to oxidative stress and that are involved in the haem biosynthetic pathway.(...)