Browsing by Author "Almeida, Rita"
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- Alkyl deoxyglycoside-polymyxin combinations against critical priority carbapenem-resistant gram-negative bacteriaPublication . Matos, Ana M. de; Calado, Patrícia; Miranda, Mónica; Almeida, Rita; Rauter, Amélia P.; Oliveira, M. Conceição; Manageiro, Vera; Caniça, ManuelaThe escalating antimicrobial resistance crisis urges the development of new antibacterial treatments with innovative mechanisms of action, particularly against the critical priority carbapenem-resistant Acinetobacter baumannii (CRAB), Pseudomonas aeruginosa (CRPA) and Enterobacteriaceae (CRE). Membrane-disrupting dodecyl deoxyglycosides have been reported for their interesting phosphatidylethanolamine-associated bactericidal activity against Gram-positive strains; however, their inability to penetrate the Gram-negative outer membrane (OM) renders them useless against the most challenging pathogens. Aiming to repurpose alkyl deoxyglycosides against Gram-negative bacteria, this study investigates the antimicrobial effects of five reference compounds with different deoxygenation patterns or anomeric configurations in combination with polymyxins as adjuvants for enhanced OM permeability. The generation of the lead 4,6-dideoxy scaffold was optimized through a simultaneous dideoxygenation step and applied to the synthesis of a novel alkyl 4,6-dideoxy C-glycoside 5, herein reported for the first time. When combined with subtherapeutic colistin concentrations, most glycosides demonstrated potent antimicrobial activity against several multidrug-resistant clinical isolates of CRAB, CRE and CRPA exhibiting distinct carbapenem resistance mechanisms, together with acceptable cytotoxicity against human HEK-293T and Caco-2 cells. The novel 4,6-dideoxy C-glycoside 5 emerged as the most promising prototype structure for further development (MIC 3.1 μg/mL when combined with colistin 0.5 μg/mL against CRPA or 0.25 μg/mL against several CRE and CRAB strains), highlighting the potential of C-glycosylation for an improved bioactive profile. This study is the first to show the potential of IM-targeting carbohydrate-based compounds for the treatment of infections caused by MDR Gram-negative pathogens of clinical importance.
- Loss of the Y chromosome in male patients with haematological disordersPublication . Geraldes, Maria; Ambrósio, Ana; Almeida, Rita; Furtado, José; Correia, HildebertoThe clinical association between loss of the Y (L0Y) chromosome and haematological disorders has been continuously debated because both phenomena can be age-related. In order to understand the relationship between the L0Y chromosome and the different haematological diseases, we retrospectively analysed cytogenetic results of 1,241 male patients from 1995 to 2010. Seventyeight patients (6.3%) showed L0Y. Of the 78 patients without Y chromosome, 15 (19.2%) had B cell lymphomas (B lymphomas), 12 (15.4%) had myelodysplastic syndromes (MDS), 10 (12.8%) had chronic myelogeneous leukaemia (CML), 10 (12.8%) had acute myeloid leukaemia (AML), 8 (10.3%) had myeloproliferative neoplasms (MN), 6 (7.7%) had chronic lymphocytic leukaemia (CLL), 5 (6.4%) had multiple myeloma (MM), 5 (6.4%) had other mature B cell neoplasms (BN), 3 (3.8%) had MDS/MN, 3 (3.8%) had other mature T cell neoplasms (TN), and 1 (1.3%) had acute lymphoblastic leukaemia (ALL). We did not observe the L0Y chromosome in the 15 patients (1.2% of all patients studied) with Hodgkin’s disease. These percentages can be different if we consider only the pathology in which the L0Y was found: 4.1% of all patients with MN, 5.7% of all patients with MDS, 9.3% in the patients with AML, 12.5% in patients with ALL, 5.8% in patients with CLL, 5.8% in B lymphoma patients, 8.2% in the CML patients, 4.5% in MM patients, 9.1% in BN patients, 9.1% in MDS/MN patients and 15.8% in TN patients. Twenty-five patients (32.1%) had the L0Y associated with other cytogenetic anomalies. There are few reports of L0Y associated with haematological disorders since this has been considered mainly an age-related event. Therefore, the tendency of L0Y diseases to be associated that seems apparent in our data indicates that careful consideration should be taken when evaluating male patients with L0Y.