Submitted by Renata Lopes (renatasil82@gmail.com) on 2016-01-21T17:43:23Z No. of bitstreams: 1 thiagocesarnascimento.pdf: 3494952 bytes, checksum: 3356415ad599be16280e8e70cee1950d (MD5) / Approved for entry into archive by Adriana Oliveira (adriana.oliveira@ufjf.edu.br) on 2016-01-25T18:47:50Z (GMT) No. of bitstreams: 1 thiagocesarnascimento.pdf: 3494952 bytes, checksum: 3356415ad599be16280e8e70cee1950d (MD5) / Made available in DSpace on 2016-01-25T18:47:50Z (GMT). No. of bitstreams: 1 thiagocesarnascimento.pdf: 3494952 bytes, checksum: 3356415ad599be16280e8e70cee1950d (MD5) Previous issue date: 2014-04-24 / CAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior / Staphylococcus aureus é uma das principais causas de infecções associadas à saúde em todo o mundo. O objetivo deste trabalho foi avaliar as características epidemiológicas, fisiológicas e moleculares de S. aureus resistente à oxacilina (ORSA), isolados de infecções em um hospital terciário universitário e avaliar sua susceptibilidade a novas moléculas síntéticas. Foram avaliadas um total de 103 amostras de ORSA quanto a dados clínicos e epidemiológicos relacionados aos pacientes, perfil de susceptibilidade a drogas antimicrobianas, avaliação da produção de biofilme e da capacidade hemolítica e confirmação da identidade genética, detecção do gene mecA e caracterização do SCCmec, por PCR. Para 45 amostras oriundas do CTI, também foram realizadas a análise do perfil de fragmentação do DNA cromossômico por PFGE e caracterização do CC, por PCR. Para 21 amostras foi avaliada a susceptibilidade a aminas aromáticas alquiladas (aminoálcoois). Considerando-se as amostras clínicas, a maioria das amostras foi isolada no sexo masculino (71%) a partir de secreção traqueal (26,2%) e sangue (23,3%) seguido de swab de sítio cirúrgico e ponta do cateter (15,5%), exsudados (14,6%) e urina (4,9%), associados à infecção do sistema respiratório (34%) e bacteremia (20,4%), em unidade de terapia intensiva (43,7%). No geral, uma alta frequência de resistência foi observada contra clindamicina (100%), eritromicina (100%), azitromicina (99%), levofloxacina (93,2%), gentamicina (84,5%), sulfametoxazol-trimetoprim (75,7%), tetraciclina (77,6%), cloranfenicol (59,3%) e rifampicina (50,5%). Os aminoálcoois também apresentaram atividade antibacteriana contra a maioria dos isolados de ORSA. Tipos de SCCmec III (66,7%) , II (17,8%) , IV (4,4% ), I (2,2%) foram encontrados. A maioria (66,7%) dos isolados foram relacionados ao clone epidemico brasileiro (CEB)/CC8/SCCmec III , que prevaleceu entre 2005 e 2008 , enquanto que a linhagem USA100/CC5/SCCmec II surgiu em 2007 e foi mais frequente em 2009 e 2010, na UTI. Os isolados que transportam o tipo de SCCmec IV (USA400/CC1 e USA800/CC5 linhagens) e I (USA500/CC5) também foram detectadas. Nossos dados são altamente relevantes para os sistemas de vigilância permitiu mapear em maior escala a circulação dinâmica de ORSA e levantar discussões sobre estratégias de contenção e uso racional da quimioterapia empírica. / Staphylococcus aureus is a major cause of health care associated infections worldwide. The aim of this work was to evaluate epidemiological, physiological and molecular characteristics of aureus oxacillin resistant S. aureus (ORSA) isolated from infections in a tertiary university hospital and evaluated their susceptibility to new synthetic molecules. A total of 103 samples of ORSA for clinical and epidemiological data related to patients susceptibility profile to antimicrobial drugs, assessment of biofilm production and hemolytic capacity and confirmation of genetic identity, detection of the mecA gene and characterization of SCCmec were evaluated, PCR. For 45 samples from CTI, also the profile of DNA analysis by PFGE and characterization of the CC, PCR were performed. For 21 samples susceptibility to alkylated aromatic amines was evaluated. Considering the clinical samples, most samples contained in males (71%) from tracheal secretion (26.2%) and blood (23.3%) followed by surgical site and swab tip of the catheter (15.5%), exudates (14.6 %) and urine (4.9%), associated with infection of the respiratory system (34%) and bacteremia (20.4%) in the intensive care unit (43.7%). Overall, a high frequency of resistance was observed against clindamycin and erythromycin (100%), azithromycin (99%), levofloxacin (93.2%), gentamicin (84.5%), trimethoprim-sulfamethoxazole (75.7%), tetracycline (77.6%), chloramphenicol (59.3%) and rifampicin (50.5%). The amino alcohols also showed antibacterial activity against most isolates of ORSA. SCCmec type III (66.7%), II (17.8%), IV (4.4%) and I (2.2%) were found. The majority (66.7%) isolates were related to the brazilian epidemic clone (CEB)/CC8/SCCmec III, which prevailed between 2005 and 2008, while the USA100/CC5/SCCmec lineage II emerged in 2007 and was more frequent in 2009 and 2010 in the ICU. The strains carrying the SCCmec type IV (USA400/CC1 and USA800/CC5 lineages) and I (USA500/CC5) were also detected. Our data are highly relevant to surveillance systems enabled map on a larger scale the dynamic movement of ORSA and raise discussions on containment strategies and rational use of empirical chemotherapy.

Les travaux présentés dans ce mémoire décrivent une nouvelle voie de synthèse d'aminoalcools 1,2 à partir de γ-bromo-β-cétosulfoxydes, dans lesquels seul le centre stéréogène du soufre est défini. Cette synthèse s'appuie sur deux processus hautement stéréocontrôlés dirigés par le groupement sulfoxyde : le dédoublement cinétique dynamique lors de la substitution nucléophile du brome par la dibenzylamine et la réduction diastéréosélective du carbonyle. Les syn-γ-N,N-dibenzylamino-β-hydroxysulfoxydes correspondants ont été obtenus avec des excès diastéréoisomériques supérieurs à 95%. Les syn-γ-N,N-dibenzylamino-β-hydroxysulfoxydes se sont avérés être des intermédiaires très intéressants pour la synthèse de produits comportant le motif aminoalcool 1,2. Ainsi, nous avons décrit la préparation d'un 3-N,N-dibenzylamino-1,2-diol et son utilisation dans une nouvelle stratégie de déprotection régiodivergente d'acétals cycliques. Nous avons également décrit un nouvel accès aux cis-2-méthyl-6-alkylpipéridin-3-ols, via l'ouverture de cycle d'un 3-N,N-dibenzylamino-1,2-époxyde par l'azaénolate dérivé d'une hydrazone, et l'avons appliqué à la synthèse d'un alcaloïde, la (+)-déoxocassine. Parallèlement, nous avons débuté une étude de synthèse d'aminoalcools 1,3 par la réduction diastéréosélective d'une oxime dérivée d'un δ-céto-β-hydroxysulfoxyde. / In this thesis manuscript, we report on a new pathway to 1,2-aminoalcohols starting from chiral nonracemic γ-bromo-β-ketosulfoxides. This two-step approach, where the stereo control is provided by the sulfoxide group, relies on a highly stereocontrolled nucleophilic substitution of the bromine by dibenzylamine, combined with a dynamic kinetic resolution process, and the reduction of the carbonyl group. The corresponding syn-γ-N,N-dibenzylamino-β-hydroxysulfoxides were obtained with more than 95% diasteroisomeric excess. These syn-γ-N,N-dibenzylamino-β-hydroxysulfoxides turned out to be very useful intermediates for the synthesis of aminoalcohol containing products. Thus, we described the preparation of a 3-N,N-dibenzylamino-1,2-diol, and its use in an original strategy of regiodivergent cyclic acetals deprotection. We also developed a new access to "all cis"-2-methyl-6-alkylpiperidin-3-ols, by the mean of a 3-N,N-dibenzylamino-1,2-epoxide ring opening reaction with the azaenolate derived from an hydrazone. We applied this methodology to the synthesis of an alkaloid, (+)-deoxocassine. In addition, we studied a synthesis of 1,3-aminoalcohols using a diasteroselective reduction of a δ-keto-β-hydroxysulfoxyde-derived oxime.