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Assessment of the genetic determinants involved in the expression of hight level of oxacilin resistence in contemporany clinical methicillin-resistant Staphylococcus aureus (MRSA) strains
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Staphylococcus aureus resistentes à meticilina (MRSA) são agentes frequentes de infeções bacterianas, a nível hospitalar e na comunidade. Uma das causas é a sua capacidade de aquisição de resistência aos β-lactâmicos, a classe de antimicrobianos mais usada em clínica. A maioria dos isolados de estafilococos expressa resistência aos β-lactâmicos de forma heterogénea e diversos fatores genéticos são necessários para a expressão total da resistência.
Um dos objetivos do trabalho apresentado nesta tese foi a identificação de determinantes genéticos responsáveis pela elevada expressão de resistência aos β-lactâmicos em estirpes do clone brasileiro (ST239-III). Com este objetivo, fizemos a sequenciação completa do genoma de dois pares de estirpes representativos deste clone.
Os resultados demonstraram a presença de sete genes afetados com mutações não-sinónimas nos dois pares de estirpes: rpoB, sasC, sdrD, coa, ebh, sak, e int. Adicionalmente, foram identificadas mutações nos genes fmt, murA2, relA, valS, lysS, guaB, dfrB, gyr, tcaB, pbp2, pbp4, ccrA blaZ, scn, cadA, mecA, merB, geh, lyt A, nuc, tagB e pbp3 num ou no outro par de estirpes. Contudo, são necessários mais estudos para confirmar que as mutações encontradas e identificadas como associadas com a resistência aos β-lactâmicos têm de facto um papel no nível de resistência
A mobilização do elemento SCCmec que contém o gene mecA, o elemento central da resistência à meticilina, é devida a três genes que codificam recombinases: ccrA, ccrB e ccrC. De forma a estudarmos a variabilidade do gene ccrB (o mais comum de entre os genes ccr), sequenciámos este locus numa coleção de estirpes MRSA selecionadas, com o objectivo de maximizar diferenças tanto a nível geográfico como temporal. Os resultados obtidos sugerem um baixo grau de mutação no locus ccrB entre as clones estudados. Contudo serão necessários estudos complementares para confirmar o papel destes alelos ccrB na estabilização das cassetes SCCmec.
Methicillin resistantStaphylococcus aureus(MRSA)is one of the leading causes of life threateninginfectionsin hospital and community settings.In large part, this is due to the acquisition of resistance to ß-lactams, the most used class of antimicrobials. The majority of clinical MRSA isolates express β-lactam resistance ina heterogeneous way and several genetic factors are needed for expression of full resistance. One of the aims of our work was to identify genetic determinants responsible for the optimal expression of β-lactam resistance in strains belonging to the Brazilian clone (ST239-III). Whole genome sequencing (WGS) of two pairs of strains belonging to this clone was performed.Our results demonstrated the presence of sevengenes affected with non-synonymous mutations in both pair of strains. These genes were: rpoB,sasC, sdrD,coa, ebh,saK,int.Additionally we identified other genes mutated in one or the other pair of strains:fmt, murA2, relA, valS, lysS, guaB, dfrB, gyr, tcaB, pbp2, pbp4, ccrA, blaZ, scn, cadA, mecA, merB, geh, lytA, nuc, tagB andpbp3.However more studies are needed in order to confirm that the identified mutations have in fact a role in the phenotypic resistance level in the strains in study. The mobility of the staphylococcal chromosomal cassette (SCCmec), which contains the mecAgene, the central element of methicillin resistance, is due to recombinase genes, namely ccrA, ccrBand ccrC. To assess the allelic variability of the ccrBlocus(the most ubiquitous of the ccrgenes) we sequenced this locus in a collection of representativeMRSA strains selected in order to maximize temporal and geographical differences.The results obtained show very low mutation rate inccrB locusamong the clonal lineagesstudied. Further studies to confirm the functionality of these ccrBalleles and their role in the stabilization of the SCCmeccassettes should be performed.
Methicillin resistantStaphylococcus aureus(MRSA)is one of the leading causes of life threateninginfectionsin hospital and community settings.In large part, this is due to the acquisition of resistance to ß-lactams, the most used class of antimicrobials. The majority of clinical MRSA isolates express β-lactam resistance ina heterogeneous way and several genetic factors are needed for expression of full resistance. One of the aims of our work was to identify genetic determinants responsible for the optimal expression of β-lactam resistance in strains belonging to the Brazilian clone (ST239-III). Whole genome sequencing (WGS) of two pairs of strains belonging to this clone was performed.Our results demonstrated the presence of sevengenes affected with non-synonymous mutations in both pair of strains. These genes were: rpoB,sasC, sdrD,coa, ebh,saK,int.Additionally we identified other genes mutated in one or the other pair of strains:fmt, murA2, relA, valS, lysS, guaB, dfrB, gyr, tcaB, pbp2, pbp4, ccrA, blaZ, scn, cadA, mecA, merB, geh, lytA, nuc, tagB andpbp3.However more studies are needed in order to confirm that the identified mutations have in fact a role in the phenotypic resistance level in the strains in study. The mobility of the staphylococcal chromosomal cassette (SCCmec), which contains the mecAgene, the central element of methicillin resistance, is due to recombinase genes, namely ccrA, ccrBand ccrC. To assess the allelic variability of the ccrBlocus(the most ubiquitous of the ccrgenes) we sequenced this locus in a collection of representativeMRSA strains selected in order to maximize temporal and geographical differences.The results obtained show very low mutation rate inccrB locusamong the clonal lineagesstudied. Further studies to confirm the functionality of these ccrBalleles and their role in the stabilization of the SCCmeccassettes should be performed.
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Microbiologia médica Bacteriologia Infeções bacterianas Genética
Contexto Educativo
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Instituto de Higiene e Medicina Tropical