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Artigo em Inglês | MEDLINE | ID: mdl-31818817

RESUMO

With the aim to identify potential new targets to restore antimicrobial susceptibility of multidrug-resistant (MDR) Pseudomonas aeruginosa isolates, we generated a high-density transposon (Tn) insertion mutant library in an MDR P. aeruginosa bloodstream isolate (isolate ID40). The depletion of Tn insertion mutants upon exposure to cefepime or meropenem was measured in order to determine the common resistome for these clinically important antipseudomonal ß-lactam antibiotics. The approach was validated by clean deletions of genes involved in peptidoglycan synthesis/recycling, such as the genes for the lytic transglycosylase MltG, the murein (Mur) endopeptidase MepM1, the MurNAc/GlcNAc kinase AmgK, and the uncharacterized protein YgfB, all of which were identified in our screen as playing a decisive role in survival after treatment with cefepime or meropenem. We found that the antibiotic resistance of P. aeruginosa can be overcome by targeting usually nonessential genes that turn essential in the presence of therapeutic concentrations of antibiotics. For all validated genes, we demonstrated that their deletion leads to the reduction of ampC expression, resulting in a significant decrease in ß-lactamase activity, and consequently, these mutants partly or completely lost resistance against cephalosporins, carbapenems, and acylaminopenicillins. In summary, the determined resistome may comprise promising targets for the development of drugs that may be used to restore sensitivity to existing antibiotics, specifically in MDR strains of P. aeruginosa.


Assuntos
Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Elementos de DNA Transponíveis , Farmacorresistência Bacteriana Múltipla/genética , Pseudomonas aeruginosa/genética , Resistência beta-Lactâmica/genética , Proteínas de Bactérias/metabolismo , Cefepima/farmacologia , Endopeptidases/deficiência , Endopeptidases/genética , Deleção de Genes , Regulação Bacteriana da Expressão Gênica , Glicosiltransferases/deficiência , Glicosiltransferases/genética , Humanos , Meropeném/farmacologia , Testes de Sensibilidade Microbiana , Mutagênese , Fosfotransferases (Aceptor do Grupo Álcool)/deficiência , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Infecções por Pseudomonas/tratamento farmacológico , Infecções por Pseudomonas/microbiologia , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/isolamento & purificação , beta-Lactamases/genética , beta-Lactamases/metabolismo
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