RESUMO
A high-throughput phenotypic screen for novel antibacterial agents led to the discovery of a novel pyrazolopyrimidinedione, PPD-1, with preferential activity against methicillin-resistant Staphylococcus aureus (MRSA). Resistance mapping revealed the likely target of inhibition to be lysyl tRNA synthetase (LysRS). Preliminary structure-activity relationship (SAR) studies led to an analog, PPD-2, which gained Gram-negative antibacterial activity at the expense of MRSA activity and resistance to this compound mapped to prolyl tRNA synthetase (ProRS). These targets of inhibition were confirmed in vitro, with PPD-1 showing IC50s of 21.7 and 35 µM in purified LysRS and ProRS enzyme assays, and PPD-2, 151 and 0.04 µM, respectively. The highly attractive chemical properties of these compounds combined with intriguing preliminary SAR suggest that further exploration of this compelling novel series is warranted.
Assuntos
Aminoacil-tRNA Sintetases/antagonistas & inibidores , Antibacterianos/farmacologia , Proteínas de Bactérias/antagonistas & inibidores , Desenho de Fármacos , Descoberta de Drogas , Pirazóis/farmacologia , Pirimidinonas/farmacologia , Aminoacil-tRNA Sintetases/genética , Aminoacil-tRNA Sintetases/metabolismo , Antibacterianos/síntese química , Antibacterianos/química , Proteínas de Bactérias/genética , Proteínas de Bactérias/metabolismo , Farmacorresistência Bacteriana , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Escherichia coli/efeitos dos fármacos , Escherichia coli/enzimologia , Escherichia coli/crescimento & desenvolvimento , Proteínas de Escherichia coli/antagonistas & inibidores , Proteínas de Escherichia coli/genética , Proteínas de Escherichia coli/metabolismo , Ensaios de Triagem em Larga Escala , Lisina-tRNA Ligase/antagonistas & inibidores , Lisina-tRNA Ligase/genética , Lisina-tRNA Ligase/metabolismo , Resistência a Meticilina , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/enzimologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Testes de Sensibilidade Microbiana , Neisseria gonorrhoeae/efeitos dos fármacos , Neisseria gonorrhoeae/enzimologia , Neisseria gonorrhoeae/crescimento & desenvolvimento , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/enzimologia , Pseudomonas aeruginosa/crescimento & desenvolvimento , Pirazóis/síntese química , Pirazóis/química , Pirimidinonas/síntese química , Pirimidinonas/química , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Relação Estrutura-Atividade , Aminoacilação de RNA de Transferência/efeitos dos fármacosRESUMO
We describe the investigation and control of a Klebsiella pneumoniae carbapenemase-producing K. pneumoniae outbreak in a 20-bed surgical intensive care unit during the period from January 1, 2009 through January 1, 2010. Nine patients were either colonized or infected with a monoclonal strain of K. pneumoniae. The implementation of a bundle of interventions on July 2009 successfully controlled the further horizontal spread of this organism.
Assuntos
Antibacterianos/uso terapêutico , Proteínas de Bactérias/biossíntese , Cuidados Críticos , Surtos de Doenças/prevenção & controle , Controle de Infecções/métodos , Infecções por Klebsiella/tratamento farmacológico , Klebsiella pneumoniae/efeitos dos fármacos , beta-Lactamases/biossíntese , Antibacterianos/farmacologia , Proteínas de Bactérias/genética , Feminino , Florida/epidemiologia , Hospitais de Ensino , Humanos , Infecções por Klebsiella/epidemiologia , Infecções por Klebsiella/microbiologia , Klebsiella pneumoniae/enzimologia , Klebsiella pneumoniae/genética , Klebsiella pneumoniae/isolamento & purificação , Masculino , Testes de Sensibilidade Microbiana , Pessoa de Meia-Idade , Resultado do Tratamento , beta-Lactamases/genéticaRESUMO
We report a multicity outbreak of cfr-containing linezolid-resistant Staphylococcus epidermidis in Ohio. Thirty-nine isolates were obtained from 2 hospitals. Two clones with different mechanisms of linezolid resistance were circulating in hospital A. One of these contained the cfr gene, and the other a ribosomal mutation. The clone containing cfr was identical in both hospitals.
Assuntos
Acetamidas/farmacologia , Antibacterianos/farmacologia , Surtos de Doenças , Farmacorresistência Bacteriana , Oxazolidinonas/farmacologia , Infecções Estafilocócicas/epidemiologia , Infecções Estafilocócicas/microbiologia , Staphylococcus epidermidis/efeitos dos fármacos , Proteínas de Bactérias/genética , Técnicas de Tipagem Bacteriana , Impressões Digitais de DNA , DNA Bacteriano/genética , Eletroforese em Gel de Campo Pulsado , Genótipo , Hospitais , Humanos , Linezolida , Ohio/epidemiologia , Staphylococcus epidermidis/isolamento & purificaçãoRESUMO
OBJECTIVES: The prevalence of linezolid-resistant coagulase-negative Staphylococcus (CoNS) in the MD Anderson Cancer Center rose from 0.6% in 2007 to 5.5% in 2009. The aim of our study was to analyse the relationship between linezolid use and an outbreak of linezolid-resistant CoNS. PATIENTS AND METHODS: We retrospectively identified 27 infection or colonization events. Eleven isolates were available for supplemental investigation; species identification, clonal relatedness and linezolid resistance mutation analysis. The medical records of the affected patients were reviewed and linezolid utilization data were obtained from the pharmacy. RESULTS: Available isolates were confirmed as clonally related Staphylococcus epidermidis. Partial 23S rRNA gene sequencing found a G2576T mutation in all of the isolates tested. All patients received linezolid within 3 months prior to an event. Patients without a prior hospitalization had a longer time from admission to event; 29 versus 3.5 days (P = 0.002). The outbreak was preceded by a 51% increase in inpatient linezolid utilization and 64% of affected patients belonged to the leukaemia service, which had a utilization rate 3.1 times that of the other services (95% confidence interval: 2.96-3.23). CONCLUSIONS: Increased linezolid utilization preceded the appearance of a linezolid-resistant CoNS clone. Patients probably acquired the clonal strain nosocomially, given the longer time from admission to event among patients with no previous admission to the MD Anderson Cancer Center. Linezolid administration then selected this strain, since all patients received linezolid prior to an event. A linezolid utilization rate of >or=13 defined daily doses/100 patient-days was similar to that reported in two other outbreaks and may be the threshold required to generate an outbreak.
