RESUMO
Extracellular protein toxins contribute to the pathogenesis of a wide variety of Staphylococcus aureus infections. The present study investigated the effects that cell-wall active antibiotics and protein-synthesis inhibitors have on transcription and translation of genes for Panton-Valentine leukocidin, alpha-hemolysin, and toxic-shock syndrome toxin 1, in both methicillin-sensitive and methicillin-resistant S. aureus. Subinhibitory concentrations of nafcillin induced and prolonged mRNA for Panton-Valentine leukocidin, alpha-toxin, and toxic-shock syndrome toxin 1 and increased toxin production. In contrast, clindamycin and linezolid markedly suppressed translation, but not transcription, of toxin genes. These results suggest (1) that protein-synthesis inhibition is an important consideration in the selection of antimicrobial agents to treat serious infections caused by toxin-producing gram-positive pathogens and (2) that, by inducing and enhancing toxin production, inadvertent use of beta-lactam antibiotics to treat methicillin-resistant S. aureus infections may contribute to worse outcomes.
Assuntos
Antibacterianos/farmacologia , Exotoxinas/biossíntese , Resistência a Meticilina , Inibidores da Síntese de Proteínas/farmacologia , Staphylococcus aureus/patogenicidade , Acetamidas/farmacologia , Animais , Toxinas Bacterianas/biossíntese , Toxinas Bacterianas/genética , Clindamicina/farmacologia , Enterotoxinas/biossíntese , Enterotoxinas/genética , Exotoxinas/genética , Proteínas Hemolisinas/biossíntese , Proteínas Hemolisinas/efeitos dos fármacos , Proteínas Hemolisinas/genética , Leucocidinas/biossíntese , Leucocidinas/genética , Linezolida , Meticilina/farmacologia , Testes de Sensibilidade Microbiana , Nafcilina/farmacologia , Oxazolidinonas/farmacologia , Coelhos , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/crescimento & desenvolvimento , Superantígenos/biossíntese , Superantígenos/efeitos dos fármacos , Superantígenos/genética , Vancomicina/farmacologia , VirulênciaAssuntos
Acetamidas/uso terapêutico , Antibacterianos/farmacologia , Toxinas Bacterianas/metabolismo , Enterotoxinas/metabolismo , Oxazolidinonas/uso terapêutico , Choque Séptico/tratamento farmacológico , Infecções Estafilocócicas/tratamento farmacológico , Superantígenos/metabolismo , Humanos , Linezolida , Masculino , Pessoa de Meia-Idade , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/metabolismoRESUMO
Rapid tissue destruction in group A streptococcal (GAS) necrotizing fasciitis/myonecrosis often necessitates extensive debridement to ensure survival. The mechanisms responsible for this fulminant process remain unknown; we hypothesized that toxin-induced ischemia contributes to necrosis. In a rat model, Doppler flowmetry was used to measure local blood flow at the site of the intramuscular injection of exotoxins from an invasive M-type 1 GAS, which caused a rapid, dose-dependent decrease in perfusion that was irreversible at the highest toxin concentration tested. Videomicroscopic results revealed that blood flow was impeded by occlusive intravascular cellular aggregates. Flow-cytometric results confirmed that GAS toxins induced the coaggregation of platelets and neutrophils, that this activity was attributable to streptolysin O, and that platelet/neutrophil complex formation was largely mediated by platelet P-selectin (CD62P). Strategies that target platelet adherence molecules may prevent vascular occlusion, maintain tissue viability, and reduce the need for amputation in necrotizing GAS infections.
