Telavancin targets the bacterial membrane of Staphylococcus aureus: analysis of membrane effects by flow cytometry
Abstract number: 1732_158
Lunde C., Renelli M., Janc J., Mammen M., Humphrey P., Benton B.
Objectives: Telavancin is a novel, multivalent, lipoglycopeptide antibiotic that exerts rapid bactericidal activity against a broad range of Gram-positive pathogens. Telavancin has a unique multifunctional mechanism of action that includes both inhibition of bacterial cell wall synthesis and disruption of bacterial membrane function. Previous studies with methicillin-resistant Staphylococcus aureus (MRSA) revealed that telavancin increases cell membrane permeability and causes rapid dissipation of the bacterial membrane potential. This study aimed to further characterise the effects of telavancin on the functional integrity of the MRSA cell membrane using flow cytometry.
Methods: Cell membrane potential and membrane permeability were studied in telavancin-treated S. aureus ATCC 33591 (MRSA) cells. The fluorescent dyes, DiOC2(3) and propidium iodide, were used to assess membrane potential and permeability, respectively. Flow cytometry was used to analyse uptake of these dyes in telavancin-treated cells.
Results: Telavancin (MIC, 0.5 mg/mL) caused a concentration- and time-dependent dissipation of the membrane potential in MRSA cells. After 60 minutes' exposure to telavancin, 67% of the bacterial population was depolarised at 8 mg/mL (approximate human plasma trough concentration), while 32 mg/mL resulted in 95% depolarisation. Membrane permeability was also concentration- and time-dependent, as seen when cells were exposed to telavancin concentrations ranging from 2 to 64 mg/mL, with 32 and 64 mg/mL yielding rapid, >90% permeabilisation of the cell population.
Conclusion: Exposure of MRSA cells to telavancin initiated concentration- and time-dependent membrane depolarisation and increases in permeability, further demonstrating that telavancin interferes with bacterial cell membrane function. These effects were observed at telavancin concentrations that are achieved clinically with 10 mg/kg intravenous dosing, and further highlight the therapeutic relevance of telavancin's multifunctional mechanism of action.
|Session name:||European Society of Clinical Microbiology and Infectious Diseases|
|Location:||ICC, Munich, Germany|
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