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Glyburide reduces bacterial dissemination in a mouse model of melioidosis
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Koh, Gavin C. K. W., Weehuizen, Tassili A., Breitbach, Katrin, Krause, Kathrin, Jong, Hanna K. de, Kager, Liesbeth M., Hoogendijk, Arjan J., Bast, Antje, Peacock, Sharon J., van der Poll, Tom, Steinmetz, Ivo and Wiersinga, W. Joost (2013) Glyburide reduces bacterial dissemination in a mouse model of melioidosis. PLoS Neglected Tropical Diseases, Volume 7 (Number 10). e2500. doi:10.1371/journal.pntd.0002500 ISSN 1935-2727.
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WRAP_Koh_pntd.0002500.pdf - Published Version Available under License Creative Commons Attribution. Download (713Kb) | Preview |
Official URL: http://dx.doi.org/10.1371/journal.pntd.0002500
Abstract
Background:
Burkholderia pseudomallei infection (melioidosis) is an important cause of community-acquired Gram-negative
sepsis in Northeast Thailand, where it is associated with a ,40% mortality rate despite antimicrobial chemotherapy. We
showed in a previous cohort study that patients taking glyburide ( = glibenclamide) prior to admission have lower mortality
and attenuated inflammatory responses compared to patients not taking glyburide. We sought to define the mechanism
underlying this observation in a murine model of melioidosis.
Methods: Mice (C57BL/6) with streptozocin-induced diabetes were inoculated with ,66102 cfu B. pseudomallei
intranasally, then treated with therapeutic ceftazidime (600 mg/kg intraperitoneally twice daily starting 24 h after
inoculation) in order to mimic the clinical scenario. Glyburide (50 mg/kg) or vehicle was started 7 d before inoculation
and continued until sacrifice. The minimum inhibitory concentration of glyburide for B. pseudomallei was determined by
broth microdilution. We also examined the effect of glyburide on interleukin (IL) 1b by bone-marrow-derived
macrophages (BMDM).
Results: Diabetic mice had increased susceptibility to melioidosis, with increased bacterial dissemination but no effect was
seen of diabetes on inflammation compared to non-diabetic controls. Glyburide treatment did not affect glucose levels but
was associated with reduced pulmonary cellular influx, reduced bacterial dissemination to both liver and spleen and
reduced IL1b production when compared to untreated controls. Other cytokines were not different in glyburide-treated
animals. There was no direct effect of glyburide on B. pseudomallei growth in vitro or in vivo. Glyburide directly reduced the
secretion of IL1b by BMDMs in a dose-dependent fashion.
Conclusions: Diabetes increases the susceptibility to melioidosis. We further show, for the first time in any model of sepsis,
that glyburide acts as an anti-inflammatory agent by reducing IL1b secretion accompanied by diminished cellular influx and
reduced bacterial dissemination to distant organs. We found no evidence for a direct effect of glyburide on the bacterium.
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