Abstract
Melioidosis is caused by the facultative intracellular bacterium Burkholderia pseudomallei and is potentially fatal. Despite a growing global burden and high fatality rate, little is known about the disease. Recent studies demonstrate that cyclooxygenase-2 (COX-2) inhibition is an effective post-exposure therapeutic for pulmonary melioidosis, which works by inhibiting the production of prostaglandin E2 (PGE2). This treatment, while effective, was conducted using an experimental COX-2 inhibitor that is not approved for human or animal use. Therefore, an alternative COX-2 inhibitor needs to be identified for further studies. Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug (NSAID) COX-2 inhibitor marketed outside of the United States for the treatment of migraines. While this drug was developed for COX-2 inhibition, it has been found to modulate other aspects of inflammation as well. In this study, we used RAW 264.7 cells infected with B pseudomallei to analyze the effect of TA on cell survival, PGE2 production and regulation of COX-2 and nuclear factor- kappaB (NF-ĸB) protein expression. To evaluate the effectiveness of post-exposure treatment with TA, results were compared to Ceftazidime (CZ) treatments alone and the co-treatment of TA with a sub-therapeutic treatment of CZ determined in a study of BALB/c mice. Results revealed an increase in cell viability in vitro with TA and were able to reduce both COX-2 expression and PGE2 production while also decreasing NF-ĸB activation during infection. Co-treatment of orally administered TA and a sub-therapeutic treatment of CZ significantly increased survival outcome and cleared the bacterial load within organ tissue. Additionally, we demonstrated that post-exposure TA treatment with sub-therapeutic CZ is effective to treat melioidosis in BALB/c mice.
Highlights
Melioidosis is a tropical and often fatal disease caused by the aerobic, Gram-negative facultative intracellular bacterium Burkholderia pseudomallei [1]
Burkholderia pseudomallei is the causative agent of melioidosis, a fatal tropical disease endemic in parts of Southwest Asia and Northern Australia
While it was once believed to be isolated to these areas, recent research indicates the global burden on melioidosis is growing
Summary
Melioidosis is a tropical and often fatal disease caused by the aerobic, Gram-negative facultative intracellular bacterium Burkholderia pseudomallei [1]. The typical treatment regime for melioidosis lasts 20 weeks with both intravenous and oral phases of antibiotic administration Due to these intense treatment requirements and antibacterial resistant isolates, relapse of the disease is common [2]. Recent evidence suggests that modulating the immune modulation by inhibiting cyclooxygenase-2 (COX-2) to reduce prostaglandin E2 (PGE2) expression is an effective post-exposure therapeutic. A COX-2 inhibitor with similar effects as NS-398 in a form administered to patients would be one step closer to developing a successful immune modulation regimen to treat melioidosis This has profound implications as effective immune modulation treatment can reduce the selective pressure for bacteria to evolve to become drug resistant. Such interventions are promising developments toward the ultimate goal of eliminating an infectious disease by optimizing the host innate immune response [6]
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