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The nitric oxide scavenger cobinamide profoundly improves survival in a Drosophila melanogaster model of bacterial sepsis

Kate E. Broderick^*, Jake Feala, Andrew McCulloch, Giovanni Paternostro, Vijay S. Sharma^*, Renate B. Pilz^* and Gerry R. Boss^*,1

Departments of
^* Medicine, and

Bioengineering, University of California San Diego, La Jolla, California, USA; and The Burnham Institute for Medical Research,

La Jolla, California, USA

¹Correspondence: 9500 Gilman Dr., University of California, San Diego, La Jolla, CA 92093-0652, USA. E-mail: gboss{at}ucsd.edu

Septic shock has an extremely high mortality rate, with 200,000 people dying from sepsis annually in the U.S. The high mortality results in part from severe hypotension secondary to high serum NO concentrations. Reducing NO levels should be beneficial in sepsis, but NOS inhibitors have had a checkered history in animal models, and one such agent increased mortality in a clinical trial. An alternative approach to reduce NO levels in sepsis is to use an NO scavenger, which should leave sufficient free NO for normal physiological functions. Using a well-established model of bacterial sepsis in Drosophila melanogaster, we found that cobinamide, a B₁₂ analog and an effective NO scavenger in vitro, dramatically improved fly survival. Cobinamide augmented the effect of an antibiotic and was beneficial even in immune-deficient flies. Cobinamide’s mechanism of action appeared to be from reducing NO levels and improving cardiac function.—Broderick, K. E., Feala, J., McCulloch, A., Paternostro, G., Sharma, V. S., Pilz, R. B., Boss, G. R. The nitric oxide scavenger cobinamide profoundly improves survival in a Drosophila melanogaster model of bacterial sepsis.

Key Words: septic shock • cobalamin • cardiac function

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