title: The nitric oxide scavenger cobinamide profoundly improves survival in a Drosophila melanogaster model of bacterial sepsis.
abstract: Septic shock has an extremely high mortality rate, with approximately 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 B(12) 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.
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla 92093-0652, USA.
authors.forename: Kate E
authors.initials: KE
authors.lastname: Broderick
authors.forename: Jake
authors.initials: J
authors.lastname: Feala
authors.forename: Andrew
authors.initials: A
authors.lastname: McCulloch
authors.forename: Giovanni
authors.initials: G
authors.lastname: Paternostro
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Sharma
authors.forename: Renate B
authors.initials: RB
authors.lastname: Pilz
authors.forename: Gerry R
authors.initials: GR
authors.lastname: Boss
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000503:physiopathology*; D003038:Cobamides / Q000008:administration & dosage / Q000494:pharmacology* / Q000502:physiology*; D019587:Dietary Supplements; D029721:Drosophila Proteins / Q000172:deficiency; D004331:Drosophila melanogaster / Q000235:genetics / Q000254:growth & development / Q000382:microbiology*; D004926:Escherichia coli / Q000187:drug effects / Q000254:growth & development; D004927:Escherichia coli Infections / Q000503:physiopathology; D012772:Shock, Septic / Q000517:prevention & control; D013203:Staphylococcal Infections / Q000503:physiopathology; D013211:Staphylococcus aureus / Q000187:drug effects / Q000254:growth & development
chemical_list: D003038:Cobamides; D029721:Drosophila Proteins; C439909:imd protein, Drosophila; C017142:cobinamide