title: Nitric oxide-dependent killing of aerobic, anaerobic and persistent Burkholderia pseudomallei.
abstract: Burkholderia pseudomallei infections are fastidious to treat with conventional antibiotic therapy, often involving a combination of drugs and long-term regimes. Bacterial genetic determinants contribute to the resistance of B. pseudomallei to many classes of antibiotics. In addition, anaerobiosis and hypoxia in abscesses typical of melioidosis select for persistent populations of B. pseudomallei refractory to a broad spectrum of antibacterials. We tested the susceptibility of B. pseudomallei to the drugs hydroxyurea, spermine NONOate and DETA NONOate that release nitric oxide (NO). Our investigations indicate that B. pseudomallei are killed by NO in a concentration and time-dependent fashion. The cytoxicity of this diatomic radical against B. pseudomallei depends on both the culture medium and growth phase of the bacteria. Rapidly growing, but not stationary phase, B. pseudomallei are readily killed upon exposure to the NO donor spermine NONOate. NO also has excellent antimicrobial activity against anaerobic B. pseudomallei. In addition, persistent bacteria highly resistant to most conventional antibiotics are remarkably susceptible to NO. Sublethal concentrations of NO inhibited the enzymatic activity of [4Fe-4S]-cofactored aconitase of aerobic and anaerobic B. pseudomallei. The strong anti-B. pseudomallei activity of NO described herein merits further studies on the application of NO-based antibiotics for the treatment of melioidosis.
authors.affiliation: Department of Microbiology, University of Colorado School of Medicine, Aurora, CO 80045, United States.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jones-Carson
authors.forename: James R
authors.initials: JR
authors.lastname: Laughlin
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Stewart
authors.forename: Martin I
authors.initials: MI
authors.lastname: Voskuil
authors.forename: Andrés
authors.initials: A
authors.lastname: Vázquez-Torres
mesh_terms: D000154:Aconitate Hydratase / Q000187:drug effects / Q000378:metabolism; D000693:Anaerobiosis; D000900:Anti-Bacterial Agents / Q000378:metabolism / Q000494:pharmacology*; D016957:Burkholderia pseudomallei / Q000187:drug effects* / Q000502:physiology; D003470:Culture Media; D006801:Humans; D008554:Melioidosis / Q000382:microbiology; D008826:Microbial Sensitivity Tests; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000378:metabolism / Q000494:pharmacology; D009603:Nitroso Compounds / Q000378:metabolism / Q000494:pharmacology; D013096:Spermine / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000900:Anti-Bacterial Agents; D003470:Culture Media; D020030:Nitric Oxide Donors; D009603:Nitroso Compounds; C091861:spermine nitric oxide complex; C094210:2,2'-(hydroxynitrosohydrazono)bis-ethanamine; D013096:Spermine; D009569:Nitric Oxide; D000154:Aconitate Hydratase