title: Nitric oxide from IFNγ-primed macrophages modulates the antimicrobial activity of β-lactams against the intracellular pathogens Burkholderia pseudomallei and Nontyphoidal Salmonella.
abstract: Our investigations show that nonlethal concentrations of nitric oxide (NO) abrogate the antibiotic activity of β-lactam antibiotics against Burkholderia pseudomallei, Escherichia coli and nontyphoidal Salmonella enterica serovar Typhimurium. NO protects B. pseudomallei already exposed to β-lactams, suggesting that this diatomic radical tolerizes bacteria against the antimicrobial activity of this important class of antibiotics. The concentrations of NO that elicit antibiotic tolerance repress consumption of oxygen (O2), while stimulating hydrogen peroxide (H2O2) synthesis. Transposon insertions in genes encoding cytochrome c oxidase-related functions and molybdenum assimilation confer B. pseudomallei a selective advantage against the antimicrobial activity of the β-lactam antibiotic imipenem. Cumulatively, these data support a model by which NO induces antibiotic tolerance through the inhibition of the electron transport chain, rather than by potentiating antioxidant defenses as previously proposed. Accordingly, pharmacological inhibition of terminal oxidases and nitrate reductases tolerizes aerobic and anaerobic bacteria to β-lactams. The degree of NO-induced β-lactam antibiotic tolerance seems to be inversely proportional to the proton motive force (PMF), and thus the dissipation of ΔH+ and ΔΨ electrochemical gradients of the PMF prevents β-lactam-mediated killing. According to this model, NO generated by IFNγ-primed macrophages protects intracellular Salmonella against imipenem. On the other hand, sublethal concentrations of imipenem potentiate the killing of B. pseudomallei by NO generated enzymatically from IFNγ-primed macrophages. Our investigations indicate that NO modulates the antimicrobial activity of β-lactam antibiotics.
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America; Division of Infectious Diseases, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Jessica
authors.initials: J
authors.lastname: Jones-Carson
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Adrienne E
authors.initials: AE
authors.lastname: Zweifel
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Timothy
authors.initials: T
authors.lastname: Tapscott
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Chad
authors.initials: C
authors.lastname: Austin
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Department of Biochemistry and Molecular Genetics, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Jones
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America.
authors.forename: Martin I
authors.initials: MI
authors.lastname: Voskuil
authors.affiliation: Department of Immunology and Microbiology, University of Colorado School of Medicine, Aurora, Colorado, United States of America; Veterans Affairs Eastern Colorado Health Care System, Denver, Colorado, United States of America.
authors.forename: Andrés
authors.initials: A
authors.lastname: Vázquez-Torres
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D016957:Burkholderia pseudomallei / Q000187:drug effects*; D002478:Cells, Cultured; D015378:Imipenem / Q000494:pharmacology*; D007371:Interferon-gamma / Q000494:pharmacology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D009569:Nitric Oxide / Q000502:physiology*; D018384:Oxidative Stress; D018892:Proton-Motive Force; D012486:Salmonella typhimurium / Q000187:drug effects*
chemical_list: D000900:Anti-Bacterial Agents; D009569:Nitric Oxide; D015378:Imipenem; D007371:Interferon-gamma