title: Nitric oxide protects bacteria from aminoglycosides by blocking the energy-dependent phases of drug uptake.
abstract: Our investigations have identified a mechanism by which exogenous production of nitric oxide (NO) induces resistance of Gram-positive and -negative bacteria to aminoglycosides. An NO donor was found to protect Salmonella spp. against structurally diverse classes of aminoglycosides of the 4,6-disubstituted 2-deoxystreptamine group. Likewise, NO generated enzymatically by inducible NO synthase of gamma interferon-primed macrophages protected intracellular Salmonella against the cytotoxicity of gentamicin. NO levels that elicited protection against aminoglycosides repressed Salmonella respiratory activity. NO nitrosylated terminal quinol cytochrome oxidases, without exerting long-lasting inhibition of NADH dehydrogenases of the electron transport chain. The NO-mediated repression of respiratory activity blocked both energy-dependent phases I and II of aminoglycoside uptake but not the initial electrostatic interaction of the drug with the bacterial cell envelope. As seen in Salmonella, the NO-dependent inhibition of the electron transport chain also afforded aminoglycoside resistance to the clinically important pathogens Pseudomonas aeruginosa and Staphylococcus aureus. Together, these findings provide evidence for a model in which repression of aerobic respiration by NO fluxes associated with host inflammatory responses can reduce drug uptake, thus promoting resistance to several members of the aminoglycoside family in phylogenetically diverse bacteria.
authors.affiliation: Department of Microbiology, Mail Box 8333, University of Colorado School of Medicine, P.O. Box 6511, Room P18-9131, Aurora, CO 80045, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: McCollister
authors.forename: Matthew
authors.initials: M
authors.lastname: Hoffman
authors.forename: Maroof
authors.initials: M
authors.lastname: Husain
authors.forename: Andrés
authors.initials: A
authors.lastname: Vázquez-Torres
mesh_terms: D000617:Aminoglycosides / Q000378:metabolism* / Q000494:pharmacology*; D000900:Anti-Bacterial Agents / Q000378:metabolism* / Q000494:pharmacology*; D001692:Biological Transport / Q000187:drug effects*; D009569:Nitric Oxide / Q000494:pharmacology*; D011550:Pseudomonas aeruginosa / Q000187:drug effects; D013211:Staphylococcus aureus / Q000187:drug effects
chemical_list: D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D009569:Nitric Oxide