title: The antibacterial effect of nitric oxide against ESBL-producing uropathogenic E. coli is improved by combination with miconazole and polymyxin B nonapeptide.
abstract: BACKGROUND
  Nitric oxide (NO) is produced as part of the host immune response to bacterial infections, including urinary tract infections. The enzyme flavohemoglobin, coded by the hmp gene, is involved in protecting bacterial cells from the toxic effects of NO and represents a potentially interesting target for development of novel treatment concepts against resistant uropathogenic bacteria. The aim of the present study was to investigate if the in vitro antibacterial effects of NO can be enhanced by pharmacological modulation of the enzyme flavohemoglobin.
  
  
  RESULTS
  Four clinical isolates of multidrug-resistant extended-spectrum β-lactamase (ESBL)-producing uropathogenic E. coli were included in the study. It was shown that the NO-donor substance DETA/NO, but not inactivated DETA/NO, caused an initial growth inhibition with regrowth noted after 8 h of exposure. An hmp-deficient strain showed a prolonged growth inhibition in response to DETA/NO compared to the wild type. The imidazole antibiotic miconazole, that has been shown to inhibit bacterial flavohemoglobin activity, prolonged the DETA/NO-evoked growth inhibition. When miconazole was combined with polymyxin B nonapeptide (PMBN), in order to increase the bacterial wall permeability, DETA/NO caused a prolonged bacteriostatic response that lasted for up to 24 h.
  
  
  CONCLUSIONS
  An NO-donor in combination with miconazole and PMBN showed enhanced antimicrobial effects and proved effective against multidrug-resistant ESBL-producing uropathogenic E. coli.
authors.forename: Charlotte Sahlberg
authors.initials: CS
authors.lastname: Bang
authors.forename: Annica
authors.initials: A
authors.lastname: Kinnunen
authors.forename: Marie
authors.initials: M
authors.lastname: Karlsson
authors.forename: Anna
authors.initials: A
authors.lastname: Önnberg
authors.forename: Bo
authors.initials: B
authors.lastname: Söderquist
authors.affiliation: Faculty of Medicine and Health, iRiSC - Inflammatory Response and Infection Susceptibility Centre, Örebro University, SE- 701 82 Örebro, Sweden. katarina.persson@oru.se.
authors.forename: Katarina
authors.initials: K
authors.lastname: Persson
mesh_terms: D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D004093:Dihydropteridine Reductase / Q000378:metabolism*; D004357:Drug Synergism; D029968:Escherichia coli Proteins / Q000378:metabolism*; D006420:Hemeproteins / Q000378:metabolism*; D006801:Humans; D008825:Miconazole / Q000494:pharmacology*; D008826:Microbial Sensitivity Tests; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism*; D053758:Nanoparticles / Q000378:metabolism; D009569:Nitric Oxide / Q000494:pharmacology*; D011112:Polymyxin B / Q000031:analogs & derivatives* / Q000494:pharmacology; D056689:Uropathogenic Escherichia coli / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D001618:beta-Lactamases / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D029968:Escherichia coli Proteins; D006420:Hemeproteins; D009569:Nitric Oxide; D008825:Miconazole; C038934:polymyxin B nonapeptide; D004093:Dihydropteridine Reductase; C076538:hmp protein, E coli; D009247:NADH, NADPH Oxidoreductases; D001618:beta-Lactamases; D011112:Polymyxin B