Background: Nitric oxide (NO) is produced as part of the host immune response to bacterial infections, including\r\nurinary tract infections. The enzyme flavohemoglobin, coded by the hmp gene, is involved in protecting bacterial\r\ncells from the toxic effects of NO and represents a potentially interesting target for development of novel\r\ntreatment concepts against resistant uropathogenic bacteria. The aim of the present study was to investigate if\r\nthe in vitro antibacterial effects of NO can be enhanced by pharmacological modulation of the enzyme\r\nflavohemoglobin.\r\nResults: Four clinical isolates of multidrug-resistant extended-spectrum �Ÿ-lactamase (ESBL)-producing uropathogenic\r\nE. coli were included in the study. It was shown that the NO-donor substance DETA/NO, but not inactivated DETA/NO,\r\ncaused an initial growth inhibition with regrowth noted after 8 h of exposure. An hmp-deficient strain showed a\r\nprolonged growth inhibition in response to DETA/NO compared to the wild type. The imidazole antibiotic miconazole,\r\nthat has been shown to inhibit bacterial flavohemoglobin activity, prolonged the DETA/NO-evoked growth inhibition.\r\nWhen miconazole was combined with polymyxin B nonapeptide (PMBN), in order to increase the bacterial wall\r\npermeability, DETA/NO caused a prolonged bacteriostatic response that lasted for up to 24 h.\r\nConclusion: An NO-donor in combination with miconazole and PMBN showed enhanced antimicrobial effects and\r\nproved effective against multidrug-resistant ESBL-producing uropathogenic E. coli.
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