Abstract
BackgroundNitric 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.ResultsFour 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.ConclusionAn NO-donor in combination with miconazole and PMBN showed enhanced antimicrobial effects and proved effective against multidrug-resistant ESBL-producing uropathogenic E. coli.
Highlights
Nitric oxide (NO) is produced as part of the host immune response to bacterial infections, including urinary tract infections
The antibacterial effect of DETA/NO The antibacterial effect of the NO-donor DETA/NO on the ESBL-producing isolates was compared with the effect of the established antibiotics cefotaxime and nitrofurantoin after exposure for 8 h
The ESBL isolates 1 and 7, representing the most and the least DETA/NO-sensitive isolates were further evaluated by time-course studies after exposure to DETA/NO, cefotaxime and nitrofurantoin for 2, 4, and 8 h (Figure 2)
Summary
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. Flavohemoglobin, encoded by the hmp gene [8], is a protein that has been shown to have NO dioxygenase activity [8] and be involved in protecting bacterial cells from nitrosative stress [9,10]. The significance of flavohemoglobin in NO-protection has been shown using hmp-deficient mutants that are more sensitive to NO and nitrosative stress [8,11]. Elevated hmp expression was found in UPEC isolates isolated from patients with UTI, suggesting that UPEC isolates face host-derived nitrosative stress during human UTI and activate the NO-detoxifying enzyme flavohemoglobin [12]
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