Nim-mediated Metronidazole Resistance in Bacteroides fragilis

The anaerobic bacterium Bacteroides fragilis is an abundant human gut commensal but also one of the most important anaerobic bacterial pathogens in man. Unfortunately, Bacteroides spp. very quickly acquire resistance to a large number of antibiotics and are even intrinsically resistant to aminoglycosides. At present, the carbapenems and the 5-nitroimidazole drug metronidazole are the most reliable treatment options.Metronidazole resistance in B. fragilis is mainly attributed to so-called Nim proteins which are predominantly plasmid-encoded. Originally, Nim proteins were hypothesized to act as nitroreductases and to reduce metronidazole to a hardly reactive aminoimidazole by transferring six electrons. However, our recently published findings suggest that this is unlikely to be the case and that Nim proteins confer resistance to metronidazole differently because no correlation could be found between expression levels of Nim and the level of metronidazole resistance conferred. It is also presently unclear why metronidazole resistance occurs only in a fraction of B. fragilis strains which bear a nim gene. Based on above-stated observations and preliminary unpublished data, we hypothesize that Nim proteins have a deeper impact on the physiology of B. fragilis and that metronidazole resistance is mediated in a more indirect fashion than previously anticipated. It will be the aim of this binational project, involving two work groups from Vienna (Austria) and one from Szeged (Hungary), to deepen our understanding of Nim-mediated metronidazole resistance in B. fragilis by applying a varied range of analytic and biochemical methods, including Fourier-transformed infrared spectroscopy (FTIR), lipid profiling, oxygen scavenging measurements, comparative mRNA profiling in nim-positive and nim-negative cell lines of the same isolate (Bf 638R), and co-immunoprecipitation experiments using Nim proteins as “bait”. We expect to identify the mode of action of Nim proteins, their interaction partners in the cell and the physiological changes induced. Finally, we plan to confirm our findings obtained with strain Bf 638R in a large selection of clinical B. fragilis isolates, covering nim-positive and nim-negative strains alike.We argue that this undertaking is timely and necessary because reports on an increasing number of metronidazole-resistant clinical Bacteroides isolates stress the urge to gain a better understanding of metronidazole resistance in B. fragilis.

FWF Joint Projects

Zentrum für Pathobiologie

University of Szeged
Funktion: Partner
Abteilung: Department of Clinical Microbiology
Medizinische Universität Wien - AKH
Funktion: ProjektkoordinationGesamt
Abteilung: Institut für Spezifische Prophylaxe und Tropenmedizin, Zentrum für Pathophysiologie, Infektiologie und Immunologie,