International journal of antimicrobial agents · 2025
Downregulation of an NfsA-like nitroreductase causes metronidazole resistance in Gardnerella vaginalis.
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Paunkov Ana, Mayr Anna-Lena, Oberbauer Vera, Schwebs Timo, Corsini Lorenzo, Leitsch David
Аннотация
OBJECTIVES: The facultatively anaerobic or microaerophilic bacteria of the genus Gardnerella are the most common species associated with bacterial vaginosis (BV). The treatment of BV is greatly complicated by the high rates of resistance to metronidazole and clindamycin among Gardnerella strains. We wanted to identify factors contributing to metronidazole resistance in G. vaginalis and performed high-throughput mass spectrometry on a selection of susceptible and resistant strains.
METHODS: We wanted to identify factors contributing to metronidazole resistance in G. vaginalis and performed high-throughput mass spectrometry on a selection of susceptible and resistant strains.
RESULTS: We identified the downregulation of a novel nitroreductase, GvNR1, as the only relevant change in protein expression in a metronidazole-resistant derivative of the susceptible type of strain ATCC 14018 (emended Gardnerella genospecies 1; i.e. G. vaginalis sensu stricto). When tested in in vitro enzyme assays, GvNR1 displayed very marked nitroreductase activity with several nitro drugs, including metronidazole and other 5-nitroimidazoles. GvNR1 also rendered Escherichia coli BL21-AI much more susceptible to metronidazole when expressed in this strain. In metronidazole-resistant G. vaginalis clinical isolates (>8 µg/mL according to Clinical and Laboratory Standards Institute), GvNR1 was found to be downregulated as well. In resistant clinical strains 33 other proteins were found to be differentially expressed. Of note, these include thioredoxin reductase and vaginolysin. The lowered expression levels of GvNR1 in resistant strains were not caused by mutations in the GvNR1 gene or in sequences directly flanking the gene but by downregulation of mRNA expression. This might explain why G. vaginalis becomes resistant to metronidazole so rapidly.
CONCLUSIONS: We propose GvNR1 as a novel metronidazole resistance determinant in G. vaginalis.
METHODS: We wanted to identify factors contributing to metronidazole resistance in G. vaginalis and performed high-throughput mass spectrometry on a selection of susceptible and resistant strains.
RESULTS: We identified the downregulation of a novel nitroreductase, GvNR1, as the only relevant change in protein expression in a metronidazole-resistant derivative of the susceptible type of strain ATCC 14018 (emended Gardnerella genospecies 1; i.e. G. vaginalis sensu stricto). When tested in in vitro enzyme assays, GvNR1 displayed very marked nitroreductase activity with several nitro drugs, including metronidazole and other 5-nitroimidazoles. GvNR1 also rendered Escherichia coli BL21-AI much more susceptible to metronidazole when expressed in this strain. In metronidazole-resistant G. vaginalis clinical isolates (>8 µg/mL according to Clinical and Laboratory Standards Institute), GvNR1 was found to be downregulated as well. In resistant clinical strains 33 other proteins were found to be differentially expressed. Of note, these include thioredoxin reductase and vaginolysin. The lowered expression levels of GvNR1 in resistant strains were not caused by mutations in the GvNR1 gene or in sequences directly flanking the gene but by downregulation of mRNA expression. This might explain why G. vaginalis becomes resistant to metronidazole so rapidly.
CONCLUSIONS: We propose GvNR1 as a novel metronidazole resistance determinant in G. vaginalis.