The Role of Iron Status in the Early Progression of Metronidazole Resistance in Trichomonas vaginalis Under Microaerophilic Conditions

Trichomonas vaginalis is the etiological agent of human trichomoniasis. Metronidazole has high treatment success rate among trichomoniasis patients. However, metronidazole‐resistant T. vaginalis has been reported, contributing in an increasing number of refractory cases. The mechanism of metronidazole resistance in this parasite is still unclear. In the vaginal environment, where the microaerophilic conditions prevail but the iron concentration is constantly fluctuating, the metronidazole resistance profile of T. vaginalis could be altered. In this study, we developed metronidazole‐resistant strains of T. vaginalis and evaluate if iron availability is important to the action of the drug. The modulation of iron levels and iron chelation affected the actions of metronidazole both in susceptible and resistant strains. Interestingly, the early resistant strains exhibited minor iron content. The results of transcription analysis in the early resistant strains showed dysregulation in the expression of genes that codified proteins involved in iron transporter, iron–sulfur cluster assemblage, and oxidative stress response, which could not be observed in the late resistant and susceptible strains. Our results indicate that iron content plays an important role in the metronidazole action in T. vaginalis and likely to be related to iron–sulfur proteins involved in metronidazole activation and oxidative stress via Fenton reaction.