Journal
BIOMEDICINES
Volume 9, Issue 12, Pages -Publisher
MDPI
DOI: 10.3390/biomedicines9121817
Keywords
trichomoniasis; drug resistance; ABC transporter; ERAD
Categories
Funding
- Ministry of Science and Technology, Taiwan [MOST 110-2740-B-400-002, MOST 108-2221-E-182-043-MY3]
- National Defense Medical Center, Taiwan [MAB-108-073, MAB-109-054]
- Chang Gung Memorial Hospital Research Fund [CMRPD1I0131/2/3]
- Tri-Service General Hospital, Taiwan [TSGH-E-110268]
- [MOST 110-2320-B-016-011-MY3]
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Trichomonas vaginalis is the causative agent of trichomoniasis, a common sexually transmitted infection. Metronidazole (MTZ) is the main treatment, but drug resistance is a growing concern. RNA sequencing of MTZ-resistant and MTZ-sensitive strains revealed upregulation of drug-resistant genes and novel pathways related to drug-induced stress.
Trichomonas vaginalis is the causative agent of trichomoniasis, the most prevalent non-viral sexually transmitted infection worldwide. Metronidazole (MTZ) is the mainstay of anti-trichomonal chemotherapy; however, drug resistance has become an increasingly worrying issue. Additionally, the molecular events of MTZ-induced cell death in T. vaginalis remain elusive. To gain insight into the differential expression of genes related to MTZ resistance and cell death, we conducted RNA-sequencing of three paired MTZ-resistant (MTZ-R) and MTZ-sensitive (MTZ-S) T. vaginalis strains treated with or without MTZ. Comparative transcriptomes analysis identified that several putative drug-resistant genes were exclusively upregulated in different MTZ-R strains, such as ATP-binding cassette (ABC) transporters and multidrug resistance pumps. Additionally, several shared upregulated genes among all the MTZ-R transcriptomes were not previously identified in T. vaginalis, such as 5 '-nucleotidase surE and Na+-driven multidrug efflux pump, which are a potential stress response protein and a multidrug and toxic compound extrusion (MATE)-like protein, respectively. Functional enrichment analysis revealed that purine and pyrimidine metabolisms were suppressed in MTZ-S parasites upon drug treatment, whereas the endoplasmic reticulum-associated degradation (ERAD) pathway, proteasome, and ubiquitin-mediated proteolysis were strikingly activated, highlighting the novel pathways responsible for drug-induced stress. Our work presents the most detailed analysis of the transcriptional changes and the regulatory networks associated with MTZ resistance and MTZ-induced signaling, providing insights into MTZ resistance and cell death mechanisms in trichomonads.
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