Parasites & vectors · 2020
Proteomic signatures of metronidazole-resistant Trichomonas vaginalis reveal novel proteins associated with drug resistance.
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Lin Hsin-Chung, Chu Lichieh Julie, Huang Po-Jung, Cheng Wei-Hung, Zheng Yu-Hsing, Huang Ching-Yun, Hong Shu-Wen, Chen Lih-Chyang, Lin Hsin-An, Wang Jui-Yang, Chen Ruei-Min, Lin Wei-Ning, Tang Petrus, Huang Kuo-Yang
Аннотация
BACKGROUND: Trichomoniasis is the most common non-viral sexually transmitted disease caused by the protozoan parasite Trichomonas vaginalis. Metronidazole (MTZ) is a widely used drug for the treatment of trichomoniasis; however, increased resistance of the parasite to MTZ has emerged as a highly problematic public health issue.
METHODS: We conducted iTRAQ-based analysis to profile the proteomes of MTZ-sensitive (MTZ-S) and MTZ-resistant (MTZ-R) parasites. STRING and gene set enrichment analysis (GESA) were utilized to explore the protein-protein interaction networks and enriched pathways of the differentially expressed proteins, respectively. Proteins potentially related to MTZ resistance were selected for functional validation.
RESULTS: A total of 3123 proteins were identified from the MTZ-S and MTZ-R proteomes in response to drug treatment. Among the identified proteins, 304 proteins were differentially expressed in the MTZ-R proteome, including 228 upregulated and 76 downregulated proteins. GSEA showed that the amino acid-related metabolism, including arginine, proline, alanine, aspartate, and glutamate are the most upregulated pathways in the MTZ-R proteome, whereas oxidative phosphorylation is the most downregulated pathway. Ten proteins categorized into the gene set of oxidative phosphorylation were ATP synthase subunit-related proteins. Drug resistance was further examined in MTZ-S parasites pretreated with the ATP synthase inhibitors oligomycin and bafilomycin A1, showing enhanced MTZ resistance and potential roles of ATP synthase in drug susceptibility.
CONCLUSIONS: We provide novel insights into previously unidentified proteins associated with MTZ resistance, paving the way for future development of new drugs against MTZ-refractory trichomoniasis.
METHODS: We conducted iTRAQ-based analysis to profile the proteomes of MTZ-sensitive (MTZ-S) and MTZ-resistant (MTZ-R) parasites. STRING and gene set enrichment analysis (GESA) were utilized to explore the protein-protein interaction networks and enriched pathways of the differentially expressed proteins, respectively. Proteins potentially related to MTZ resistance were selected for functional validation.
RESULTS: A total of 3123 proteins were identified from the MTZ-S and MTZ-R proteomes in response to drug treatment. Among the identified proteins, 304 proteins were differentially expressed in the MTZ-R proteome, including 228 upregulated and 76 downregulated proteins. GSEA showed that the amino acid-related metabolism, including arginine, proline, alanine, aspartate, and glutamate are the most upregulated pathways in the MTZ-R proteome, whereas oxidative phosphorylation is the most downregulated pathway. Ten proteins categorized into the gene set of oxidative phosphorylation were ATP synthase subunit-related proteins. Drug resistance was further examined in MTZ-S parasites pretreated with the ATP synthase inhibitors oligomycin and bafilomycin A1, showing enhanced MTZ resistance and potential roles of ATP synthase in drug susceptibility.
CONCLUSIONS: We provide novel insights into previously unidentified proteins associated with MTZ resistance, paving the way for future development of new drugs against MTZ-refractory trichomoniasis.