{"id":"29c079de-1c26-5b30-87f2-69c1608f1afd","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-phe200-causes-resistance","predicate":"causes","statement":"All Haemonchus contortus tub-1 constructs encoding phenylalanine at position 200 conferred susceptibility to thiabendazole in benzimidazole-resistant Caenorhabditis elegans ben-1 mutants, whereas constructs carrying tyrosine at position 200 did not alter the resistant phenotype, leading to the conclusion that the single phenylalanine to tyrosine mutation at position 200 in beta-tubulin isotype 1 is the cause of benzimidazole resistance in Haemonchus contortus.","claim_class":"mechanistic","status":"source_derived_draft","evidence_grade":"ungraded","direction":"positive","is_public":true,"mechanism_event_id":"820e5233-c83e-516f-bef1-fbed8fe4c6a0","mechanism_event_label":"Swapping one amino acid back made resistant worms susceptible again, which makes it the cause and not a coincidence.","subject":{"id":"3716d82b-3309-5cc0-bf65-3ac9db11d932","slug":"beta-tubulin-tyr200","display_name":"Beta-tubulin carrying tyrosine at position 200","entity_type_key":"protein_state"},"object":{"id":"de0d4926-764b-531e-8fb9-961449221d21","slug":"benzimidazole-resistance","display_name":"Resistance to benzimidazole anthelmintics","entity_type_key":"cellular_process"},"evidence_count":1,"mechanism_event":{"id":"820e5233-c83e-516f-bef1-fbed8fe4c6a0","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-phe200-causes-resistance-event","event_type":"biochemical_relationship","label":"Swapping one amino acid back made resistant worms susceptible again, which makes it the cause and not a coincidence.","description":"All Haemonchus contortus tub-1 constructs encoding phenylalanine at position 200 conferred susceptibility to thiabendazole in benzimidazole-resistant Caenorhabditis elegans ben-1 mutants, whereas constructs carrying tyrosine at position 200 did not alter the resistant phenotype, leading to the conclusion that the single phenylalanine to tyrosine mutation at position 200 in beta-tubulin isotype 1 is the cause of benzimidazole resistance in Haemonchus contortus.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"a3f869c2-29ea-5655-99b1-616663462650","slug":"beta-tubulin-phe200","display_name":"Beta-tubulin carrying phenylalanine at position 200","entity_type_key":"protein_state"},"role":"susceptible_state","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"e92b4293-1cac-52a9-be7a-45492aaa6170","slug":"celegans-ben1-mutant","display_name":"The benzimidazole-resistant Caenorhabditis elegans ben-1 mutant","entity_type_key":"protein_state"},"role":"host_genotype","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c557d26e-4eee-5ce2-aef1-8cef5e87fe5e","slug":"thiabendazole","display_name":"Thiabendazole","entity_type_key":"drug"},"role":"assay_drug","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"831caace-2d1f-5f66-ace1-655fea2127b9","slug":"benomyl","display_name":"Benomyl","entity_type_key":"chemical_species"},"role":"assay_drug","stoichiometry":null,"state_label":"","sequence_order":3,"notes":""},{"entity":{"id":"bd64884e-6ee7-55df-9993-c2887f5a50df","slug":"nematode-beta-tubulin","display_name":"Nematode beta-tubulin","entity_type_key":"protein"},"role":"affected_protein","stoichiometry":null,"state_label":"","sequence_order":4,"notes":""},{"entity":{"id":"3716d82b-3309-5cc0-bf65-3ac9db11d932","slug":"beta-tubulin-tyr200","display_name":"Beta-tubulin carrying tyrosine at position 200","entity_type_key":"protein_state"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":5,"notes":""},{"entity":{"id":"de0d4926-764b-531e-8fb9-961449221d21","slug":"benzimidazole-resistance","display_name":"Resistance to benzimidazole anthelmintics","entity_type_key":"cellular_process"},"role":"target","stoichiometry":null,"state_label":"","sequence_order":6,"notes":""}]},"contexts":[{"dimension":"availability_state","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null},{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/mebendazole-research/7877171.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"091ba3ac445b68112bac29dec56d0d1a48e0d258714ebdbe090b5e7728e6ceaa\", \"start_char\": 0, \"end_char\": 1532, \"text_sha256\": \"091ba3ac445b68112bac29dec56d0d1a48e0d258714ebdbe090b5e7728e6ceaa\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Heterologous expression of Haemonchus contortus beta-tubulin alleles in Caenorhabditis elegans ben-1 mutants","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Parasite benzimidazole-sensitive and resistant alleles and in vitro mutagenised constructs, assayed with benomyl and thiabendazole","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A functional test rather than an association: the alleles were put into a resistant host and the phenotype followed the codon. The assay drugs were benomyl and thiabendazole rather than mebendazole.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"nutrient_topic","value_text":"Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.","comparator":null,"unit":null,"notes":"","entity":{"slug":"mebendazole","display_name":"Mebendazole","entity_type_key":"drug"}},{"dimension":"organism","value_text":"Nematode","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"plain_language","value_text":"Swapping one amino acid back made resistant worms susceptible again, which makes it the cause and not a coincidence.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[mbz-p7877171] Beta-tubulin genes from the parasitic nematode Haemonchus contortus modulate drug resistance in Caenorhabditis elegans. (1995). https://pubmed.ncbi.nlm.nih.gov/7877171/ DOI: 10.1006/jmbi.1994.0102","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Beta-tubulin isotype 1","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"trigger_kind","value_text":"machinery_impairment","comparator":null,"unit":null,"notes":"Imported condition classification; unverified.","entity":null}],"evidence":[{"id":"bba1897a-145b-5706-ac8c-371cb20a9a69","evidence_kind":"source_excerpt","locator":"Lines 264-275","start_line":264,"end_line":275,"excerpt":"### mbz-phe200-causes-resistance\nAll Haemonchus contortus tub-1 constructs encoding phenylalanine at position 200 conferred susceptibility to thiabendazole in benzimidazole-resistant Caenorhabditis elegans ben-1 mutants, whereas constructs carrying tyrosine at position 200 did not alter the resistant phenotype, leading to the conclusion that the single phenylalanine to tyrosine mutation at position 200 in beta-tubulin isotype 1 is the cause of benzimidazole resistance in Haemonchus contortus.\nCondition category: machinery_impairment\nnutrient_topic: Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.\nplain_language: Swapping one amino acid back made resistant worms susceptible again, which makes it the cause and not a coincidence.\norganism: Nematode\ntissue_or_cell_type: Beta-tubulin isotype 1\nexperimental_model: Heterologous expression of Haemonchus contortus beta-tubulin alleles in Caenorhabditis elegans ben-1 mutants\nlimitations: A functional test rather than an association: the alleles were put into a resistant host and the phenotype followed the codon. The assay drugs were benomyl and thiabendazole rather than mebendazole.\nexposure: Parasite benzimidazole-sensitive and resistant alleles and in vitro mutagenised constructs, assayed with benomyl and thiabendazole\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/7877171.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"091ba3ac445b68112bac29dec56d0d1a48e0d258714ebdbe090b5e7728e6ceaa\", \"start_char\": 0, \"end_char\": 1532, \"text_sha256\": \"091ba3ac445b68112bac29dec56d0d1a48e0d258714ebdbe090b5e7728e6ceaa\"}\n[mbz-p7877171] Beta-tubulin genes from the parasitic nematode Haemonchus contortus modulate drug resistance in Caenorhabditis elegans. (1995). https://pubmed.ncbi.nlm.nih.gov/7877171/ DOI: 10.1006/jmbi.1994.0102","model_system":"Heterologous expression of Haemonchus contortus beta-tubulin alleles in Caenorhabditis elegans ben-1 mutants","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [mbz-p7877171] Beta-tubulin genes from the parasitic nematode Haemonchus contortus modulate drug resistance in Caenorhabditis elegans. (1995). https://pubmed.ncbi.nlm.nih.gov/7877171/ DOI: 10.1006/jmbi.1994.0102","relationship":"supports","weight":1.0,"link_notes":"","source":{"id":"06104773-03d0-5e5c-b9da-eb484e7be657","stable_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","title":"Mebendazole: the tubulin it binds, why that is selective, the crystal form that decides whether any of it works, and the off-target that became an oncology programme (2026-09-22)","document_type":"imported_text","citation_label":"AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text.","file_path":"","sha256":"58b652636677e5033fd1dd555744485fcef18f21a97dcf68723fe072b656f413","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","review_status":"unverified_draft","notes":""}}],"relations":[],"conflicts":[{"id":"7fb3c422-5b25-5d6c-a2f4-59036b214fc8","title":"Is the phenylalanine to tyrosine change at codon 200 what makes a parasite resistant?","kind":"contradiction","status":"open","why":"Putting Haemonchus contortus beta-tubulin alleles into resistant Caenorhabditis elegans showed the phenotype following the codon exactly: Phe200 restored susceptibility, Tyr200 did not, which makes the substitution causal in that species. Albendazole-resistant Giardia lines selected in culture carried no mutation at codon 200 at all, and their authors concluded that phenylalanine at position 200 is not necessary for resistance; what those lines did show was chromosome rearrangement and a visibly altered cytoskeleton. A third record found three beta-tubulin cDNAs in Haemonchus contortus with sequences similar or identical to two of them present in both sensitive and resistant populations, so more than one gene product is in play even in the species where the codon rule was established. The organisms differ, a nematode against a protozoan, and the selecting drug differs. Codon 200 is one route to resistance and these records do not make it the only one.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 05:04:17","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/7fb3c422-5b25-5d6c-a2f4-59036b214fc8","sides":[{"conflict_id":"7fb3c422-5b25-5d6c-a2f4-59036b214fc8","ordinal":0,"label":"Swapping one amino acid back made resistant worms susceptible again, which makes it the cause and not a coincidence.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":264,"end_line":275,"quote":"### mbz-phe200-causes-resistance\nAll Haemonchus contortus tub-1 constructs encoding phenylalanine at position 200 conferred susceptibility to thiabendazole in benzimidazole-resistant Caenorhabditis elegans ben-1 mutants, whereas constructs carrying tyrosine at position 200 did not alter the resistant phenotype, leading to the conclusion that the single phenylalanine to tyrosine mutation at position 200 in beta-tubulin isotype 1 is the cause of benzimidazole resistance in Haemonchus contortus.\nCondition category: machinery_impairment\nnutrient_topic: Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.\nplain_language: Swapping one amino acid back made resistant worms susceptible again, which makes it the cause and not a coincidence.\norganism: Nematode\ntissue_or_cell_type: Beta-tubulin isotype 1\nexperimental_model: Heterologous expression of Haemonchus contortus beta-tubulin alleles in Caenorhabditis elegans ben-1 mutants\nlimitations: A functional test rather than an association: the alleles were put into a resistant host and the phenotype followed the codon. The assay drugs were benomyl and thiabendazole rather than mebendazole.\nexposure: Parasite benzimidazole-sensitive and resistant alleles and in vitro mutagenised constructs, assayed with benomyl and thiabendazole\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/7877171.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"091ba3ac445b68112bac29dec56d0d1a48e0d258714ebdbe090b5e7728e6ceaa\", \"start_char\": 0, \"end_char\": 1532, \"text_sha256\": \"091ba3ac445b68112bac29dec56d0d1a48e0d258714ebdbe090b5e7728e6ceaa\"}\n[mbz-p7877171] Beta-tubulin genes from the parasitic nematode Haemonchus contortus modulate drug resistance in Caenorhabditis elegans. (1995). https://pubmed.ncbi.nlm.nih.gov/7877171/ DOI: 10.1006/jmbi.1994.0102","source_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","source_title":"Mebendazole: the tubulin it binds, why that is selective, the crystal form that decides whether any of it works, and the off-target that became an oncology programme (2026-09-22)","claim_ids":["29c079de-1c26-5b30-87f2-69c1608f1afd"]},{"conflict_id":"7fb3c422-5b25-5d6c-a2f4-59036b214fc8","ordinal":1,"label":"Resistant parasites that never touched the famous mutation, so it cannot be the only route.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":277,"end_line":288,"quote":"### mbz-resistance-without-codon-200\nAlbendazole-resistant Giardia lines showed major chromosome rearrangements and differences in the cytoskeleton, particularly the median body, implicating the cytoskeleton in the mechanism of resistance, but sequence data spanning the region encoding phenylalanine at position 200 demonstrated that the beta-tubulin gene did not carry a mutation at that codon, suggesting that phenylalanine at position 200 is not necessary for benzimidazole resistance.\nCondition category: normal\nnutrient_topic: Mebendazole research collection; topical membership is not evidence of a direct clinical effect, and mebendazole is recorded separately from albendazole, from the benzimidazole class and from its own crystal forms.\nplain_language: Resistant parasites that never touched the famous mutation, so it cannot be the only route.\norganism: Giardia\ntissue_or_cell_type: Cytoskeleton and beta-tubulin gene\nexperimental_model: Albendazole resistance induced in three Giardia cultures by stepwise drug exposure, with beta-tubulin sequencing\nlimitations: A counterexample obtained with albendazole rather than mebendazole, in a protozoan rather than a nematode. It is recorded because it tests the codon-200 rule directly and the rule fails.\nexposure: Growth in successively increasing albendazole, with immunofluorescence and PCR across codon 200\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/9158790.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"b1e25da8738886a9f416bb8411755eca925e232495786f938ef8f9afac40de30\", \"start_char\": 0, \"end_char\": 1295, \"text_sha256\": \"b1e25da8738886a9f416bb8411755eca925e232495786f938ef8f9afac40de30\"}\n[mbz-p9158790] Albendazole resistance in Giardia is correlated with cytoskeletal changes but not with a mutation at amino acid 200 in beta-tubulin. (1996). https://pubmed.ncbi.nlm.nih.gov/9158790/ DOI: 10.1089/mdr.1996.2.303","source_key":"import-f2ec2007-88ff-5a96-a73b-8b5085e9cea9","source_title":"Mebendazole: the tubulin it binds, why that is selective, the crystal form that decides whether any of it works, and the off-target that became an oncology programme (2026-09-22)","claim_ids":["d8eb0d01-e2e1-5749-9ea3-62d148ee58f2"]}]}],"corrections":[],"research":null}