{"id":"3e0cda27-4c9b-590f-8a56-12883b63de00","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-metabolism-does-not-explain-resistance","predicate":"preserves_measured_pool","statement":"Steady-state pool sizes of glucose and metabolic intermediates including adenine nucleotides and end products revealed no differences between adult Haemonchus contortus resistant or susceptible to benzimidazoles, all three strains had similar levels of total lipid, protein and free amino acid and produced a similar sum total of end products, and although the mebendazole-resistant strain showed a diversion of carbon flow to the ethanol-producing pathway and greater cyanide-sensitive aerobic carbon dioxide output, the extent to which these metabolic differences may be related to benzimidazole resistance is not readily apparent.","claim_class":"observational","status":"source_derived_draft","evidence_grade":"ungraded","direction":"neutral","is_public":true,"mechanism_event_id":"c1ffec03-8f54-57f3-a761-0b54213a9ca6","mechanism_event_label":"Resistant and susceptible worms handle sugar much the same, so metabolism is not where resistance lives.","subject":{"id":"a27d0e8e-c0e4-5d13-97e8-6d77a98ce546","slug":"parasite-carbohydrate-metabolism","display_name":"Carbohydrate and energy metabolism of the parasite","entity_type_key":"cellular_process"},"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":"c1ffec03-8f54-57f3-a761-0b54213a9ca6","stable_key":"f2ec2007-88ff-5a96-a73b-8b5085e9cea9:mbz-metabolism-does-not-explain-resistance-event","event_type":"observed_intervention","label":"Resistant and susceptible worms handle sugar much the same, so metabolism is not where resistance lives.","description":"Steady-state pool sizes of glucose and metabolic intermediates including adenine nucleotides and end products revealed no differences between adult Haemonchus contortus resistant or susceptible to benzimidazoles, all three strains had similar levels of total lipid, protein and free amino acid and produced a similar sum total of end products, and although the mebendazole-resistant strain showed a diversion of carbon flow to the ethanol-producing pathway and greater cyanide-sensitive aerobic carbon dioxide output, the extent to which these metabolic differences may be related to benzimidazole resistance is not readily apparent.","status":"provisional","compartment":null,"participants":[{"entity":{"id":"78b5cd33-ee52-51b1-be2c-d3b261c8fd34","slug":"trehalose","display_name":"Trehalose","entity_type_key":"small_molecule"},"role":"major_reserve","stoichiometry":null,"state_label":"","sequence_order":0,"notes":""},{"entity":{"id":"05c4c656-fd3f-55da-850b-3eea7fb0bc4b","slug":"glycogen","display_name":"Glycogen","entity_type_key":"chemical_species"},"role":"preferentially_used_reserve","stoichiometry":null,"state_label":"","sequence_order":1,"notes":""},{"entity":{"id":"c60e8dba-f098-513f-bcc6-d073a25f8d09","slug":"fumarate-reductase","display_name":"Fumarate reductase of Haemonchus contortus","entity_type_key":"protein"},"role":"related_proposal","stoichiometry":null,"state_label":"","sequence_order":2,"notes":""},{"entity":{"id":"a27d0e8e-c0e4-5d13-97e8-6d77a98ce546","slug":"parasite-carbohydrate-metabolism","display_name":"Carbohydrate and energy metabolism of the parasite","entity_type_key":"cellular_process"},"role":"subject","stoichiometry":null,"state_label":"","sequence_order":3,"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":4,"notes":""}]},"contexts":[{"dimension":"evidence_span","value_text":"{\"source_cache\": \"artifacts/mebendazole-research/6427605.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"4834a68834e7916938d61b08f8dc38fb00085c0b43761372c8ef883da0d8cbf8\", \"start_char\": 0, \"end_char\": 1809, \"text_sha256\": \"4834a68834e7916938d61b08f8dc38fb00085c0b43761372c8ef883da0d8cbf8\"}","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"experimental_model","value_text":"Biochemical comparison of susceptible, mebendazole-resistant and thiabendazole-resistant Haemonchus contortus in vitro","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"exposure","value_text":"Steady-state metabolite pools, end products and labelled carbon dioxide over 30 to 60 minute and 18 hour incubations","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"limitations","value_text":"A broad metabolic survey across matched resistant and susceptible strains. Its own authors state the relationship to resistance is not apparent.","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":"Resistant and susceptible worms handle sugar much the same, so metabolism is not where resistance lives.","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"primary_references","value_text":"[mbz-p6427605] Energy metabolism of adult Haemonchus contortus in vitro: a comparison of benzimidazole-susceptible and -resistant strains. (1984). https://pubmed.ncbi.nlm.nih.gov/6427605/ DOI: 10.1016/0166-6851(84)90031-8","comparator":null,"unit":null,"notes":"","entity":null},{"dimension":"tissue_or_cell_type","value_text":"Whole adult worms","comparator":null,"unit":null,"notes":"","entity":null}],"evidence":[{"id":"4f6f0b52-dfbb-51c2-872b-e576a666bef7","evidence_kind":"source_excerpt","locator":"Lines 342-353","start_line":342,"end_line":353,"excerpt":"### mbz-metabolism-does-not-explain-resistance\nSteady-state pool sizes of glucose and metabolic intermediates including adenine nucleotides and end products revealed no differences between adult Haemonchus contortus resistant or susceptible to benzimidazoles, all three strains had similar levels of total lipid, protein and free amino acid and produced a similar sum total of end products, and although the mebendazole-resistant strain showed a diversion of carbon flow to the ethanol-producing pathway and greater cyanide-sensitive aerobic carbon dioxide output, the extent to which these metabolic differences may be related to benzimidazole resistance is not readily apparent.\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 and susceptible worms handle sugar much the same, so metabolism is not where resistance lives.\norganism: Nematode\ntissue_or_cell_type: Whole adult worms\nexperimental_model: Biochemical comparison of susceptible, mebendazole-resistant and thiabendazole-resistant Haemonchus contortus in vitro\nlimitations: A broad metabolic survey across matched resistant and susceptible strains. Its own authors state the relationship to resistance is not apparent.\nexposure: Steady-state metabolite pools, end products and labelled carbon dioxide over 30 to 60 minute and 18 hour incubations\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/6427605.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"4834a68834e7916938d61b08f8dc38fb00085c0b43761372c8ef883da0d8cbf8\", \"start_char\": 0, \"end_char\": 1809, \"text_sha256\": \"4834a68834e7916938d61b08f8dc38fb00085c0b43761372c8ef883da0d8cbf8\"}\n[mbz-p6427605] Energy metabolism of adult Haemonchus contortus in vitro: a comparison of benzimidazole-susceptible and -resistant strains. (1984). https://pubmed.ncbi.nlm.nih.gov/6427605/ DOI: 10.1016/0166-6851(84)90031-8","model_system":"Biochemical comparison of susceptible, mebendazole-resistant and thiabendazole-resistant Haemonchus contortus in vitro","directness":"author_interpretation","verification_status":"source_derived_draft","notes":"Exact curation-document quotation, not publisher quotation. Study references: [mbz-p6427605] Energy metabolism of adult Haemonchus contortus in vitro: a comparison of benzimidazole-susceptible and -resistant strains. (1984). https://pubmed.ncbi.nlm.nih.gov/6427605/ DOI: 10.1016/0166-6851(84)90031-8","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":"279d63d9-6f1b-519d-ad61-30a5341c5b86","title":"Do differences in parasite energy metabolism account for benzimidazole resistance?","kind":"qualification","status":"open","why":"Two proposals were put and both were tested against matched resistant and susceptible Haemonchus contortus strains. Fumarate reductase activity was lower in one thiabendazole-resistant strain but unchanged in a mebendazole-resistant strain that was nonetheless cross-resistant to thiabendazole, and on reassessment two further resistant strains had activities indistinguishable from susceptible controls. A broader survey found no differences in glucose or metabolic intermediate pools, in lipid, protein or free amino acid, or in the total of end products, with the strain differences that did appear leaving their own authors unable to say whether they related to resistance. Both records qualify the metabolic account rather than supporting it, while the beta-tubulin records in this collection show a substitution that reverses the phenotype outright. The metabolic findings are retained because the same enzymes are proposed elsewhere in this collection as the drug target.","resolution":"Unresolved; needs review.","created_at":"2026-09-22 05:04:17","record_type":"conflict","display_label":"Recorded conflict","record_url":"/conflicts/279d63d9-6f1b-519d-ad61-30a5341c5b86","sides":[{"conflict_id":"279d63d9-6f1b-519d-ad61-30a5341c5b86","ordinal":0,"label":"A once-popular explanation for resistance, checked across strains and found not to hold.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":329,"end_line":340,"quote":"### mbz-fumarate-reductase-retired\nFumarate reductase activity in a thiabendazole-resistant Haemonchus contortus strain was significantly lower than in a susceptible strain, but activity in a mebendazole-resistant strain did not differ from the susceptible strain even though it was cross-resistant to thiabendazole, and on reassessment two American strains resistant to thiabendazole and to cambendazole had activities indistinguishable from corresponding susceptible strains, so that benzimidazole resistance cannot be generally correlated with diminished fumarate reductase activity although it may be a contributory factor in the specific Australian thiabendazole-resistant strains.\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: A once-popular explanation for resistance, checked across strains and found not to hold.\norganism: Nematode\ntissue_or_cell_type: Mitochondrial electron transport\nexperimental_model: Fumarate reductase activity compared across benzimidazole-susceptible and resistant Haemonchus contortus strains, with reassessment of published reports\nlimitations: A proposed resistance mechanism tested across strains and largely rejected. The reassessment of other laboratories’ published values is the useful part.\nexposure: Thiabendazole-resistant, mebendazole-resistant and susceptible strains\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/6877276.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"59837d0bc8f0d0c120dd9d647dcd86cd046545768ec6ab198e2262d381aafbf7\", \"start_char\": 0, \"end_char\": 1052, \"text_sha256\": \"59837d0bc8f0d0c120dd9d647dcd86cd046545768ec6ab198e2262d381aafbf7\"}\n[mbz-p6877276] Observations on the fumarate reductase system in Haemonchus contortus and their relevance to anthelmintic resistance and to strain variations of energy metabolism. (1983). https://pubmed.ncbi.nlm.nih.gov/6877276/ DOI: 10.1016/0166-6851(83)90011-7","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":["f9b212e2-4e3e-58c3-834d-a6edead6c855"]},{"conflict_id":"279d63d9-6f1b-519d-ad61-30a5341c5b86","ordinal":1,"label":"Resistant and susceptible worms handle sugar much the same, so metabolism is not where resistance lives.","revision_id":"a2cd9c22-0549-52ca-a653-8a0c2362ec85","start_line":342,"end_line":353,"quote":"### mbz-metabolism-does-not-explain-resistance\nSteady-state pool sizes of glucose and metabolic intermediates including adenine nucleotides and end products revealed no differences between adult Haemonchus contortus resistant or susceptible to benzimidazoles, all three strains had similar levels of total lipid, protein and free amino acid and produced a similar sum total of end products, and although the mebendazole-resistant strain showed a diversion of carbon flow to the ethanol-producing pathway and greater cyanide-sensitive aerobic carbon dioxide output, the extent to which these metabolic differences may be related to benzimidazole resistance is not readily apparent.\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 and susceptible worms handle sugar much the same, so metabolism is not where resistance lives.\norganism: Nematode\ntissue_or_cell_type: Whole adult worms\nexperimental_model: Biochemical comparison of susceptible, mebendazole-resistant and thiabendazole-resistant Haemonchus contortus in vitro\nlimitations: A broad metabolic survey across matched resistant and susceptible strains. Its own authors state the relationship to resistance is not apparent.\nexposure: Steady-state metabolite pools, end products and labelled carbon dioxide over 30 to 60 minute and 18 hour incubations\nevidence_span: {\"source_cache\": \"artifacts/mebendazole-research/6427605.abstract.txt\", \"locator\": \"Indexed abstract; zero-based, end-exclusive Unicode character offsets\", \"file_sha256\": \"4834a68834e7916938d61b08f8dc38fb00085c0b43761372c8ef883da0d8cbf8\", \"start_char\": 0, \"end_char\": 1809, \"text_sha256\": \"4834a68834e7916938d61b08f8dc38fb00085c0b43761372c8ef883da0d8cbf8\"}\n[mbz-p6427605] Energy metabolism of adult Haemonchus contortus in vitro: a comparison of benzimidazole-susceptible and -resistant strains. (1984). https://pubmed.ncbi.nlm.nih.gov/6427605/ DOI: 10.1016/0166-6851(84)90031-8","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":["3e0cda27-4c9b-590f-8a56-12883b63de00"]}]}],"corrections":[],"research":null}