Resistance to benzimidazole anthelmintics

evidence_span

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experimental_model

Albendazole resistance induced in three Giardia cultures by stepwise drug exposure, with beta-tubulin sequencing

exposure

Growth in successively increasing albendazole, with immunofluorescence and PCR across codon 200

limitations

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.

nutrient_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. · Mebendazole

organism

Giardia

plain_language

Resistant parasites that never touched the famous mutation, so it cannot be the only route.

primary_references

[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

tissue_or_cell_type

Cytoskeleton and beta-tubulin gene

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) · lines 277–288

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Albendazole resistance induced in three Giardia cultures by stepwise drug exposure, with beta-tubulin sequencing · source_derived_draft · unverified_draft

### mbz-resistance-without-codon-200 Albendazole-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. Condition category: normal nutrient_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. plain_language: Resistant parasites that never touched the famous mutation, so it cannot be the only route. organism: Giardia tissue_or_cell_type: Cytoskeleton and beta-tubulin gene experimental_model: Albendazole resistance induced in three Giardia cultures by stepwise drug exposure, with beta-tubulin sequencing limitations: 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. exposure: Growth in successively increasing albendazole, with immunofluorescence and PCR across codon 200 evidence_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"} [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

evidence_span

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experimental_model

Fumarate reductase activity compared across benzimidazole-susceptible and resistant Haemonchus contortus strains, with reassessment of published reports

exposure

Thiabendazole-resistant, mebendazole-resistant and susceptible strains

limitations

A proposed resistance mechanism tested across strains and largely rejected. The reassessment of other laboratories’ published values is the useful part.

nutrient_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. · Mebendazole

organism

Nematode

plain_language

A once-popular explanation for resistance, checked across strains and found not to hold.

primary_references

[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

tissue_or_cell_type

Mitochondrial electron transport

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) · lines 329–340

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Fumarate reductase activity compared across benzimidazole-susceptible and resistant Haemonchus contortus strains, with reassessment of published reports · source_derived_draft · unverified_draft

### mbz-fumarate-reductase-retired Fumarate 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. Condition category: normal nutrient_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. plain_language: A once-popular explanation for resistance, checked across strains and found not to hold. organism: Nematode tissue_or_cell_type: Mitochondrial electron transport experimental_model: Fumarate reductase activity compared across benzimidazole-susceptible and resistant Haemonchus contortus strains, with reassessment of published reports limitations: A proposed resistance mechanism tested across strains and largely rejected. The reassessment of other laboratories’ published values is the useful part. exposure: Thiabendazole-resistant, mebendazole-resistant and susceptible strains evidence_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"} [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

evidence_span

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experimental_model

Biochemical comparison of susceptible, mebendazole-resistant and thiabendazole-resistant Haemonchus contortus in vitro

exposure

Steady-state metabolite pools, end products and labelled carbon dioxide over 30 to 60 minute and 18 hour incubations

limitations

A broad metabolic survey across matched resistant and susceptible strains. Its own authors state the relationship to resistance is not apparent.

nutrient_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. · Mebendazole

organism

Nematode

plain_language

Resistant and susceptible worms handle sugar much the same, so metabolism is not where resistance lives.

primary_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

tissue_or_cell_type

Whole adult worms

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) · lines 342–353

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Biochemical comparison of susceptible, mebendazole-resistant and thiabendazole-resistant Haemonchus contortus in vitro · source_derived_draft · unverified_draft

### mbz-metabolism-does-not-explain-resistance 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. Condition category: normal nutrient_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. plain_language: Resistant and susceptible worms handle sugar much the same, so metabolism is not where resistance lives. organism: Nematode tissue_or_cell_type: Whole adult worms experimental_model: Biochemical comparison of susceptible, mebendazole-resistant and thiabendazole-resistant Haemonchus contortus in vitro limitations: A broad metabolic survey across matched resistant and susceptible strains. Its own authors state the relationship to resistance is not apparent. exposure: Steady-state metabolite pools, end products and labelled carbon dioxide over 30 to 60 minute and 18 hour incubations evidence_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"} [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

evidence_span

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experimental_model

Cloning and sequencing of three beta-tubulin cDNAs from Haemonchus contortus

exposure

Sequence comparison across nematode and mammalian beta-tubulins and across sensitive and resistant populations

limitations

Sequence work only. It states plainly that the molecular basis of the nematode versus mammalian difference is not known, which is still the open question in this chapter.

nutrient_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. · Mebendazole

organism

Nematode

plain_language

The worm has several versions of this protein, and the differences from ours are known but not explained.

primary_references

[mbz-p1741017] Three beta-tubulin cDNAs from the parasitic nematode Haemonchus contortus. (1992). https://pubmed.ncbi.nlm.nih.gov/1741017/ DOI: 10.1016/0166-6851(92)90227-b

tissue_or_cell_type

Beta-tubulin genes

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) · lines 290–301

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Cloning and sequencing of three beta-tubulin cDNAs from Haemonchus contortus · source_derived_draft · unverified_draft

### mbz-more-than-one-isotype Three beta-tubulin cDNAs were cloned from Haemonchus contortus, two differing at only 23 nucleotides giving 4 amino acid changes and a third representing a different isotype class differing extensively in the carboxy terminus; comparison with mammalian beta-tubulins identified several regions of consistent difference whose functional significance has not been defined, and sequences very similar or identical to two of the clones were present in both benzimidazole-sensitive and benzimidazole-resistant populations although resistant organisms may differ in the presence of a gene product related to the third. Condition category: normal nutrient_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. plain_language: The worm has several versions of this protein, and the differences from ours are known but not explained. organism: Nematode tissue_or_cell_type: Beta-tubulin genes experimental_model: Cloning and sequencing of three beta-tubulin cDNAs from Haemonchus contortus limitations: Sequence work only. It states plainly that the molecular basis of the nematode versus mammalian difference is not known, which is still the open question in this chapter. exposure: Sequence comparison across nematode and mammalian beta-tubulins and across sensitive and resistant populations evidence_span: {"source_cache": "artifacts/mebendazole-research/1741017.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "5dfdd18b65ab4df953ac012978b5c922824de051db3b5fab15bac4b97abbfb5c", "start_char": 0, "end_char": 1425, "text_sha256": "5dfdd18b65ab4df953ac012978b5c922824de051db3b5fab15bac4b97abbfb5c"} [mbz-p1741017] Three beta-tubulin cDNAs from the parasitic nematode Haemonchus contortus. (1992). https://pubmed.ncbi.nlm.nih.gov/1741017/ DOI: 10.1016/0166-6851(92)90227-b

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Heterologous expression of Haemonchus contortus beta-tubulin alleles in Caenorhabditis elegans ben-1 mutants

exposure

Parasite benzimidazole-sensitive and resistant alleles and in vitro mutagenised constructs, assayed with benomyl and thiabendazole

limitations

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.

nutrient_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. · Mebendazole

organism

Nematode

plain_language

Swapping one amino acid back made resistant worms susceptible again, which makes it the cause and not a coincidence.

primary_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

tissue_or_cell_type

Beta-tubulin isotype 1

trigger_kind

machinery_impairment Imported condition classification; unverified.

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) · lines 264–275

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Heterologous expression of Haemonchus contortus beta-tubulin alleles in Caenorhabditis elegans ben-1 mutants · source_derived_draft · unverified_draft

### mbz-phe200-causes-resistance 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. Condition category: machinery_impairment nutrient_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. plain_language: Swapping one amino acid back made resistant worms susceptible again, which makes it the cause and not a coincidence. organism: Nematode tissue_or_cell_type: Beta-tubulin isotype 1 experimental_model: Heterologous expression of Haemonchus contortus beta-tubulin alleles in Caenorhabditis elegans ben-1 mutants limitations: 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. exposure: Parasite benzimidazole-sensitive and resistant alleles and in vitro mutagenised constructs, assayed with benomyl and thiabendazole evidence_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"} [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

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

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experimental_model

Site-directed mutagenesis and gene replacement of Saccharomyces cerevisiae beta-tubulin residue 167

exposure

Phenylalanine 167 changed to tyrosine, then tested against carbendazim, nocodazole and benomyl

limitations

A clean genetic test in a tractable organism, and the cold sensitivity argues the effect is on binding rather than on general microtubule stability. Yeast beta-tubulin is not nematode beta-tubulin.

nutrient_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. · Mebendazole

organism

Yeast

plain_language

The same mutation that resists one compound makes the organism more vulnerable to its near twin.

primary_references

[mbz-p8641470] Site-directed mutagenesis of Saccharomyces cerevisiae beta-tubulin: interaction between residue 167 and benzimidazole compounds. (1996). https://pubmed.ncbi.nlm.nih.gov/8641470/ DOI: 10.1016/0014-5793(96)00334-1

tissue_or_cell_type

Beta-tubulin

trigger_kind

machinery_impairment Imported condition classification; unverified.

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) · lines 303–314

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Site-directed mutagenesis and gene replacement of Saccharomyces cerevisiae beta-tubulin residue 167 · source_derived_draft · unverified_draft

### mbz-tyr167-and-negative-effect Changing Saccharomyces cerevisiae beta-tubulin residue phenylalanine 167 to tyrosine produced at least 3 to 4 fold decreased sensitivity to carbendazim and nocodazole and the mutant was cold sensitive, implying a direct effect on benzimidazole binding rather than a nonspecific increase in microtubule stability, but surprisingly the mutant had 8 fold increased sensitivity to benomyl, which is structurally identical to carbendazim except at position 1, suggesting that residue 167 interacts with benzimidazoles in the vicinity of the 1 position. Condition category: machinery_impairment nutrient_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. plain_language: The same mutation that resists one compound makes the organism more vulnerable to its near twin. organism: Yeast tissue_or_cell_type: Beta-tubulin experimental_model: Site-directed mutagenesis and gene replacement of Saccharomyces cerevisiae beta-tubulin residue 167 limitations: A clean genetic test in a tractable organism, and the cold sensitivity argues the effect is on binding rather than on general microtubule stability. Yeast beta-tubulin is not nematode beta-tubulin. exposure: Phenylalanine 167 changed to tyrosine, then tested against carbendazim, nocodazole and benomyl evidence_span: {"source_cache": "artifacts/mebendazole-research/8641470.abstract.txt", "locator": "Indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "35145959fc480be6039e088de374d7549dddc6f298511a41d2a760e7fdb8f455", "start_char": 0, "end_char": 917, "text_sha256": "35145959fc480be6039e088de374d7549dddc6f298511a41d2a760e7fdb8f455"} [mbz-p8641470] Site-directed mutagenesis of Saccharomyces cerevisiae beta-tubulin: interaction between residue 167 and benzimidazole compounds. (1996). https://pubmed.ncbi.nlm.nih.gov/8641470/ DOI: 10.1016/0014-5793(96)00334-1