Newly identified parasitic nematode beta-tubulin alleles confer resistance to benzimidazoles

Dilks, Clayton M.; Koury, Emily; Buchanan, Claire M.; Andersen, Erik C.

doi:10.1016/j.ijpddr.2021.09.006

Cited by 34 publications

(69 citation statements)

References 39 publications

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“…2018; D ilks et al . 2020; D ilks et al . 2021), indicating likely redundancy with other C. elegans β-tubulin genes.…”

Section: Resultsmentioning

confidence: 99%

“…Although TBB-2 is predicted not to bind ABZ as it is Y200, the qt1 allele has been implicated in benomyl resistance (W right and H unter 2003). This tbb-2 mutation encodes the E198K change that is ABZ resistant when edited into ben-1 (D ilks et al . 2021) and is present in the ben-1(sb159) allele from our screen.…”

Section: Resultsmentioning

confidence: 99%

“…2018; D ilks et al . 2020; D ilks et al . 2021), we found a number of nonsense alleles ( sb152 , sb158 , sb154 ) and a splice donor mutation ( sb153 ) among the 16 alleles we sequenced.…”

Section: Discussionmentioning

confidence: 99%

“…In additional to solid plate-based assays, we also performed a high-throughput phenotyping assay in response to ABZ (D ilks et al . 2020; D ilks et al . 2021).…”

Section: Methodsmentioning

confidence: 99%

“…Complete loss of ben-1 confers BZ resistance and has no detectable growth disadvantages on or off drug under laboratory conditions (DRISCOLL et al 1989;HAHNEL et al 2018;DILKS et al 2021). Indeed, many C. elegans wild isolates carry unique ben-1 variants with no appreciable effects on fitness (HAHNEL et al 2018).…”

Section: Introductionmentioning

confidence: 99%

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Interactions of C. elegans β-tubulins with the microtubule inhibitor albendazole

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Parasitic nematodes are major human and agricultural pests, and benzimidazoles are amongst the most important broad spectrum anthelmintic drug class used for their control. Benzimidazole resistance is now widespread in many species of parasitic nematodes in livestock globally and an emerging concern for the sustainable control of human soil transmitted helminths. -tubulin is the major benzimidazole target, although other genes may influence resistance. Among the six C. elegans -tubulin genes, loss of ben-1 causes resistance without other apparent defects. Here, we explored the genetics of C. elegans -tubulin genes in relation to the response to the benzimidazole derivative albendazole. The most highly expressed -tubulin isotypes, encoded by tbb-1 and tbb-2, were known to be redundant with each other for viability, and their products are predicted not to bind benzimidazoles. We found that tbb-2 mutants, and to a lesser extent tbb-1 mutants, were hypersensitive to albendazole. The double mutant tbb-2 ben-1 is uncoordinated and dumpy, resembling the wild type exposed to albendazole, but the tbb-1 ben-1 double mutant did not show the same phenotype. These results suggest that tbb-2 is a modifier of ABZ sensitivity. To better understand how BEN-1 mutates to cause benzimidazole resistance, we isolated mutants resistant to albendazole and found that 15 of 16 mutations occurred in ben-1. Mutations ranged from likely nulls to hypomorphs, and several corresponded to residues that cause resistance in other organisms. Null alleles of ben-1 are albendazole-resistant and BEN-1 shows high sequence identity with tubulins from other organisms, suggesting that many amino acid changes could cause resistance. However, our results suggest that missense mutations conferring resistance are not evenly distributed across all possible conserved sites.

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“…2018; D ilks et al . 2020; D ilks et al . 2021), indicating likely redundancy with other C. elegans β-tubulin genes.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

“…2018; D ilks et al . 2020; D ilks et al . 2021), we found a number of nonsense alleles ( sb152 , sb158 , sb154 ) and a splice donor mutation ( sb153 ) among the 16 alleles we sequenced.…”

Section: Discussionmentioning

confidence: 99%

“…In additional to solid plate-based assays, we also performed a high-throughput phenotyping assay in response to ABZ (D ilks et al . 2020; D ilks et al . 2021).…”

Section: Methodsmentioning

confidence: 99%