Discovery of novel benzimidazole resistance mechanisms

发现新的苯并咪唑耐药机制

• 批准号: 10438771
• 负责人: Erik Christian Andersen
• 金额: $ 68.21万
• 依托单位: NORTHWESTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10438771
• 关键词: Affect; Albendazole; Alleles; Anthelmintics; Biological Assay; CRISPR/Cas technology; Caenorhabditis elegans; Collaborations; Communities; Drug Design; Drug Targeting; Early Diagnosis; Economic Burden; Enzymes; Evolution; Farm; Future; Generations; Genes; Genetic; Genetic Crosses; Genome; Genomics; Goals; Growth; Haemonchus; Helminths; Hookworms; Human; Knowledge; Laboratories; Longevity; Measures; Medicine; Modeling; Molecular; Monitor; Morbidity - disease rate; Nematoda; Oxides; Parasite resistance; Parasites; Parasitic nematode; Persons; Pharmaceutical Preparations; Phenotype; Phylogenetic Analysis; Poisoning; Population; Production; Proteins; Research; Research Personnel; Resistance; Resources; Ruminants; Sampling; Soil; Structural Biologist; Testing; Time; Tissues; Transgenic Animals; Translating; Veterinary Medicine; X Chromosome; base; benzimidazole; benzimidazole resistance; beta Tubulin; disability-adjusted life years; experimental study; fitness; fitness test; follow-up; gamma Tubulin; gene discovery; genetic approach; genome editing; genome-wide; health economics; mortality; novel; offspring; pathogen; programs; resistance allele; resistance gene; resistance mechanism; success

Project summary: Parasitic nematodes impose a massive health and economic burden across much of the developing world, infecting over one billion people worldwide. The morbidity and mortality inflicted by these devastating pathogens is partly curtailed by mass drug administration (MDA) programs that depend on the continued efficacy of a limited portfolio of anthelmintic drugs. Benzimidazole (BZ) compounds are a widely used class of broad-spectrum anthelmintics that are an indispensable component of this limited chemotherapeutic arsenal. The prospects of BZ resistance pose a serious threat to the future success of nematode control programs. These prospects have been realized in the veterinary domain following intensive BZ use and are predicted to materialize in human medicine with increased selection caused by expanded MDA. Early detection of resistance-associated alleles in nematode parasite populations is essential to the goal of slowing anthelmintic resistance and extending the lifespan of this critical drug class. Based on research in the free-living nematode Caenorhabditis elegans from thirty years ago, parasitic nematode researchers focus on one BZ target, a nematode-specific beta-tubulin. Despite this knowledge, it is still a complete mystery (1) whether any alleles cause resistance (i.e. go beyond correlation), (2) the nematode tissues that are sensitive to BZ poisoning, and (3) the drug-target interactions that cause resistance. In Haemonchus contortus, we have collected both validated sensitive and resistance samples, and longitudinal samples where resistance has developed over time. These samples are not available in any human parasitic nematode species. Using quantitative resistance assays on these resources, we have shown that BZ resistance goes well beyond this single beta- tubulin target. However, we do not know these independent resistance mechanisms in C. elegans or parasite species. In Aim 1, we will test explicitly whether alleles correlated with resistance in parasites actually cause resistance, test the fitness effects of these alleles, identify the tissues targeted by BZ, and characterize the molecular mechanism for how beta-tubulin in affected by benzimidazoles. In Aim 2, we will discover beta- tubulin independent mechanisms of resistance using the tractable C. elegans model nematode. In Aim 3, we will expand our results to H. contortus where genomic and validated strain resources enable discoveries of conserved resistance mechanisms. It is not possible in any parasitic nematode species to accomplish these goals. New discoveries are possible only through this interplay between the model nematode C. elegans and the tractable veterinary parasitic nematode H. contortus. Our results will have direct impacts on how treatments are administered and resistance is monitored in human parasitic nematodes.

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