{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T00:10:20Z","timestamp":1784765420031,"version":"3.55.0"},"update-to":[{"DOI":"10.1371\/journal.ppat.1012245","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2024,5,31]],"date-time":"2024-05-31T00:00:00Z","timestamp":1717113600000}}],"reference-count":120,"publisher":"Public Library of Science (PLoS)","issue":"5","license":[{"start":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T00:00:00Z","timestamp":1716163200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01AI153088"],"award-info":[{"award-number":["R01AI153088"]}],"id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000001","name":"National Science Foundation","doi-asserted-by":"publisher","award":["2224885"],"award-info":[{"award-number":["2224885"]}],"id":[{"id":"10.13039\/100000001","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    Albendazole (a benzimidazole) and ivermectin (a macrocyclic lactone) are the two most commonly co-administered anthelmintic drugs in mass-drug administration programs worldwide. Despite emerging resistance, we do not fully understand the mechanisms of resistance to these drugs nor the consequences of delivering them in combination. Albendazole resistance has primarily been attributed to variation in the drug target, a beta-tubulin gene. Ivermectin targets glutamate-gated chloride channels (GluCls), but it is unknown whether GluCl genes are involved in ivermectin resistance in nature. Using\n                    <jats:italic>Caenorhabditis elegans<\/jats:italic>\n                    , we defined the fitness costs associated with loss of the drug target genes singly or in combinations of the genes that encode GluCl subunits. We quantified the loss-of-function effects on three traits: (i) multi-generational competitive fitness, (ii) fecundity, and (iii) development. In competitive fitness and development assays, we found that a deletion of the beta-tubulin gene\n                    <jats:italic>ben-1<\/jats:italic>\n                    conferred albendazole resistance, but ivermectin resistance required the loss of two GluCl genes (\n                    <jats:italic>avr-14<\/jats:italic>\n                    and\n                    <jats:italic>avr-15<\/jats:italic>\n                    ). The fecundity assays revealed that loss of\n                    <jats:italic>ben-1<\/jats:italic>\n                    did not provide any fitness benefit in albendazole conditions and that no GluCl deletion mutants were resistant to ivermectin. Next, we searched for evidence of multi-drug resistance across the three traits. Loss of\n                    <jats:italic>ben-1<\/jats:italic>\n                    did not confer resistance to ivermectin, nor did loss of any single GluCl subunit or combination confer resistance to albendazole. Finally, we assessed the development of 124\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    wild strains across six benzimidazoles and seven macrocyclic lactones to identify evidence of multi-drug resistance between the two drug classes and found a strong phenotypic correlation within a drug class but not across drug classes. Because each gene affects various aspects of nematode physiology, these results suggest that it is necessary to assess multiple fitness traits to evaluate how each gene contributes to anthelmintic resistance.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1012245","type":"journal-article","created":{"date-parts":[[2024,5,20]],"date-time":"2024-05-20T13:52:01Z","timestamp":1716213121000},"page":"e1012245","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":14,"title":["Quantifying the fitness effects of resistance alleles with and without anthelmintic selection pressure using Caenorhabditis elegans"],"prefix":"10.1371","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2910-1505","authenticated-orcid":true,"given":"Amanda O.","family":"Shaver","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella R.","family":"Miller","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Etta S.","family":"Schaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas D.","family":"Moya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. B.","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janneke","family":"Wit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa H.","family":"Blanco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona M.","family":"Shao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elliot J.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharik A.","family":"Khan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gracie","family":"Paredes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0229-9651","authenticated-orcid":true,"given":"Erik C.","family":"Andersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2024,5,20]]},"reference":[{"key":"ppat.1012245.ref001","volume-title":"Global Health Estimates 2020: Disease burden by Cause, Age, Sex, by Country and by Region, 2000\u20132019","author":"Organization WH","year":"2021"},{"key":"ppat.1012245.ref002","article-title":"How to become a parasite\u2013lessons from the genomes of nematodes.","author":"Sommer Dieterich","journal-title":"Trends Genet."},{"key":"ppat.1012245.ref003","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1038\/ng1472","article-title":"A transcriptomic analysis of the phylum Nematoda","volume":"36","author":"J Parkinson","year":"2004","journal-title":"Nat Genet"},{"key":"ppat.1012245.ref004","doi-asserted-by":"crossref","first-page":"2021","DOI":"10.1016\/S0140-6736(07)60942-8","article-title":"Prevalence and intensity of Onchocerca volvulus infection and efficacy of ivermectin in endemic communities in Ghana: a two-phase epidemiological study","volume":"369","author":"MY Osei-Atweneboana","year":"2007","journal-title":"Lancet"},{"key":"ppat.1012245.ref005","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1179\/000349804225003442","article-title":"Thirty-month follow-up of sub-optimal responders to multiple treatments with ivermectin, in two onchocerciasis-endemic foci in Ghana","volume":"98","author":"K Awadzi","year":"2004","journal-title":"Ann Trop Med Parasitol"},{"key":"ppat.1012245.ref006","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1179\/000349802125001942","article-title":"Soil-transmitted nematode infections and mebendazole treatment in Mafia Island schoolchildren","volume":"96","author":"M Albonico","year":"2002","journal-title":"Ann Trop Med Parasitol"},{"key":"ppat.1012245.ref007","doi-asserted-by":"crossref","first-page":"25","DOI":"10.4269\/ajtmh.1997.57.25","article-title":"Failure of mebendazole in treatment of human hookworm infections in the southern region of Mali","volume":"57","author":"D De Clercq","year":"1997","journal-title":"Am J Trop Med Hyg"},{"key":"ppat.1012245.ref008","first-page":"128","article-title":"Persistence of microfilaremia in bancroftian filariasis after diethylcarbamazine citrate therapy","volume":"39","author":"ML Eberhard","year":"1988","journal-title":"Trop Med Parasitol"},{"key":"ppat.1012245.ref009","article-title":"Challenges and opportunities for the adoption of molecular diagnostics for anthelmintic resistance.","author":"AC Kotze","year":"2020","journal-title":"Int J Forecast."},{"key":"ppat.1012245.ref010","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1016\/j.pt.2010.11.008","article-title":"Anthelmintic resistance in nematode parasites of cattle: a global issue?","volume":"27","author":"IA Sutherland","year":"2011","journal-title":"Trends Parasitol"},{"key":"ppat.1012245.ref011","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.pt.2006.11.004","article-title":"New anthelmintics for livestock: the time is right","volume":"23","author":"B. 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