{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T06:09:36Z","timestamp":1791439776250,"version":"4.3.3"},"update-to":[{"DOI":"10.1371\/journal.ppat.1011146","type":"new_version","label":"New version","source":"publisher","updated":{"date-parts":[[2023,3,14]],"date-time":"2023-03-14T00:00:00Z","timestamp":1678752000000}}],"reference-count":66,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T00:00:00Z","timestamp":1677715200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["R01AI153088"],"award-info":[{"award-number":["R01AI153088"]}]},{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["2021-02489"],"award-info":[{"award-number":["2021-02489"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["OPP1172974"],"award-info":[{"award-number":["OPP1172974"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008349","name":"Boehringer Ingelheim","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100008349","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Alberta Graduate Excellence Scholarship"}],"content-domain":{"domain":["www.plospathogens.org"],"crossmark-restriction":false},"short-container-title":["PLoS Pathog"],"abstract":"<jats:p>\n                    <jats:italic>Ancylostoma caninum<\/jats:italic>\n                    is an important zoonotic gastrointestinal nematode of dogs worldwide and a close relative of human hookworms. We recently reported that racing greyhound dogs in the USA are infected with\n                    <jats:italic>A<\/jats:italic>\n                    .\n                    <jats:italic>caninum<\/jats:italic>\n                    that are commonly resistant to multiple anthelmintics. Benzimidazole resistance in\n                    <jats:italic>A<\/jats:italic>\n                    .\n                    <jats:italic>caninum<\/jats:italic>\n                    in greyhounds was associated with a high frequency of the canonical F167Y(T\n                    <jats:underline>T<\/jats:underline>\n                    C&gt;T\n                    <jats:underline>A<\/jats:underline>\n                    C) isotype-1 \u03b2-tubulin mutation. In this work, we show that benzimidazole resistance is remarkably widespread in\n                    <jats:italic>A<\/jats:italic>\n                    .\n                    <jats:italic>caninum<\/jats:italic>\n                    from domestic dogs across the USA. First, we identified and showed the functional significance of a novel benzimidazole isotype-1 \u03b2-tubulin resistance mutation, Q134H(CA\n                    <jats:underline>A<\/jats:underline>\n                    &gt;CA\n                    <jats:underline>T<\/jats:underline>\n                    ). Several benzimidazole resistant\n                    <jats:italic>A<\/jats:italic>\n                    .\n                    <jats:italic>caninum<\/jats:italic>\n                    isolates from greyhounds with a low frequency of the F167Y(T\n                    <jats:underline>T<\/jats:underline>\n                    C&gt;T\n                    <jats:underline>A<\/jats:underline>\n                    C) mutation had a high frequency of a Q134H(CA\n                    <jats:underline>A<\/jats:underline>\n                    &gt;CA\n                    <jats:underline>T<\/jats:underline>\n                    ) mutation not previously reported from any eukaryotic pathogen in the field. Structural modeling predicted that the Q134 residue is directly involved in benzimidazole drug binding and that the 134H substitution would significantly reduce binding affinity. Introduction of the Q134H substitution into the\n                    <jats:italic>C<\/jats:italic>\n                    .\n                    <jats:italic>elegans<\/jats:italic>\n                    \u03b2-tubulin gene\n                    <jats:italic>ben-1<\/jats:italic>\n                    , by CRISPR-Cas9 editing, conferred similar levels of resistance as a\n                    <jats:italic>ben-1<\/jats:italic>\n                    null allele. Deep amplicon sequencing on\n                    <jats:italic>A<\/jats:italic>\n                    .\n                    <jats:italic>caninum<\/jats:italic>\n                    eggs from 685 hookworm positive pet dog fecal samples revealed that both mutations were widespread across the USA, with prevalences of 49.7% (overall mean frequency 54.0%) and 31.1% (overall mean frequency 16.4%) for F167Y(T\n                    <jats:underline>T<\/jats:underline>\n                    C&gt;T\n                    <jats:underline>A<\/jats:underline>\n                    C) and Q134H(CA\n                    <jats:underline>A<\/jats:underline>\n                    &gt;CA\n                    <jats:underline>T<\/jats:underline>\n                    ), respectively. Canonical codon 198 and 200 benzimidazole resistance mutations were absent. The F167Y(T\n                    <jats:underline>T<\/jats:underline>\n                    C&gt;T\n                    <jats:underline>A<\/jats:underline>\n                    C) mutation had a significantly higher prevalence and frequency in Western USA than in other regions, which we hypothesize is due to differences in refugia. This work has important implications for companion animal parasite control and the potential emergence of drug resistance in human hookworms.\n                  <\/jats:p>","DOI":"10.1371\/journal.ppat.1011146","type":"journal-article","created":{"date-parts":[[2023,3,2]],"date-time":"2023-03-02T13:46:40Z","timestamp":1677764800000},"page":"e1011146","update-policy":"https:\/\/doi.org\/10.1371\/journal.ppat.corrections_policy","source":"Crossref","is-referenced-by-count":96,"title":["Molecular evidence of widespread benzimidazole drug resistance in Ancylostoma caninum from domestic dogs throughout the USA and discovery of a novel \u03b2-tubulin benzimidazole resistance mutation"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9036-1357","authenticated-orcid":true,"given":"Abhinaya","family":"Venkatesan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5596-7380","authenticated-orcid":true,"given":"Pablo D.","family":"Jimenez Castro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Arianna","family":"Morosetti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Horvath","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Redman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kayla","family":"Dunn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0808-5216","authenticated-orcid":true,"given":"James Bryant","family":"Collins","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5080-2859","authenticated-orcid":true,"given":"James S.","family":"Fraser","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"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3068-5528","authenticated-orcid":true,"given":"Ray M.","family":"Kaplan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6787-4699","authenticated-orcid":true,"given":"John S.","family":"Gilleard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,3,2]]},"reference":[{"key":"ppat.1011146.ref001","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/j.cvsm.2009.07.002","article-title":"Intestinal Nematodes: Biology and Control","volume":"39","author":"C. 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