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The ESX-3 secretion system is essential for the <jats:italic>Mycobacterium tuberculosis<\/jats:italic> growth and plays a role in iron\/zinc homeostasis and virulence. The aim of this study was to evaluate the quaternary interface of EccD3, a component of the ESX-3 secretion system, and to evaluate the association of an <jats:italic>eccD3<\/jats:italic> mutant with drug resistance. The molecular structures of EccD3 protein and other ESX-3 secretion system proteins of the <jats:italic>M. tuberculosis<\/jats:italic> were predicted based in homology with the <jats:italic>Mycolicibacterium smegmatis<\/jats:italic> tertiary protein structures. According to the <jats:italic>in silico<\/jats:italic> results, selamectin, avermectin, ivermectin, and moxidectin were selected as prospective drugs. Selamectin and moxidectin had favorable \u0394G values for the EccB3 and EccD3 dimer interfaces, whereas the ESX-3 Protomer 1 interface had the best \u0394G + with avermectin, ivermectin, and moxidectin. Furthermore, ivermectin susceptibility increased when the <jats:italic>eccD3<\/jats:italic> gene was inhibited using CRISPRi in <jats:italic>M. smegmatis<\/jats:italic>. Blockage of EccD3 increased the ivermectin action, but the modest changes observed may be explained by the compensatory mechanisms or other ivermectin targets in absence of this Esx3 component. Further <jats:italic>in vitro<\/jats:italic> and preclinical studies are required to validate our findings.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1012936","type":"journal-article","created":{"date-parts":[[2025,4,17]],"date-time":"2025-04-17T17:46:18Z","timestamp":1744911978000},"page":"e1012936","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":3,"title":["Mycobacterium susceptibility to ivermectin by inhibition of eccD3, an ESX-3 secretion system component."],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8383-8436","authenticated-orcid":true,"given":"Ana Laura","family":"Granados-Trist\u00e1n","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauricio","family":"Carrillo-Tripp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlos Eduardo","family":"Hern\u00e1ndez-Luna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aldo","family":"Herrera-Rodulfo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Adiene","family":"Gonz\u00e1lez-Escalante","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Leticia","family":"Arriaga-Guerrero","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Silva-Ram\u00edrez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda Leticia","family":"Escobedo-Guajardo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"Mercado-Hern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mario","family":"Berm\u00fadez de Le\u00f3n","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9220-2421","authenticated-orcid":true,"given":"Katia","family":"Pe\u00f1uelas-Urquides","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,4,17]]},"reference":[{"key":"pcbi.1012936.ref001","unstructured":"WHO. 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