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Our recent study showed that deletion of this system caused a significantly increased sensitivity of<jats:italic>Aeromonas hydrophila<\/jats:italic>to the macrolides erythromycin and roxithromycin, but had no effect on other classes of antibiotics. In this study, we found the sensitivity of<jats:italic>\u0394tonB123<\/jats:italic>to all macrolides tested revealed a 8- to 16-fold increase compared with the wild-type (WT) strain, but this increase was not related with iron deprivation caused by<jats:italic>tonB123<\/jats:italic>deletion. Further study demonstrated that the deletion of<jats:italic>tonB123<\/jats:italic>did not damage the integrity of the bacterial membrane but did hinder the function of macrolide efflux. Compared with the WT strain, deletion of<jats:italic>macA<\/jats:italic><jats:sub><jats:italic>2<\/jats:italic><\/jats:sub><jats:italic>B<\/jats:italic><jats:sub><jats:italic>2<\/jats:italic><\/jats:sub>, one of two ATP-binding cassette (ABC) types of the macrolide efflux pump, enhanced the sensitivity to the same levels as those of<jats:italic>\u0394tonB123<\/jats:italic>. Interestingly, the deletion of<jats:italic>macA<\/jats:italic><jats:sub><jats:italic>2<\/jats:italic><\/jats:sub><jats:italic>B<\/jats:italic><jats:sub><jats:italic>2<\/jats:italic><\/jats:sub>in the<jats:italic>\u0394tonB123<\/jats:italic>mutant did not cause further increase in sensitivity to macrolide resistance, indicating that the macrolide resistance afforded by the MacA<jats:sub>2<\/jats:sub>B<jats:sub>2<\/jats:sub>pump was completely abrogated by<jats:italic>tonB123<\/jats:italic>deletion. In addition,<jats:italic>macA<\/jats:italic><jats:sub><jats:italic>2<\/jats:italic><\/jats:sub><jats:italic>B<\/jats:italic><jats:sub><jats:italic>2<\/jats:italic><\/jats:sub>expression was not altered in the<jats:italic>\u0394tonB123<\/jats:italic>mutant, indicating that any influence of TonB on MacA<jats:sub>2<\/jats:sub>B<jats:sub>2<\/jats:sub>-mediated macrolide resistance was at the pump activity level. In conclusion, inactivation of the TonB system significantly compromises the resistance of<jats:italic>A. hydrophila<\/jats:italic>to macrolides, and the mechanism of action is related to the function of MacA<jats:sub>2<\/jats:sub>B<jats:sub>2<\/jats:sub>-mediated macrolide efflux.<\/jats:p>","DOI":"10.1186\/s13567-021-00934-w","type":"journal-article","created":{"date-parts":[[2021,4,29]],"date-time":"2021-04-29T11:06:42Z","timestamp":1619694402000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The TonB system in Aeromonas hydrophila NJ-35 is essential for MacA2B2 efflux pump-mediated macrolide resistance"],"prefix":"10.1186","volume":"52","author":[{"given":"Yuhao","family":"Dong","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jinzhu","family":"Geng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qing","family":"Cao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dan","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingguo","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shougang","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chengping","family":"Lu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7301-9501","authenticated-orcid":false,"given":"Yongjie","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,4,29]]},"reference":[{"key":"934_CR1","doi-asserted-by":"publisher","first-page":"a000414","DOI":"10.1101\/cshperspect.a000414","volume":"2","author":"TJ Silhavy","year":"2010","unstructured":"Silhavy TJ, Kahne D, Walker S (2010) The bacterial cell envelope. 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