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The F-type ATPase\/ATP synthase (F<jats:sub>O<\/jats:sub>F<jats:sub>1<\/jats:sub>) is a central player in cellular bioenergetics of bacteria and eukaryotes, and its potential as a selective antibiotic target has been confirmed by the success of bedaquiline in combatting multidrug-resistant tuberculosis. Venturicidin macrolides were initially identified for their antifungal properties and were found to specifically inhibit F<jats:sub>O<\/jats:sub>F<jats:sub>1<\/jats:sub> of eukaryotes and bacteria. Venturicidins alone are not effective antibacterials but recently were found to have adjuvant activity, potentiating the efficacy of aminoglycoside antibiotics against several species of resistant bacteria. Here we discovered more complex effects of venturicidins on the ATPase activity of F<jats:sub>O<\/jats:sub>F<jats:sub>1<\/jats:sub> in bacterial membranes from <jats:italic>Escherichia coli<\/jats:italic> and <jats:italic>Pseudomonas aeruginosa<\/jats:italic>. Our major finding is that higher concentrations of venturicidin induce time\u2013 and ATP\u2013dependent decoupling of F<jats:sub>1<\/jats:sub>-ATPase activity from the venturicidin-inhibited, proton-transporting F<jats:sub>O<\/jats:sub> complex. This dysregulated ATPase activity is likely to be a key factor in the depletion of cellular ATP induced by venturicidins in prior studies with <jats:italic>P. aeruginosa<\/jats:italic> and <jats:italic>Staphylococcus aureus<\/jats:italic>. Further studies of how this functional decoupling occurs could guide development of new antibiotics and\/or adjuvants that target the F-type ATPase\/ATP synthase.<\/jats:p>","DOI":"10.1038\/s41598-021-93098-8","type":"journal-article","created":{"date-parts":[[2021,7,1]],"date-time":"2021-07-01T10:05:24Z","timestamp":1625133924000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Complex effects of macrolide venturicidins on bacterial F-ATPases likely contribute to their action as antibiotic adjuvants"],"prefix":"10.1038","volume":"11","author":[{"given":"Yakov M.","family":"Milgrom","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas M.","family":"Duncan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,7,1]]},"reference":[{"key":"93098_CR1","doi-asserted-by":"publisher","first-page":"717","DOI":"10.1146\/annurev.biochem.66.1.717","volume":"66","author":"PD Boyer","year":"1997","unstructured":"Boyer, P. 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