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Qu\u00e9bec\u2014Nature et Technology (FRQ-NT)","award":["2020-04811"],"award-info":[{"award-number":["2020-04811"]}]},{"name":"Fonds de Recherche du Qu\u00e9bec\u2014Nature et Technology (FRQ-NT)","award":["2022-04028"],"award-info":[{"award-number":["2022-04028"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Tomatidine (TO) is a natural narrow-spectrum antibiotic acting on the Staphylococcus aureus small colony variant (SCV) with a minimal inhibitory concentration (MIC) of 0.06 \u00b5g\/mL while it shows no activity against prototypical strains (MIC &gt; 128 \u00b5g\/mL). To expand the spectrum of activity of TO, the 3\u03b2-hydroxyl group was substituted with an ethane-1,2-diamine, resulting in two diastereoisomers, TM-02 (C3-\u03b2) and TM-03 (C3-\u03b1). These molecules are equally potent against prototypical S. aureus and E. coli strains (MIC 8 and 32 \u00b5g\/mL, respectively), whereas TM-02 is more potent against SCV (MIC 0.5 \u00b5g\/mL) and hyperpermeable E. coli strains (MIC 1 \u00b5g\/mL). The differences in their modes of action were investigated. We used membrane vesicles to confirm the inhibition of the bacterial ATP synthase, the documented target of TO, and measured effects on bacterial cell membranes. Both molecules inhibited E. coli ATP synthase, with Ki values of 1.1 \u00b5M and 3.5 \u00b5M for TM-02 and TM-03, respectively, and the bactericidal effect of TM-02 was linked to ATP synthase inhibition. Furthermore, TM-02 had no major effect on the membrane fluidity and gradually reduced membrane potential. In contrast, TM-03 caused structural damages to membranes and completely disrupted the membrane potential (&gt;90%). We were successful in broadening the spectrum of activity of TO. C3-\u03b2-diastereoisomers may have more specific antibacterial action than C3-\u03b1.<\/jats:p>","DOI":"10.3390\/molecules29020343","type":"journal-article","created":{"date-parts":[[2024,1,10]],"date-time":"2024-01-10T05:47:21Z","timestamp":1704865641000},"page":"343","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Mode of Antibacterial Action of Tomatidine C3-Diastereoisomers"],"prefix":"10.3390","volume":"29","author":[{"given":"Jean-Philippe","family":"Langlois","sequence":"first","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Audrey","family":"Larose","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Brouillette","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien A.","family":"Delbrouck","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pharmacologie et Physiologie, Facult\u00e9 de M\u00e9decine et des Sciences de la Sant\u00e9, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2032-7970","authenticated-orcid":false,"given":"Pierre-Luc","family":"Boudreault","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Pharmacologie et Physiologie, Facult\u00e9 de M\u00e9decine et des Sciences de la Sant\u00e9, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5031-345X","authenticated-orcid":false,"given":"Fran\u00e7ois","family":"Malouin","sequence":"additional","affiliation":[{"name":"D\u00e9partement de Biologie, Facult\u00e9 des Sciences, Universit\u00e9 de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,1,10]]},"reference":[{"key":"ref_1","unstructured":"World Health Organization (WHO) (2017). 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PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0065018"}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/2\/343\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T13:43:35Z","timestamp":1760103815000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/29\/2\/343"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,1,10]]},"references-count":33,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2024,1]]}},"alternative-id":["molecules29020343"],"URL":"https:\/\/doi.org\/10.3390\/molecules29020343","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,1,10]]}}}