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Since the efflux pumps Cdr1 and Mdr1 are key mediators of the MDR phenotype, particularly by conferring resistance to azoles, their inhibition has emerged as a promising strategy to restore antifungal susceptibility. Bioassay-guided fractionation of Solanum atriplicifolium, selected based on its ability to inhibit Mdr1 and Cdr1, led to the isolation of six previously undescribed acylhexoses, including four acylglucoses, named atriplicifolin A (1), atriplicifolin B (2), atriplicifolin C (3) and atriplicifolin D (4) and two acylinositols, named atriplicifolin E (5) and atriplicifolin F (6). Among these, compounds 3 and 4 successfully restored fluconazole sensitivity in resistant Saccharomyces cerevisiae strains overexpressing Mdr1 (AD\/CaMDR1) and Cdr1 (AD\/CaCDR1), with greater activity against the latter, with minimum effective concentrations (MECs) of 6.2 and 7.5 \u00b5M, respectively. Both compounds also significantly increased the intracellular accumulation of Nile red and rhodamine 6G in AD\/CaMDR1 and AD\/CaCDR1 strains, again showing a stronger effect in the Cdr1-overexpressing strain, where MEC values ranged from 3.1 to 15.5 \u00b5M. Molecular dynamics simulations supported these results by revealing that compounds 3 and 4 displayed higher binding affinity for Cdr1 than fluconazole, Nile red or rhodamine 6G. Furthermore, analysis of the persistence and energetic contribution of individual ligand\u2013transporter interactions over time, particularly within specific regions of the transporter, provided valuable insights for the rational design of novel inhibitors. Overall, these findings identify compounds 3 and 4 as promising scaffolds for the development of Mdr1 and Cdr1 modulators aimed at overcoming fungal multidrug resistance.<\/jats:p>","DOI":"10.3390\/plants15162523","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T12:57:53Z","timestamp":1787230673000},"page":"2523","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["New Acylglucoses from Solanum atriplicifolium as Multidrug Resistance Reversal Agents Targeting Cdr1 and Mdr1"],"prefix":"10.3390","volume":"15","author":[{"given":"Florimar","family":"Gil","sequence":"first","affiliation":[{"name":"Fine Chemical and Natural Products Laboratory, CIDIE CONICET-UCC, Universidad Cat\u00f3lica de C\u00f3rdoba, C\u00f3rdoba X5016DHK, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-5200-4842","authenticated-orcid":false,"given":"Erika","family":"Ripani","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, College of Exact and Natural Sciences, National University of Mar del Plata\u2014QUIAMM\u2014INBIOTEC CONICET, Mar del Plata B7602AYL, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9042-6926","authenticated-orcid":false,"given":"Mariana Bel\u00e9n","family":"Joray","sequence":"additional","affiliation":[{"name":"Fine Chemical and Natural Products Laboratory, CIDIE CONICET-UCC, Universidad Cat\u00f3lica de C\u00f3rdoba, C\u00f3rdoba X5016DHK, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda Paula","family":"del Valle","sequence":"additional","affiliation":[{"name":"Department of Chemistry and Biochemistry, College of Exact and Natural Sciences, National University of Mar del Plata\u2014QUIAMM\u2014INBIOTEC CONICET, Mar del Plata B7602AYL, Argentina"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5398-2066","authenticated-orcid":false,"given":"Richard D.","family":"Cannon","sequence":"additional","affiliation":[{"name":"Sir John Walsh Research Institute, School of Dentistry, University of Otago, P.O. 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