New Acylglucoses from Solanum atriplicifolium as Multidrug Resistance Reversal Agents Targeting Cdr1 and Mdr1

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Abstract
The increasing prevalence of multidrug resistance (MDR) in Candida species poses a major obstacle to effective antifungal therapy. 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 µM, 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 µM. 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–transporter 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.
Funding Information
  • Catholic University of Córdoba, National University of Mar del Plata, National Scientific and Technical Research Council (PIP 2021–2023)
  • Catholic University of Córdoba, National University of Mar del Plata, National Scientific and Technical Research Council (PIP 2022–2024)
  • National Agency for Scientific and Technological Promotion (PICT 2019-2019-00721)
  • National Agency for Scientific and Technological Promotion (PICT-2020-SERIEA-01627)
  • National Agency for Scientific and Technological Promotion (PICT-2021-CAT-II-00045)
  • National Agency for Scientific and Technological Promotion (PICT-2023-2027-I-A-00940)
  • Secretary of Innovation, Science and Technology of Argentina (Clementina XXI, IPAC PCI_123)

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