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<p>Potassium-competitive acid blockers (P-CABs), such as revaprazan (REV), act by competitively inhibiting potassium (K<sup>+</sup>) binding on the proton pump (H<sup>+</sup>/K<sup>+</sup>-ATPase) and are reversible K<sup>+</sup> antagonists. This study evaluated REV combined with triazoles (itraconazole, ITR; voriconazole, VOR; posaconazole, POS) against 30 clinical <i>Aspergillus</i> isolates (14 <i>A. fumigatus</i>, 12 <i>A. flavus</i>, 4 <i>A. terreus</i>) using MIC and FICI assays. REV demonstrated dose-dependent synergy (FICI ≤ 0.5) with POS in 90% of isolates (27/30), reducing MIC values by 4–8fold, while synergy with ITR occurred in 20% (6/30). Species-specific analysis revealed highest efficacy against <i>A. flavus</i> (91.7%, 11/12) and <i>A. terreus</i> (100%, 4/4). No synergy was observed with VOR. Furthermore, the mechanisms underlying the synergistic effects of REV with triazoles were investigated using an <i>A. fumigatus</i> major facilitator superfamily (MFS) transporter gene-deficient strains. Knockout strains <i>ΔAF-MFS32</i> and <i>ΔAF-MFS35</i>, selected from our MFS transporter gene-deficient strains, showed a abolishment of synergistic interaction when combined with REV and the triazoles ITR and POS. Suggesting a functional link between these transporters and the drug interaction. Disk diffusion and efflux pump assays corroborated these findings (<i>P</i> &lt; 0.05). These in vitro results identify REV + POS as a promising combination against <i>Aspergillus</i>, though in vivo studies and mechanistic validation of transporter inhibition are warranted.</p><p>Overall, this study shows that the potassium-competitive acid pump antagonist REV exhibits synergistic antifungal activity with triazoles in treating <i>Aspergillus</i> infections. The MFS transporter <i>AF-MFS32</i> and <i>AF-MFS35</i> are implicated as possible targets mediating the synergistic interaction between REV and these antifungal drugs.</p>

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In vitro combination effects and mechanisms of Revaprazan with Triazole antifungal drugs on Aspergillus

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月5日

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  • Wenxu Cheng,
  • Min Shen,
  • Lijia Wan,
  • Tian Chen,
  • Lingxi Wang,
  • Heng Zhang,
  • Yi Sun

摘要

Potassium-competitive acid blockers (P-CABs), such as revaprazan (REV), act by competitively inhibiting potassium (K+) binding on the proton pump (H+/K+-ATPase) and are reversible K+ antagonists. This study evaluated REV combined with triazoles (itraconazole, ITR; voriconazole, VOR; posaconazole, POS) against 30 clinical Aspergillus isolates (14 A. fumigatus, 12 A. flavus, 4 A. terreus) using MIC and FICI assays. REV demonstrated dose-dependent synergy (FICI ≤ 0.5) with POS in 90% of isolates (27/30), reducing MIC values by 4–8fold, while synergy with ITR occurred in 20% (6/30). Species-specific analysis revealed highest efficacy against A. flavus (91.7%, 11/12) and A. terreus (100%, 4/4). No synergy was observed with VOR. Furthermore, the mechanisms underlying the synergistic effects of REV with triazoles were investigated using an A. fumigatus major facilitator superfamily (MFS) transporter gene-deficient strains. Knockout strains ΔAF-MFS32 and ΔAF-MFS35, selected from our MFS transporter gene-deficient strains, showed a abolishment of synergistic interaction when combined with REV and the triazoles ITR and POS. Suggesting a functional link between these transporters and the drug interaction. Disk diffusion and efflux pump assays corroborated these findings (P < 0.05). These in vitro results identify REV + POS as a promising combination against Aspergillus, though in vivo studies and mechanistic validation of transporter inhibition are warranted.

Overall, this study shows that the potassium-competitive acid pump antagonist REV exhibits synergistic antifungal activity with triazoles in treating Aspergillus infections. The MFS transporter AF-MFS32 and AF-MFS35 are implicated as possible targets mediating the synergistic interaction between REV and these antifungal drugs.