Scholarlink

<p><i>Candida albicans</i> is a commensal fungus that naturally inhabits the vagina. However, overgrowth of <i>C. albicans</i> can result in vulvovaginal candidiasis (VVC), one of the most prevalent fungal infections affecting women. The rapid emergence of azole resistance in <i>C. albicans</i>, in addition to the limited available antifungal agents, complicates the treatment and emphasizes the urgent need for novel therapeutic options. Efflux-mediated azole resistance is a common resistance mechanism in fluconazole (FLZ)-resistant <i>C. albicans.</i> Combination therapy using natural compounds is a potential approach that can restore fluconazole’s antifungal activity in azole-resistant isolates via efflux pump inhibition. This study aimed to evaluate the ability of celastrol, a natural triterpene, to retrieve FLZ antifungal activity against azole-resistant <i>C. albicans in vitro</i> and <i>in vivo</i>. Celastrol did not exhibit antifungal activity against the tested clinical isolates; however, the sub-MIC of celastrol inhibited rhodamine 6G (R6G) efflux and increased R6G accumulation inside celastrol-treated <i>C. albicans</i> cells. Synergy was spotted between celastrol and FLZ via a checkerboard assay. Quantification of m-RNA levels of efflux-mediated azole resistance genes within azole-resistant <i>C. albicans</i> demonstrated <i>CDR1</i> overexpression. Upon celastrol treatment, a significant decline in ABC transporters transcript levels were detected. Moreover, molecular docking demonstrated that celastrol is a potential ABC efflux transporters blocker that successfully fits into target binding pockets. A negligible hemolytic effect of celastrol against human erythrocytes was observed. In the <i>in vivo</i> model of VVC, the combination of FLZ and celastrol in vaginal gel revealed a drastic reduction in the fungal burden with apparently normal vaginal tissue. Celastrol promising <i>in vitro</i> and <i>in vivo</i> findings strengthen its future use for the treatment of azole-resistant <i>C. albicans.</i></p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Celastrol boosts fluconazole efficacy against vaginal candidiasis: in vitro and in vivo evidence

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年1月29日

查看全文
  • Fatma Al-zahraa A. Yehia,
  • Hisham A Abbas,
  • Tarek M. Ibrahim,
  • Basem Mansour,
  • Zuhier A. Awan,
  • Mohammed W. Al-Rabia,
  • Wesam H. Abdulaal,
  • Mustafa Adnan Zeyadi,
  • Solomon Z. Okbazghi,
  • Tarek S. Ibrahim,
  • Wael A. H. Hegazy,
  • Salwa E. Gomaa

摘要

Candida albicans is a commensal fungus that naturally inhabits the vagina. However, overgrowth of C. albicans can result in vulvovaginal candidiasis (VVC), one of the most prevalent fungal infections affecting women. The rapid emergence of azole resistance in C. albicans, in addition to the limited available antifungal agents, complicates the treatment and emphasizes the urgent need for novel therapeutic options. Efflux-mediated azole resistance is a common resistance mechanism in fluconazole (FLZ)-resistant C. albicans. Combination therapy using natural compounds is a potential approach that can restore fluconazole’s antifungal activity in azole-resistant isolates via efflux pump inhibition. This study aimed to evaluate the ability of celastrol, a natural triterpene, to retrieve FLZ antifungal activity against azole-resistant C. albicans in vitro and in vivo. Celastrol did not exhibit antifungal activity against the tested clinical isolates; however, the sub-MIC of celastrol inhibited rhodamine 6G (R6G) efflux and increased R6G accumulation inside celastrol-treated C. albicans cells. Synergy was spotted between celastrol and FLZ via a checkerboard assay. Quantification of m-RNA levels of efflux-mediated azole resistance genes within azole-resistant C. albicans demonstrated CDR1 overexpression. Upon celastrol treatment, a significant decline in ABC transporters transcript levels were detected. Moreover, molecular docking demonstrated that celastrol is a potential ABC efflux transporters blocker that successfully fits into target binding pockets. A negligible hemolytic effect of celastrol against human erythrocytes was observed. In the in vivo model of VVC, the combination of FLZ and celastrol in vaginal gel revealed a drastic reduction in the fungal burden with apparently normal vaginal tissue. Celastrol promising in vitro and in vivo findings strengthen its future use for the treatment of azole-resistant C. albicans.