Ehab A Salama, Yehia Elgammal, Aruna Wijeratne, Nadia A Lanman, Sagar M Utturkar, Atena Farhangian, Jianing Li, Brigitte Meunier, Tony R Hazbun, Mohamed N Seleem
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引用次数: 0
摘要
白色念珠菌已成为一种棘手的真菌病原体,发病率和死亡率都很高。两性霉素 B(AmB)是治疗侵袭性真菌念珠菌病最有效的抗真菌药物,临床分离株很少出现耐药性。然而,念珠菌对包括两性霉素 B 在内的所有现有抗真菌药物都具有极强的耐药性。为了寻求潜在的解决方案,我们筛选了 727 种美国食品及药物管理局批准的药物。我们发现质子泵抑制剂兰索拉唑(LNP)能有效增强 AmB 对阿氏杆菌的活性。LNP 还能增强 AmB 对其他重要医学念珠菌和隐球菌的抗真菌活性。我们对其作用机制的研究发现,LNP 代谢物与线粒体呼吸链(复合体 III,即细胞色素 bc1)中的一个关键靶点相互作用。这种相互作用增加了真菌细胞内的氧化应激。我们的研究结果表明,活跃的呼吸功能在 LNP 的抗真菌活性中起着关键作用。最重要的是,LNP 恢复了 AmB 在免疫功能低下小鼠模型中的疗效,使肾脏中的阴沟肠杆菌负担减少了 1.7 个菌落(∼98%)。我们的研究结果强烈建议将 LNP 作为细胞色素 bc1 抑制剂进行全面评估,以抗击耐药性蛔虫感染。
Lansoprazole interferes with fungal respiration and acts synergistically with amphotericin B against multidrug-resistant Candida auris.
Candida auris has emerged as a problematic fungal pathogen associated with high morbidity and mortality. Amphotericin B (AmB) is the most effective antifungal used to treat invasive fungal candidiasis, with resistance rarely observed among clinical isolates. However, C. auris possesses extraordinary resistant profiles against all available antifungal drugs, including AmB. In our pursuit of potential solutions, we screened a panel of 727 FDA-approved drugs. We identified the proton pump inhibitor lansoprazole (LNP) as a potent enhancer of AmB's activity against C. auris. LNP also potentiates the antifungal activity of AmB against other medically important species of Candida and Cryptococcus. Our investigations into the mechanism of action unveiled that LNP metabolite(s) interact with a crucial target in the mitochondrial respiratory chain (complex III, known as cytochrome bc1). This interaction increases oxidative stress within fungal cells. Our results demonstrated the critical role of an active respiratory function in the antifungal activity of LNP. Most importantly, LNP restored the efficacy of AmB in an immunocompromised mouse model, resulting in a 1.7-log (∼98%) CFU reduction in the burden of C. auris in the kidneys. Our findings strongly advocate for a comprehensive evaluation of LNP as a cytochrome bc1 inhibitor for combating drug-resistant C. auris infections.
期刊介绍:
Emerging Microbes & Infections is a peer-reviewed, open-access journal dedicated to publishing research at the intersection of emerging immunology and microbiology viruses.
The journal's mission is to share information on microbes and infections, particularly those gaining significance in both biological and clinical realms due to increased pathogenic frequency. Emerging Microbes & Infections is committed to bridging the scientific gap between developed and developing countries.
This journal addresses topics of critical biological and clinical importance, including but not limited to:
- Epidemic surveillance
- Clinical manifestations
- Diagnosis and management
- Cellular and molecular pathogenesis
- Innate and acquired immune responses between emerging microbes and their hosts
- Drug discovery
- Vaccine development research
Emerging Microbes & Infections invites submissions of original research articles, review articles, letters, and commentaries, fostering a platform for the dissemination of impactful research in the field.