Screening the CALIBR ReFRAME Library in Search for Inhibitors of Candida auris Biofilm Formation.
Screening the CALIBR ReFRAME Library in Search for Inhibitors of Candida auris Biofilm Formation.
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DOI：
10.3389/fcimb.2020.597931
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发表时间：
2020
影响因子：
5.7
通讯作者：
Lopez-Ribot JL
中科院分区：
文献类型：
--
作者：
Wall G;Chen E;Hull MV;Lopez-Ribot JL
金黄色念珠菌是一种新兴的酵母，自从大约十年前首次分离以来，它已经迅速传播，并在世界各地的卫生保健机构引发了重大传染病暴发。金黄色葡萄球菌菌株通常对临床使用的抗真菌药物表现出抗药性，导致高死亡率。因此，迫切需要新的抗真菌药物来遏制这种新的多重耐药病原体的传播，并改善患者的预后。然而，一种新的抗真菌药物的开发时间通常超过10-15年。因此，改变现有药物的用途可以大大加快治疗金黄色葡萄球菌感染的新疗法的开发和最终部署。为此，在这项研究中，我们建立了一个已知药物文库，其中包括大约12,000个临床阶段或FDA批准的小分子，以寻找对金黄色葡萄球菌具有抗真菌活性的已知分子；更具体地说，那些能够抑制金黄色葡萄球菌生物被膜形成的分子。从这个文库中，初步筛选出100个具有抗真菌活性的化合物，其中26个化合物可以确定其对金黄色葡萄球菌的生物膜抑制活性具有剂量-反应关系。在这些人中，有五人被确定为最有趣的潜在可重新定位候选人。由于它们已知的药理和人体安全特性，对这些化合物的鉴定应该允许它们加速临床前和临床开发，用于治疗金黄色葡萄球菌感染。
Candida auris is an emerging yeast which, since its first isolation about a decade ago, has spread rapidly and triggered major infectious outbreaks in health care facilities around the world. C. auris strains often display resistance to clinically-used antifungal agents, contributing to high mortality rates. Thus, there is an urgent need for new antifungals to contain the spread of this emerging multi-drug resistant pathogen and to improve patient outcomes. However, the timeline for the development of a new antifungal agent typically exceeds 10‑15 years. Thus, repurposing of current drugs could significantly accelerate the development and eventual deployment of novel therapies for the treatment of C. auris infections. Toward this end, in this study we have profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules in search for known molecules with antifungal activity against C. auris; more specifically, those capable of inhibiting C. auris biofilm formation. From this library, 100 compounds displaying antifungal activity were identified in the initial screen, including 26 compounds for which a dose-response relationship with biofilm-inhibitory activity against C. auris could be confirmed. Of these, five were identified as the most interesting potential repositionable candidates. Due to their known pharmacological and human safety profiles, identification of such compounds should allow for their accelerated preclinical and clinical development for the treatment of C. auris infections.
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DOI：
10.1073/pnas.1810137115
发表时间：
2018-10-16
影响因子：
11.1
作者：
Janes J;Young ME;Chen E;Rogers NH;Burgstaller-Muehlbacher S;Hughes LD;Love MS;Hull MV;Kuhen KL;Woods AK;Joseph SB;Petrassi HM;McNamara CW;Tremblay MS;Su AI;Schultz PG;Chatterjee AK
通讯作者：
Chatterjee AK
影响因子：
4.5
作者：
Cadnum, Jennifer L.;Shaikh, Aaron A.;Donskey, Curtis J.
通讯作者：
Donskey, Curtis J.
影响因子：
4.7
作者：
Dewaele, Klaas;Lagrou, Katrien;Vernelen, Kris
通讯作者：
Vernelen, Kris
影响因子：
4.9
作者：
Machado Vila, Taissa Vieira;Chaturvedi, Ashok K.;Lopez-Ribot, Jose L.
通讯作者：
Lopez-Ribot, Jose L.
影响因子：
3
作者：
Romera, David;Jairo Aguilera-Correa, John;Esteban, Jaime
通讯作者：
Esteban, Jaime