Donlin Maureen J, Zunica Anthony, Lipnicky Ashlyn, Garimallaprabhakaran Aswin K, Berkowitz Alex J, Grigoryan Alexandre, Meyers Marvin J, Tavis John E, Murelli Ryan P
Edward A. Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, St. Louis, Missouri, USA
Department of Molecular Microbiology and Immunology, Saint Louis University School of Medicine, St. Louis, Missouri, USA.
Antimicrob Agents Chemother. 2017 Mar 24;61(4). doi: 10.1128/AAC.02574-16. Print 2017 Apr.
is a pathogen that is common in immunosuppressed patients. It can be treated with amphotericin B and fluconazole, but the mortality rate remains 15 to 30%. Thus, novel and more effective anticryptococcal therapies are needed. The troponoids are based on natural products isolated from western red cedar, and have a broad range of antimicrobial activities. Extracts of western red cedar inhibit the growth of several fungal species, but neither western red cedar extracts nor troponoid derivatives have been tested against We screened 56 troponoids for their ability to inhibit growth and to assess whether they may be attractive candidates for development into anticryptococcal drugs. We determined MICs at which the compounds inhibited 80% of cryptococcal growth relative to vehicle-treated controls and identified 12 compounds with MICs ranging from 0.2 to 15 μM. We screened compounds with MICs of ≤20 μM for cytotoxicity in liver hepatoma cells. Fifty percent cytotoxicity values (CCs) ranged from 4 to >100 μM. The therapeutic indexes (TI, CC/MIC) for most of the troponoids were fairly low, with most being <8. However, two compounds had TI values that were >8, including a tropone with a TI of >300. These tropones are fungicidal and are not antagonistic when used in combination with fluconazole or amphotericin B. Inhibition by these two tropones remains unchanged under conditions favoring cryptococcal capsule formation. These data support the hypothesis that troponoids may be a productive scaffold for the development of novel anticryptococcal therapies.
是一种在免疫抑制患者中常见的病原体。它可以用两性霉素B和氟康唑治疗，但死亡率仍为15%至30%。因此，需要新的、更有效的抗隐球菌疗法。类卓酚酮基于从西部红雪松中分离出的天然产物，具有广泛的抗菌活性。西部红雪松提取物能抑制几种真菌的生长，但西部红雪松提取物和类卓酚酮衍生物均未针对[未提及的相关内容]进行测试。我们筛选了56种类卓酚酮抑制[未提及的相关内容]生长的能力，并评估它们是否可能是开发抗隐球菌药物的有吸引力的候选物。我们确定了相对于载体处理对照，化合物抑制80%隐球菌生长的最低抑菌浓度（MIC），并鉴定出12种MIC范围为0.2至15μM的化合物。我们筛选了MIC≤20μM的化合物在肝癌细胞中的细胞毒性。50%细胞毒性值（CC）范围为4至>100μM。大多数类卓酚酮的治疗指数（TI，CC/MIC）相当低，大多数<8。然而，有两种化合物的TI值>8，包括一种TI>300的卓酚酮。这些卓酚酮具有杀菌作用，与氟康唑或两性霉素B联合使用时无拮抗作用。在有利于隐球菌荚膜形成的条件下，这两种卓酚酮的抑制作用保持不变。这些数据支持了类卓酚酮可能是开发新型抗隐球菌疗法的有效支架的假设。
