Department of Clinical Microbiology and Infectious Diseases, Hadassah-Hebrew University Medical Center, PO Box 12000, Jerusalem 91120, Israel.
J Antimicrob Chemother. 2014 Feb;69(2):416-27. doi: 10.1093/jac/dkt365. Epub 2013 Sep 26.
The aims of this study were to develop new anti-biofilm drugs, examine their activity against Candida albicans biofilm and investigate their structure-activity relationship and mechanism of action.
A series of thiazolidinedione and succinimide derivatives were synthesized and their ability to inhibit C. albicans biofilm formation and destroy pre-formed biofilm was tested. The biofilms' structure, metabolic activity and viability were determined by XTT assay and propidium iodide and SYTO 9 live/dead stains combined with confocal microscopic analysis. The effect of the most active compounds on cell morphology, sterol distribution and cell wall morphology and composition was then determined by specific fluorescent stains and transmission electron microscopy.
Most of the compounds were active at sub-MICs. Elongation of the aliphatic side chain resulted in reduced anti-biofilm activity and the sulphur atom contributed to biofilm killing, indicating a structure-activity relationship. The compounds differed in their effects on biofilm viability, yeast-to-hyphal form transition, hyphal morphology, cell wall morphology and composition, and sterol distribution. The most effective anti-biofilm compounds were the thiazolidinedione S8H and the succinimide NA8.
We developed novel anti-biofilm agents that both inhibited and destroyed C. albicans biofilm. With some further development, these agents might be suitable for therapeutic purposes.
本研究旨在开发新型抗生物膜药物，研究其对白色念珠菌生物膜的活性，并探讨其结构-活性关系和作用机制。
合成了一系列噻唑烷二酮和琥珀酰亚胺衍生物，测试它们抑制白色念珠菌生物膜形成和破坏已形成生物膜的能力。通过 XTT 测定法以及与荧光染料碘化丙啶和 SYTO 9 活/死染色结合的共聚焦显微镜分析，确定生物膜的结构、代谢活性和活力。然后，通过特定的荧光染料和透射电子显微镜确定最活跃的化合物对细胞形态、甾醇分布以及细胞壁形态和组成的影响。
大多数化合物在亚最小抑菌浓度下具有活性。脂肪侧链的延长导致抗生物膜活性降低，而硫原子有助于生物膜杀伤，表明存在结构-活性关系。这些化合物在生物膜活力、酵母到菌丝形态转变、菌丝形态、细胞壁形态和组成以及甾醇分布方面的作用不同。最有效的抗生物膜化合物是噻唑烷二酮 S8H 和琥珀酰亚胺 NA8。
我们开发了既能抑制又能破坏白色念珠菌生物膜的新型抗生物膜剂。经过进一步开发，这些药物可能适合治疗用途。
