Wnętrzak Anita, Feder-Kubis Joanna, Chachaj-Brekiesz Anna, Łukawski Krzysztof, Kobierski Jan, Petelska Aneta D, Dynarowicz-Latka Patrycja
Faculty of Chemistry, Jagiellonian University, Gronostajowa 2, 30-387 Kraków, Poland.
Department of Inorganic Chemistry, Technische Universität Dresden, 01069 Dresden, Germany; Faculty of Chemistry, Wrocław University of Science and Technology, Wybrzeże Wyspiańskiego 27, 50-370 Wrocław, Poland.
Arch Biochem Biophys. 2025 Sep;771:110524. doi: 10.1016/j.abb.2025.110524. Epub 2025 Jun 26.
The development of selective antifungal agents is crucial to improve therapeutic options while minimizing side effects. This study assessed the potential antimicrobial efficacy of ionic liquids, particularly against fungal pathogens. For this, a functionalized chiral ionic liquid (FCIL) with a naturally occurring (1R,2S,5R)-(-)-menthol moiety and a long alkyl chain was synthesized and characterized using spectral and thermal methods. The antifungal potential of this FCIL was evaluated by examining interactions with artificial fungal and mammalian membranes modeled as Langmuir monolayers. Thermodynamic analyses, complemented by adsorption and penetration experiments, Brewster angle microscopy, polarization modulation infrared reflection absorption spectroscopy, and molecular dynamics simulations, showed that FCIL incorporated into membranes and caused fungal membrane disintegration. This can be related to π-π interactions with ergosterol, a primary fungal membrane sterol, and favorable assimilation into membranes containing dioleoylphosphatidylcholine, an unsaturated phospholipid abundant in fungal cells. Conversely, interactions with mammalian membranes modeled using dipalmitoylphosphatidylcholine and cholesterol were thermodynamically unfavorable due to their tighter packing. These findings underline the FCIL's ability to selectively disrupt fungal membranes and suggest its potential use as a targeted antifungal agent with reduced mammalian cell toxicity. This research highlights the benefit of integrating experimental and computational methods to understand the molecular mechanics driving selective antifungal activity.
开发选择性抗真菌药物对于改善治疗选择并同时将副作用降至最低至关重要。本研究评估了离子液体的潜在抗菌功效，尤其是对真菌病原体的功效。为此，合成了一种具有天然存在的(1R,2S,5R)-(-)-薄荷醇部分和长烷基链的功能化手性离子液体(FCIL)，并使用光谱和热分析方法对其进行了表征。通过检查与模拟为朗缪尔单分子层的人工真菌膜和哺乳动物膜的相互作用，评估了该FCIL的抗真菌潜力。热力学分析，辅以吸附和渗透实验、布鲁斯特角显微镜、偏振调制红外反射吸收光谱和分子动力学模拟，表明FCIL融入膜中并导致真菌膜解体。这可能与与麦角甾醇（一种主要的真菌膜甾醇）的π-π相互作用以及顺利同化到含有二油酰磷脂酰胆碱（一种在真菌细胞中丰富的不饱和磷脂）的膜中有关。相反，由于其紧密堆积，与使用二棕榈酰磷脂酰胆碱和胆固醇模拟的哺乳动物膜的相互作用在热力学上是不利的。这些发现强调了FCIL选择性破坏真菌膜的能力，并表明其作为具有降低哺乳动物细胞毒性的靶向抗真菌剂的潜在用途。这项研究突出了整合实验和计算方法以了解驱动选择性抗真菌活性的分子机制的益处。
