Department of Chemistry, Rice University, Houston, TX, 77005, USA.
IdISBA - Fundación de Investigación Sanitaria de las Islas Baleares, Palma, 07120, Spain.
Adv Sci (Weinh). 2023 Apr;10(10):e2205781. doi: 10.1002/advs.202205781. Epub 2023 Jan 30.
Invasive fungal infections are a growing public health threat. As fungi become increasingly resistant to existing drugs, new antifungals are urgently needed. Here, it is reported that 405-nm-visible-light-activated synthetic molecular machines (MMs) eliminate planktonic and biofilm fungal populations more effectively than conventional antifungals without resistance development. Mechanism-of-action studies show that MMs bind to fungal mitochondrial phospholipids. Upon visible light activation, rapid unidirectional drilling of MMs at ≈3 million cycles per second (MHz) results in mitochondrial dysfunction, calcium overload, and ultimately necrosis. Besides their direct antifungal effect, MMs synergize with conventional antifungals by impairing the activity of energy-dependent efflux pumps. Finally, MMs potentiate standard antifungals both in vivo and in an ex vivo porcine model of onychomycosis, reducing the fungal burden associated with infection.
侵袭性真菌感染是一个日益严重的公共卫生威胁。随着真菌对现有药物的耐药性不断增加，我们迫切需要新的抗真菌药物。本文报道了 405nm 可见光激活的合成分子机器（MMs）比传统抗真菌药物更有效地消除浮游和生物膜真菌种群，而不会产生耐药性。作用机制研究表明，MMs 与真菌线粒体磷脂结合。在可见光激活后，MMs 以 ≈300 万次/秒（MHz）的速度快速单向钻进，导致线粒体功能障碍、钙超载，最终导致坏死。除了直接的抗真菌作用外，MMs 通过抑制能量依赖性外排泵的活性与传统抗真菌药物协同作用。最后，MMs 在体内和猪指甲真菌病的体外模型中增强了标准抗真菌药物的疗效，降低了与感染相关的真菌负荷。
