Journal
ADVANCED SCIENCE
Volume 10, Issue 10, Pages -Publisher
WILEY
DOI: 10.1002/advs.202205781
Keywords
antifungal; fungal mitochondrial phospholipids; molecular machines; reduction of infection-associated mortality and fungal burden; visible light activation
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405-nm-visible-light-activated synthetic molecular machines (MMs) effectively eliminate fungal infections without resistance development. They bind to fungal mitochondrial phospholipids and produce a drilling effect upon visible light activation, leading to mitochondrial dysfunction and cell death. Additionally, they enhance the effectiveness of conventional antifungals by impairing energy-dependent efflux pumps.
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 approximate to 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.
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