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Here, it is reported that 405\u2010nm\u2010visible\u2010light\u2010activated synthetic molecular machines (MMs) eliminate planktonic and biofilm fungal populations more effectively than conventional antifungals without resistance development. Mechanism\u2010of\u2010action studies show that MMs bind to fungal mitochondrial phospholipids. Upon visible light activation, rapid unidirectional drilling of MMs at \u22483 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\u2010dependent 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.<\/jats:p>","DOI":"10.1002\/advs.202205781","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T09:40:36Z","timestamp":1675071636000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Visible\u2010Light\u2010Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload"],"prefix":"10.1002","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5450-9414","authenticated-orcid":false,"given":"Ana L.","family":"Santos","sequence":"first","affiliation":[{"name":"Department of Chemistry Rice University  Houston TX 77005 USA"},{"name":"IdISBA \u2013 Fundaci\u00f3n de Investigaci\u00f3n Sanitaria de las Islas Baleares  Palma 07120 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2787-3712","authenticated-orcid":false,"given":"Jacob L.","family":"Beckham","sequence":"additional","affiliation":[{"name":"Department of Chemistry Rice University  Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7877-5477","authenticated-orcid":false,"given":"Dongdong","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Chemistry Rice University  Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5295-7769","authenticated-orcid":false,"given":"Gang","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Chemistry Rice University  Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"van Venrooy","sequence":"additional","affiliation":[{"name":"Department of Chemistry Rice University  Houston TX 77005 USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonio","family":"Oliver","sequence":"additional","affiliation":[{"name":"IdISBA \u2013 Fundaci\u00f3n de Investigaci\u00f3n Sanitaria de las Islas Baleares  Palma 07120 Spain"},{"name":"Servicio de Microbiologia Hospital Universitari Son Espases  Palma 07120 Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3737-8491","authenticated-orcid":false,"given":"George P.","family":"Tegos","sequence":"additional","affiliation":[{"name":"Office of Research Reading Hospital  Tower Health, 420 S. 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