Visible‐Light‐Activated Molecular Machines Kill Fungi by Necrosis Following Mitochondrial Dysfunction and Calcium Overload

Abstract

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.

Nonlethal Molecular Nanomachines Potentiate Antibiotic Activity Against Gram-Negative Bacteria by Increasing Cell Permeability and Attenuating Efflux

“…18 MNMs also exhibit potent antimicrobial activity. 14,19 Indeed, we have previously described a library of visible-light-activated MNMs that exhibited significant antibacterial activity. However, these antibacterial MNMs displayed limited biocompatibility with mammalian cells, 14 which was partly due to the high doses of light required to elicit the bactericidal activity of MNMs.…”

“…Visible-light-activated molecular nanomachines (MNMs) have been increasingly recognized for their potential in various biological applications, from killing cancer cells , to modulating cell signaling . MNMs also exhibit potent antimicrobial activity. , Indeed, we have previously described a library of visible-light-activated MNMs that exhibited significant antibacterial activity. However, these antibacterial MNMs displayed limited biocompatibility with mammalian cells, which was partly due to the high doses of light required to elicit the bactericidal activity of MNMs .…”

Distinguishing Molecular Mechanical Action from Photothermal and Photodynamic Behavior

“…Irradiation of cells treated with 0.5 × 10 −6 m of MM causes rapid cell death (Figure 5b,c), with a time-to-necrosis of the terms of the CC-BY license. [12] Copyright 2023, The Authors, Wiley-VCH.…”

“…d) Administration of MitoTempo is insufficient to prevent cell death in C. albicans treated with MM 1 (1× MIC). Figures adapted with permissionunderthe terms of the CC-BY license [12]. Copyright 2023, The Authors, Wiley-VCH.…”

Light-activation of molecular motors in polymersomes

“…These motors can also kill fungi by disrupting the mitochondrial phospholipid membrane. 16 Moreover, at lower light intensities (5-60 mW cm −2 ), the motors rotate slower, allowing the modulation of the membrane fluidity without disassembling the bilayer, which was used to promote the transport of K + ions in synthetic lipid vesicles and cancer cells. 17,18 Remarkably, motors designed to rotate at lower frequencies (mHz) facilitated up to 18% of cargo release from lipid vesicles when irradiated at 0.2 mW cm −2 .…”