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Targeting F₁F₀-ATP Synthase Vulnerability: A Strategy to Overcome Antifungal Resistance

ABSTRACT: The global spread of drug-resistant fungi poses a severe challenge to the clinical treatment of invasive fungal disease (IFD). It remains unknown how drug-resistant fungi adapt to drug pressure through metabolic remodeling. We discovered that drug-resistant fungi undergo energy metabolism reprogramming, becoming highly dependent on the F₁F₀-ATP synthase, a key hub of the oxidative phosphorylation (OXPHOS) pathway, for survival. Notably, this 'metabolic addiction' is accompanied by a decline in the stress tolerance of F₁F₀-ATP synthase in both function and structure, rendering it an unexpected 'metabolic vulnerability.' Mechanistic studies indicate that the upregulated molecular chaperone HSP90 interacts with the OSCP subunit of the enzyme to enhance its activity, thereby promoting massive ATP production. However, this process drives mitochondrial hyperfunction, induces oxidative stress, and consequently impairs the functional and structural stability of F₁F₀-ATP synthase. Based on this unique vulnerability, we screened for the inhibitor F6, which specifically targets the OSCP subunit of F₁F₀-ATP synthase. F6 exhibits potent antifungal activity against drug-resistant fungi and acts synergistically with first-line clinical antifungal agents. It effectively reverses drug resistance without inducing a high risk of drug or cross-resistance. In summary, targeting the vulnerability of F₁F₀-ATP synthase in drug-resistant fungi may provide a new strategy for overcoming clinical fungal resistance.

ORGANISM(S): Candida Albicans

SUBMITTER: Hong Zhang

PROVIDER: PXD080461 | iProX | Wed Jul 01 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:Invasive fungal infections threaten the lives and health of humans, especially immunodeficient patients or hospitalized patients with serious underlying diseases, and impose a heavy economic burden on society. The emergence of drug-resistant fungi, the formation of biofilms, and the limits and side effects of existing antifungal drugs increase the difficulty of clinical treatment, and there is an urgent need for the development of novel antifungal drugs. Therefore, based on previous kinase chemical library antifungal activity screening studies, this paper further investigates the activity of the ALK inhibitor HG-14-10-04 (HG) against various fungi and elucidates its mechanism of action. The in vitro antifungal activity of HG was evaluated by micro liquid-dilution method, time-killing curve, mycelium and biofilm formation. The results showed that HG exhibited inhibitory and even fungicidal effects against sensitive and resistant Candida albicans, Candida krusei, Cryptococcus neoformans, Candida tropicalis, Candida glabrata and Candida parapsilosis (MICs=8-16 μg/mL); HG significantly inhibited the mycelium and biofilm formation, and destroyed the mature biofilm; and it exhibited synergistic antifungal effects with amphotericin B. The antifungal mechanism of HG was investigated by flow cytometry and transmission electron microscopy, etc. Sequencing analysis showed a total of 1041 differentially expressed genes, of which 666 were up-regulated and 375 were down-regulated. According to the GO functional classification results, the up-regulated genes were mainly involved in ribosome production, oxidation-reduction and other functions, while the down-regulated genes were mainly involved in the synthesis of carbohydrate, glycoproteins, glycolipids and their metabolism, GPI anchor synthesis, and cytoskeleton and other functions. In addition, HG could significantly increase the level of ROS, induce the fungal necrosis, block the cell cycle at the G0/G1 phase, and change the ultrastructure of the fungi, especially the structure of the fungal cell wall. Therefore, the enhanced inhibitory and fungicidal activity of HG may be attributed to the elevation of ROS, alteration of cellular ultrastructure (especially cell wall structure), cell cycle arrest at the G0/G1 phase, and induction of fungal necrosis, providing a basis for the discovery of novel antifungal drugs or lead compounds.

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Targeting F₁F₀-ATP Synthase Vulnerability: A Strategy to Overcome Antifungal Resistance

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