When Antifungal Drugs Fail, Do We Have a Backup Plan? Antimicrobial Peptides Emerge as New Hope Against "Superfungi"

Globally, with the increasing number of immunocompromised patients, advancements in intensive care, and the widespread use of immunosuppressive drugs, the incidence and mortality rates of invasive fungal infections are continuously rising. Facing this severe challenge, the World Health Organization (WHO), for the first time in 2022, released a "Fungal Priority Pathogens List," categorizing Candida auris, Aspergillus fumigatus, Cryptococcus neoformans, and Candida albicansas "critical priority" pathogens. These fungi not only possess multidrug resistance but also exhibit strong capabilities in biofilm formation and host immune evasion mechanisms, leading to frequent failures of existing antifungal drugs in clinical treatment.

In this context, Antimicrobial Peptides (AMPs), as an emerging therapeutic strategy, are garnering high attention from scientists and clinicians. The review titled "Repositioning Antimicrobial Peptides Against WHO‐Priority Fungi" published in Advanced Sciencesystematically revisits the mechanisms, optimization strategies, and application prospects of AMPs in antifungal therapy, offering new ideas to combat drug-resistant fungi.

▌ Antimicrobial Peptides: Not Just "Killers," but "Versatile Players"

Antimicrobial peptides are a class of small molecular peptides naturally occurring in organisms, possessing broad-spectrum antimicrobial activity. Unlike traditional antifungal drugs that typically target a single site (e.g., cell wall or membrane synthesis), AMPs act through synergistic multiple mechanisms:

• Rapid Disruption of Fungal Cell Membranes:​ Through electrostatic interactions, they recognize and bind to negatively charged components on the fungal cell membrane, forming pores that lead to leakage of cellular contents.
• Interference with Intracellular Signaling Pathways:​ Some AMPs can enter fungal cells, inducing mitochondrial dysfunction, reactive oxygen species accumulation, and even regulating programmed cell death.

• Modulation of Host Immune Response:​ Certain AMPs can recruit macrophages, regulate the release of inflammatory factors, and enhance the host's own ability to clear fungi.

This "multi-target" mechanism of action makes it difficult for fungi to develop resistance through single mutations, offering potential to address the current clinical dilemma of drug resistance.

▌ From Natural to Synthetic: The "Engineering" of Antimicrobial Peptides

Although natural AMPs possess good bioactivity, their clinical application has been limited by issues such as susceptibility to degradation in vivo, short half-lives, and potential toxic side effects. To address this, researchers have optimized them through various strategies:

• Structural Modifications:​ Such as cyclization, lipidation, PEGylation, etc., to enhance their stability.
• Nanocarrier Delivery:​ Utilizing liposomes, metal nanoparticles, etc., as carriers to improve their targeting and bioavailability.
• Computational-Aided Design:​ Combining artificial intelligence and deep learning to predict novel AMP sequences with high activity and low toxicity.

For example, the AI platform DL-QSARES successfully designed the antimicrobial peptide AFP-13 by analyzing thousands of peptide sequences. It demonstrated significant antifungal effects in animal models with relatively low cytotoxicity to host cells.

▌ Preclinical and Clinical Progress: Preliminary Efficacy of AMPs

In numerous preclinical studies, AMPs have shown encouraging results. For instance:

• In experiments against Candida glabrataand Candida auris, certain AMPs combined with existing drugs (e.g., caspofungin) significantly reduced the Minimum Inhibitory Concentration (MIC) and improved efficacy.
• In animal infection models, nano-formulations loaded with AMPs effectively reduced fungal burden and increased survival rates.

Currently, several AMPs have entered clinical trial stages, such as PAC113 for oral candidiasis and hLF1-11 for systemic infections. Preliminary results show good safety and tolerability.

▌ Challenges Remain, but the Future is Promising

Despite the promising prospects of AMPs, their path to the clinic still faces many challenges:

• High Cost of Large-Scale Production:​ Complex chemical synthesis and purification processes hinder their large-scale application.
• Balancing Immunogenicity and Toxicity:​ Sequences need further optimization to avoid triggering excessive immune responses or damaging host cells.
• Low but Not Zero Risk of Resistance:​ Studies have found that fungi can combat AMPs by altering cell membrane composition or secreting proteases, necessitating vigilance against potential resistance risks.

▌ Conclusion

As a class of therapeutic molecules combining direct fungicidal and immunomodulatory functions, antimicrobial peptides hold promise as a "next-generation weapon" against drug-resistant fungal infections. With the integrated development of synthetic biology, nanotechnology, and artificial intelligence, we have reason to believe that more efficient and safe AMP-based drugs will gradually reach the clinic, providing new solutions for the global prevention and control of fungal infections.

Looking ahead, it is necessary not only to strengthen basic research to reveal the deeper mechanisms of interaction between AMPs and fungi but also to promote interdisciplinary collaboration to accelerate their translation from the laboratory to the bedside. Perhaps in the near future, antimicrobial peptides can truly become a key force in our fight against "superfungi."

Original Article：

Roque-Borda CA, Medina-Alarcón KP, Gonçalves Pereira JPS, Sevilhano TCDA, Aguilar-Morón B, Díaz-Cárdenas F, da Cruz LS, Xavier-Júnior FH, Vicente EF, Perdigão J, de la Torre BG, Albericio F, Pavan FR. Repositioning Antimicrobial Peptides Against WHO-Priority Fungi. Adv Sci (Weinh). 2025 Oct;12(37):e09567.

doi: 10.1002/advs.202509567. Epub 2025 Aug 30.