Antimicrobial Peptides Emerge as Promising Alternative to Antibiotics in Oral Disease Treatment

Antimicrobial peptides (AMPs) are emerging as a promising alternative to traditional antibiotics for treating oral diseases that affect approximately 3.5 billion people globally, according to a comprehensive review published in Translational Dental Research. The study examines AMP classification, antimicrobial mechanisms, and therapeutic applications for major oral conditions including dental caries, periodontitis, oral cancer, oral candidiasis, and oral mucositis.

Traditional treatments for oral diseases have primarily relied on antibiotics, but widespread bacterial resistance has significantly reduced their efficacy. AMPs, which are small-molecule polypeptides and key components of the innate immune system, offer a different approach. Unlike traditional antibiotics that target specific metabolic pathways, AMPs primarily act by physically destroying microbial cell membranes—a mechanism that minimizes the risk of inducing resistance. Additionally, AMPs possess multiple biological functions including regulating immune responses, reducing inflammation, and promoting tissue repair, with high biocompatibility to human cells.

In the treatment of dental caries, AMPs like Temporin-GHa derivatives, ZXR-2, and GH12 can inhibit the growth of cariogenic bacteria such as Streptococcus mutans, interfere with biofilm formation, and even promote tooth remineralization. For periodontitis, human-derived AMPs (e.g., α-defensins, β-defensins) and synthetic peptides (e.g., Nal-P-113) effectively kill periodontal pathogens, regulate inflammatory responses by inhibiting pro-inflammatory cytokine secretion, and enhance periodontal tissue regeneration.

In oral cancer therapy, AMPs such as Piscidin-1 and LL-37 induce cancer cell death through membrane disruption and apoptotic pathways while also modulating anti-tumor immune responses. AMPs like P-113 and Nisin A have shown significant efficacy in treating oral candidiasis, and peptides such as IB-367 and Histatin-5 alleviate oral mucositis by inhibiting infection and promoting wound healing.

Several AMPs have entered clinical trials, including C16G2 for dental caries, Nal-P-113 for periodontitis, and P-113 for oral candidiasis, demonstrating their clinical potential. Beyond direct therapy, AMPs are being developed into implant coatings to prevent peri-implant infections, oral dressings for sustained release, and combined with antibiotics or nanoparticles to enhance therapeutic effects. They also show promise as diagnostic markers for oral diseases by detecting changes in their expression levels.

However, clinical translation of AMPs faces significant challenges: oral enzymes, pH fluctuations, and high salt concentrations affect their stability; cationic and amphiphilic properties may lead to cytotoxicity and immunogenicity; and large-scale production is costly. Researchers have developed strategies such as chemical modification (e.g., N-acetylation, lipidation), nanocarrier delivery systems, sequence optimization with D-amino acids, and microbial/plant-based heterologous expression to improve stability, reduce toxicity, and lower production costs.

The full study is available at https://doi.org/10.1016/j.tdr.2025.100046. Future research should focus on clarifying AMP interaction mechanisms with oral microbiota and host cells, accelerating peptide screening through artificial intelligence, and developing tailored formulations for the oral microenvironment to promote clinical application.