Toward microbiota-friendly design and evaluation of antimicrobial peptides: a mini-review

The rise of multidrug-resistant (MDR) bacteria driven by the prolonged use and misuse of conventional antibiotics poses a severe threat to global healthcare systems. To combat this risk, considerable research efforts have focused on the discovery of new antibacterial agents. Over the last decade, antimicrobial peptides (AMPs) have emerged as a highly promising alternative therapy due to their broad-spectrum activity and low propensity for inducing resistance. While numerous therapeutic AMPs have been introduced in the literature and examined for safety and antimicrobial efficacy, their impact on the human microbiota has remained relatively underexplored. Owing to the structural similarities between pathogenic and beneficial bacteria, some of these peptides may adversely affect commensal bacteria, especially at higher doses or following certain routes of administration. Given the importance of preserving ecological homeostasis, this review emphasizes the integration of microbiota safety evaluations at all stages of AMP design and development. It proposes a structured framework for microbiota-inclusive assessment and strategies for the design and delivery of microbiota-friendly variants. This work offers a comprehensive perspective that has received limited systematic attention, providing valuable insights for future research in microbiology and pharmacology.