Antimicrobial Peptides Targeting Salmonella enterica serovar Typhi: Mechanism of Action, Structural Insights, and Translational Challenges - A Review.

The emergence of multidrug- and extensively drug-resistant Salmonella enterica serovar Typhi has become a major global health concern, particularly in regions with limited sanitation and healthcare infrastructure. The declining effectiveness of conventional antibiotics has intensified the search for alternative antimicrobial strategies. Antimicrobial peptides (AMPs), short cationic molecules that form a fundamental component of innate immunity, have gained increasing attention due to their rapid bactericidal activity, multifunctional mechanisms, and reduced propensity for resistance development. This review systematically summarizes the sources, structural characteristics, and mechanism of action of AMPs investigated against S. typhi, with particular emphasis on their antibacterial mechanisms, therapeutic potential, and challenges in the treatment of S. typhi infections. A PRISMA-guided literature search was conducted using PubMed, Scopus, and ScienceDirect, complemented by manual screening of relevant studies. Multiple AMPs, including human β-defensins, cathelicidins, and peptides derived from microbial, marine, and synthetic origins, demonstrated notable in vitro and in vivo activity against S. typhi. These peptides display diverse structural conformations, such as α-helical, β-sheet, and mixed architectures, which influence their interactions with bacterial membranes, intracellular targets, and other cellular components, thereby contributing to their antimicrobial potency. Despite encouraging preclinical findings, challenges related to stability, toxicity, and delivery continue to limit clinical translation. Overall, AMPs represent promising candidates for addressing drug-resistant S. typhi infections, with future progress dependent on optimized peptide design and advanced delivery strategies.