Human gut microbiota-derived antimicrobials against Salmonella Typhi: diversity, mechanisms, and therapeutic potential.

Salmonella enterica serovar Typhi (S. Typhi) is a strictly human-restricted Gram-negative pathogen and the causative agent of typhoid fever, a major global health concern. Current treatment relies heavily on antibiotics, however, the rapid emergence of multidrug-resistant strains has severely compromised their efficacy, underscoring the urgent need for alternative therapeutic strategies. The human gut microbiota has emerged as a promising source of antimicrobial molecules, including both peptide and non-peptide compounds. These microbiota-derived agents can inhibit Gram-negative pathogens through diverse mechanisms, such as direct bactericidal activity, modulation of host immune responses, and promotion of colonization resistance. Recent advances in artificial intelligence (AI) and multi-omics technologies have further accelerated the discovery and functional characterization of gut-derived antimicrobials with potent activity against drug-resistant bacteria. In this review, we summarize current understanding of S. Typhi pathogenesis and resistance, highlight the diversity and mechanisms of gut microbiota-derived antimicrobials, and explore their translational potential as innovative therapeutic options for typhoid fever.