Exploring the Structure–Activity Relationships and Molecular Mechanisms of Black Soldier Fly-Derived Antimicrobial Peptides with AI Insights

Antimicrobial resistance (AMR) was associated with 4.95 million deaths in 2019 and may cause 10 million deaths annually by 2050. We synthesize evidence on how the black soldier fly (<i>Hermetia illucens</i>) has evolved an expanded antimicrobial peptide (AMP) repertoire, which structural features drive family-specific activity, what mechanisms are directly demonstrated in <i>H. illucens</i>, and how AI contributes. PubMed, Web of Science, and Scopus (plus targeted Google Scholar) were searched from inception to 1 February 2026; studies were included when they reported BSF peptide identities, expression/proteomics, evolutionary analyses, quantitative activity, mechanistic assays, or BSF-focused computation, and claims were tiered as predicted, expression-supported, or experimentally supported. The literature supports 50-80 BSF AMP genes, plausibly shaped by gene duplication and balancing/diversifying selection in microbe-rich substrates, with marked induction plasticity across tissues, development, diet, and challenge. SAR is family-dependent: defensin-like peptides rely on disulfide-stabilized CSαβ folds and cationic surface topology; cecropin-like peptides on amphipathic α-helices with selectivity trade-offs; attacin-like peptides on β-architecture where charge-based heuristics are weak; and diptericin/proline-rich peptides remain largely inference-driven in BSF. Mechanistic evidence is strongest for membrane/envelope-centered killing by DLP4 and pore-associated envelope disruption by a recombinant attacin-like peptide, whereas pore geometry, oligomerization, intracellular targets, and broad "resistance-proof" claims remain unresolved. Key gaps include assay heterogeneity, salt/serum stability, selectivity/toxicity, resistance-risk testing, and limited <i>in vivo</i> validation, which must be addressed for credible AMR-relevant translation.