###### Abstract  
Overcoming the growing challenge of antimicrobial resistance (AMR), which affects millions of people worldwide, has driven attention for the exploration of marine-derived antimicrobial peptides (AMPs) for innovative solutions. Cnidarians, such as corals, sea anemones, and jellyfish, are a promising valuable resource of these bioactive peptides due to their robust innate immune systems yet are still poorly explored. Hence, we employed an in silico proteolysis strategy to search for novel AMPs from omics data of 111 Cnidaria species. Millions of peptides were retrieved and screened using shallow- and deep-learning models, prioritizing AMPs with a reduced toxicity and with a structural distinctiveness from characterized AMPs. After complex network analysis, a final dataset of 3130 Cnidaria singular non-haemolytic and non-toxic AMPs were identified. Such unique AMPs were mined for their putative antibacterial activity, revealing 20 favourable candidates for in vitro testing against important ESKAPEE pathogens, offering potential new avenues for antibiotic development. C nidaria; antimicrobial; omics; artificial intelligence; complex networks +
Footnote †: journal: _mocules_  
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charged membranes of microorganisms over the mammalian membranes [3; 4; 6; 7]. To accelerate the development of AMPs as therapeutic agents, researchers have compiled comprehensive databases that have integrated information from various sources and analysis tools [8]. The StarPepDB [9], a graph database that integrates peptides and their metadata from 40 distinct AMP databases, stands out as one of the most complete curated repositories, addressing challenges related to data redundancy, duplication, and user interface. Other notable databases include DRAMP (Data Repository of Antimicrobial Peptides) [10] and DBAASP (Database of Antimicrobial Activity and Structure of Peptides) [11], which have been continuously updated to provide researchers with valuable resources. Marine invertebrates, having evolved in challenging environments for more than 450 million years with high microbial and viral loads (about \(10^{6}\) bacteria/mL and \(10^{9}\) virus/mL of seawater [12]) and without adaptative immune responses, have developed robust innate immune systems that rely heavily on AMP production [4; 6; 13]. Hence, these animals have gained increasing attention as a source of AMPs, with unique structures and diverse antimicrobial activities, accounting for 67% of all marine-derived AMPs (statistics as of December 2022) [7; 13]. AMPs have been identified in horseshoe crabs [14; 15], polychaetas [16; 17], mussels [18; 19], ascidians [20; 21], and sea urchins [22; 23]. While AMPs have been isolated from numerous marine invertebrates, cnidarians-encompassing Anthozoa (corals and sea anemones) and Medusozoa (jellyfish and hydroids)--stand out as particularly promising organisms. To date, around 13 AMPs from this group have been thoroughly characterized (Table 1). With an estimated 13,300 species, these venomous animals possess nematocysts, specialized singing cells loaded with toxins, which are used for both hunting and protection [24; 25; 26; 27]. The pioneering isolation of Aurelin from the scyphoid jellyfish _Aurelia aurita_ marked a significant breakthrough in cnidarian AMP research. This peptide, extracted from the mesoglea, demonstrated potent antimicrobial activity against both Gram-positive and Gram-negative bacteria, and its unique structure set it apart from other known AMPs [28]. Later, Damicornin, isolated from the stony coral _Pocillopora damicornis_, has exhibited both antibacterial and antifungal properties [29]. Intriguingly, some sea anemone's neurotoxins also possess antimicrobial properties, suggesting a dual role in their survival.