Optimized Antimicrobial Peptide Jelleine-I Derivative Br-J-I Inhibits Fusobacterium Nucleatum to Suppress Colorectal Cancer Progression

Colorectal cancer (CRC) is a major health burden worldwide due to its high morbidity, mortality, and complex etiology.Fusobacterium nucleatum(Fn), a Gram-negative anaerobe found in 30% of CRC patients, promotes CRC carcinogenesis, metastasis, and chemoresistance. Effective antimicrobial treatment is an unmet need for the rising CRC burden. Antimicrobial peptides (AMPs) represent a new class of antimicrobial drugs. In our previous study, we did the structure-activity study of Jelleine-I (J-I) and identified several halogenated J-I derivatives Cl-J-I, Br-J-I, and I-J-I. To determine whether those J-I derivatives can be a new therapy for bacterial-associated CRC, here we tested the antibacterial activities of these AMPs againstFnand their effects on CRC development. We found that Br-J-I showed the highest anti-Fnactivity and Br-J-I may target membrane-associated FadA forFnmembrane disruption. More importantly,Fnpromoted the growth of CRC cells-derived xenograft tumors. Br-J-I suppressedFnload, colon inflammation, andFn-induced CRC growth. Of note, Br-J-I induced better anti-CRC effects than common antibiotic metronidazole and Br-J-I sensitized the cancer-killing effect of chemotherapy drug 5-fluorouracil. These results suggest that Br-J-I could be considered as an adjunctive agent for CRC treatment and AMPs-based combination treatment is a new strategy for CRC in the future.Keywords:colorectal cancer;fusobacterium nucleatum;antimicrobial peptides;adjunctive therapy;antimicrobial treatment