Dual‐Mechanism Peptide SR25 has Broad Antimicrobial Activity and Potential Application for Healing Bacteria‐infected Diabetic Wounds

• Published in: Advanced science Vol. 11; no. 30; pp. e2401793 - n/a
• Main Authors: Luo, Xue‐Yue, Hu, Chun‐Mei, Yin, Qi, Zhang, Xiao‐Mei, Liu, Zhen‐Zhen, Zhou, Cheng‐Kai, Zhang, Jian‐Gang, Chen, Wei, Yang, Yong‐Jun
• Format: Journal Article
• Language: English
• Published: Germany John Wiley & Sons, Inc 01.08.2024; John Wiley and Sons Inc; Wiley
• Subjects: Animals; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Antimicrobial agents; antimicrobial peptides; Antimicrobial Peptides - pharmacology; Bacteria; Bacterial infections; Biocompatibility; Biofilms; Dairy cattle; Diabetes; Diabetes Mellitus, Experimental - drug therapy; diabetic wound; Disease Models, Animal; Drug resistance; E coli; Escherichia coli - drug effects; Genomes; hydrogel; Hydrogels; Listeria; membrane disrupting; Methicillin-Resistant Staphylococcus aureus - drug effects; Mice; Microbial Sensitivity Tests; Natural products; Peptides; Physiology; Salmonella; Staphylococcus infections; succinate:quinone reductase; uncultured bacteria; Wound Healing - drug effects; Wound Infection - drug therapy; Wound Infection - microbiology; membrane disrupting; diabetic wound; hydrogel; succinate:quinone reductase; antimicrobial peptides; uncultured bacteria
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202401793

The rise of antibiotic resistance poses a significant public health crisis, particularly due to limited antimicrobial options for the treatment of infections with Gram‐negative pathogens. Here, an antimicrobial peptide (AMP) SR25 is characterized, which effectively kills both Gram‐negative and Gram‐positive bacteria through a unique dual‐targeting mechanism without detectable resistance. Meanwhile, an SR25‐functionalized hydrogel is developed for the efficient treatment of infected diabetic wounds. SR25 is obtained through genome mining from an uncultured bovine enteric actinomycete named Nonomuraea Jilinensis sp. nov. Investigations reveal that SR25 has two independent cellular targets, disrupting bacterial membrane integrity and restraining the activity of succinate:quinone oxidoreductase (SQR). In a diabetic mice wound infection model, the SR25‐incorporated hydrogel exhibits high efficacy against mixed infections of Escherichia coli (E. coli) and methicillin‐resistant Staphylococcus aureus (MRSA), accelerating wound healing. Overall, these findings demonstrate the therapeutic potential of SR25 and highlight the value of mining drugs with multiple mechanisms from uncultured animal commensals for combating challenging bacterial pathogens. The previously uncultured bacterium presents a viable strategy for the discovery of novel antimicrobial peptides. The antimicrobial peptide SR25 operates through a dual mechanism, targeting both the bacterial cell membrane and succinate:quinone oxidoreductase. It exhibits outstanding antibacterial efficacy and promotes the recovery of infected diabetes wounds.