title: In vitro and in vivo activities of antimicrobial peptides developed using an amino acid-based activity prediction method.
abstract: To design and discover new antimicrobial peptides (AMPs) with high levels of antimicrobial activity, a number of machine-learning methods and prediction methods have been developed. Here, we present a new prediction method that can identify novel AMPs that are highly similar in sequence to known peptides but offer improved antimicrobial activity along with lower host cytotoxicity. Using previously generated AMP amino acid substitution data, we developed an amino acid activity contribution matrix that contained an activity contribution value for each amino acid in each position of the model peptide. A series of AMPs were designed with this method. After evaluating the antimicrobial activities of these novel AMPs against both Gram-positive and Gram-negative bacterial strains, DP7 was chosen for further analysis. Compared to the parent peptide HH2, this novel AMP showed broad-spectrum, improved antimicrobial activity, and in a cytotoxicity assay it showed lower toxicity against human cells. The in vivo antimicrobial activity of DP7 was tested in a Staphylococcus aureus infection murine model. When inoculated and treated via intraperitoneal injection, DP7 reduced the bacterial load in the peritoneal lavage solution. Electron microscope imaging and the results indicated disruption of the S. aureus outer membrane by DP7. Our new prediction method can therefore be employed to identify AMPs possessing minor amino acid differences with improved antimicrobial activities, potentially increasing the therapeutic agents available to combat multidrug-resistant infections.
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Xiaozhe
authors: X
authors: Wu
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Zhenling
authors: Z
authors: Wang
authors: Institute of Burn Research, Southwest Hospital, State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University, Chongqing, People's Republic of China.
authors: Xiaolu
authors: X
authors: Li
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Yingzi
authors: Y
authors: Fan
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Gu
authors: G
authors: He
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Yang
authors: Y
authors: Wan
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Chaoheng
authors: C
authors: Yu
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Jianying
authors: J
authors: Tang
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Meng
authors: M
authors: Li
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Xian
authors: X
authors: Zhang
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Hailong
authors: H
authors: Zhang
authors: Nankai University School of Medicine, Tianjin, People's Republic of ChinaState Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Rong
authors: R
authors: Xiang
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Ying
authors: Y
authors: Pan
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Yan
authors: Y
authors: Liu
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China.
authors: Lian
authors: L
authors: Lu
authors: State Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy, West China Hospital, Sichuan University, Chengdu, People's Republic of China yl.tracy73@gmail.com.
authors: Li
authors: L
authors: Yang
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D000890:Anti-Infective Agents / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D023181:Antimicrobial Cationic Peptides / Q000009:adverse effects / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use*; D015195:Drug Design; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008826:Microbial Sensitivity Tests; D008854:Microscopy, Electron; D008954:Models, Biological; D013203:Staphylococcal Infections / Q000188:drug therapy; D013211:Staphylococcus aureus / Q000187:drug effects / Q000648:ultrastructure; D013329:Structure-Activity Relationship
chemical_list: D000596:Amino Acids; D000890:Anti-Infective Agents; D023181:Antimicrobial Cationic Peptides