Discovery of cationic nonribosomal peptides as Gram-negative antibiotics through global genome mining

• Published in: Nature communications 2018-08, Vol.9 (1), p.3273-9, Article 3273
• Main Authors: Li, Yong-Xin, Zhong, Zheng, Zhang, Wei-Peng, Qian, Pei-Yuan
• Format: Article
• Language: English
• Subjects: 140/131; 140/58; 147/3; 45; 45/70; 631/326/22/1290; 631/92; 631/92/60; 64/60; Animals; Anti-Bacterial Agents - pharmacology; Antibiotic resistance; Antibiotics; Antimicrobial Cationic Peptides - chemistry; Antimicrobial Cationic Peptides - pharmacology; Bacteria; Biosynthesis; Cationic peptides; Cations; Colistin; Drug resistance; E coli; Escherichia coli; Genome, Bacterial; Genomes; Gram-negative bacteria; Gram-Negative Bacteria - drug effects; HeLa Cells; Humanities and Social Sciences; Humans; Mice; Microbial Sensitivity Tests; multidisciplinary; Organic chemistry; Pathogens; Peptides; Pseudomonas aeruginosa; Public health; Ribosomes - metabolism; Science; Science (multidisciplinary); Thigh
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-05781-6

The worldwide prevalence of infections caused by antibiotic-resistant Gram-negative bacteria poses a serious threat to public health due to the limited therapeutic alternatives. Cationic peptides represent a large family of antibiotics and have attracted interest due to their diverse chemical structures and potential for combating drug-resistant Gram-negative pathogens. Here, we analyze 7395 bacterial genomes to investigate their capacity for biosynthesis of cationic nonribosomal peptides with activity against Gram-negative bacteria. Applying this approach, we identify two novel compounds (brevicidine and laterocidine) showing bactericidal activities against antibiotic-resistant Gram-negative pathogens, such as Pseudomonas aeruginosa and colistin-resistant Escherichia coli , and an apparently low risk of resistance. The two peptides show efficacy against E. coli in a mouse thigh infection model. These findings may contribute to the discovery and development of Gram-negative antibiotics. Microbial genomes encode enzymes for biosynthesis of many uncharacterized peptides. Here, the authors screen over 7,300 bacterial genomes for potential biosynthesis of cationic non-ribosomal peptides, and identify two novel peptides with activities against antibiotic-resistant Gram-negative pathogens.