An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteria

• Published in: Nature biotechnology 2003-12, Vol.21 (12), p.1480-1485
• Main Authors: Wan, Lin, Cheng, Jing-Qiu, Lu, Xiao-Fong, Qiu, Xiao-Qing, Zuo, Jun-Yong, Yang, Li, Zhong, Zi-Cheng, Wang, He, Cheng, Gang, Li, You-Ping, Li, Sheng-Fu, Ou, Zheng-Rong, Zhou, Yu-Qi, Wang, Hai-Yun, Zhang, Jie, Cheng, Xin, Wu, George Y, Zhang, Su-Hua
• Format: Article
• Language: English
• Subjects: Agriculture; Amino Acid Sequence; Animals; Anti-Bacterial Agents - biosynthesis; Anti-Bacterial Agents - pharmacology; Antibiotics; Antibody Specificity - physiology; Bacterial diseases; Bacterial Proteins - biosynthesis; Bacterial Proteins - genetics; Bacterial Proteins - pharmacology; Bioinformatics; Biological and medical sciences; Biomedical and Life Sciences; Biomedical Engineering/Biotechnology; Biomedicine; Biotechnology; Cells, Cultured; colicin Ia; Colicins - biosynthesis; Colicins - genetics; Colicins - pharmacology; Drug Delivery Systems - methods; Female; Fundamental and applied biological sciences. Psychology; Health. Pharmaceutical industry; Humans; Industrial applications and implications. Economical aspects; Kidneys; Life Sciences; Male; Mice; Molecular Sequence Data; Peptides; Peptides - genetics; Peptides - metabolism; Peptides - pharmacology; Peptides, Cyclic; pheromonicin; Production of active biomolecules; Protein Engineering - methods; Protein Structure, Tertiary; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - pharmacology; Sensitivity and Specificity; Staphylococcus - classification; Staphylococcus - drug effects; Staphylococcus aureus; Staphylococcus epidermidis; Streptococcus - drug effects; Streptococcus pneumoniae
• ISSN: 1087-0156; 1546-1696
• DOI: 10.1038/nbt913

We constructed a peptide consisting of a staphylococcal AgrD1 pheromone fused to the channel-forming domain of colicin Ia and named it pheromonicin. This fusion peptide had bactericidal effects against methicillin-sensitive and methicillin-resistant Staphylococcus aureus (MSSA and MRSA, respectively), but not against Staphylococcus epidermidis or Streptococcus pneumoniae . Growth rates, vital staining and colony forming unit (CFU) counts showed that pheromonicin did not merely suppress growth but killed S. aureus cells. The specificity of pheromonicin was shown by the absence of bactericidal effects against an accessory gene regulator ( agr ) locus knockout of S. aureus , and a dose-dependent inhibition of the bactericidal effects of pheromonicin by competition with corresponding free AgrD pheromone. In vivo , all pheromonicin-treated mice survived administration of MRSA that was lethal to controls. No toxicity was detectable in human liver or renal cells in culture, or in livers, kidneys or spleens of pheromonicin-treated mice. The results suggest that these types of chimeric peptides may be of value as antibiotics against specific bacterial infections.