Nature Biotechnology
21, 1480 - 1485 (2003)
Published online: 16 November 2003; | doi:10.1038/nbt913
There is a Corrigenda (December 2004) associated with this Article.
An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteriaXiao-Qing Qiu1, 6, He Wang2, Xiao-Fong Lu1, Jie Zhang3, Sheng-Fu Li1, Gang Cheng1, Lin Wan1, Li Yang1, Jun-Yong Zuo1, Yu-Qi Zhou1, Hai-Yun Wang1, Xin Cheng1, Su-Hua Zhang4, Zheng-Rong Ou4, Zi-Cheng Zhong1, Jing-Qiu Cheng1, You-Ping Li1
& George Y Wu5, 61
Laboratory of Transplant Immunology, West China Hospital, Sichuan University, No. 37 GuoXueXiang, Chengdu, Sichuan, China 610041. 2
Laboratory of Genetics, West China, 2nd Hospital, Sichuan University, Chengdu, China 610041. 3
Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, China 610041. 4
Laboratory of Pharmacology, National Sichuan Institute of Antibiotic Industry, Chengdu, China. 5
Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, Connecticut 06030-1845, USA. 6
These authors contributed equally to this work.
Correspondence should be addressed to Xiao-Qing Qiu qiu@mrsa.com.cn or George Y Wu wu@nso.uchc.eduWe 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.
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