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

Nature Biotechnology volume 21, pages 1480–1485 (2003)Cite this article

A Corrigendum to this article was published on 01 December 2004

Abstract

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.

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Figure 1: Structure and voltage-dependent channel gating of pheromonicin.
Figure 2: In vitro bactericidal activity of pheromonicin against S. aureus.
Figure 3: In vitro MRSA cell growth after withdrawal of treatments.
Figure 4: Effects of pheromonicins and controls on cell growth of S. aureus.
Figure 5: Cumulative survival of mice after S. aureus infection.
Figure 6: Toxicity of pheromonicin in human cells.

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Acknowledgements

This work was supported by National Nature Science Foundation of China grants 39725009, 39770243 and 30276820 to X.Q., 39700700 to H.W. and 39880002 to J.C., grant 1999054001 from National Basic Research of China to X.Q., grant 88486 from the China Medical Board of New York to X.Q., grant DK-42182 from the US National Institute of Diabetes and Digestive and Kidney Diseases to G.Y.W., and the Herman Lopata Chair in Hepatitis Research awarded to G.Y.W. We thank H. Deng and R. Angeletti for expert assistance in mass spectrometry, and Hamamatsu Photonics for technical assistance in cooled-CCD instruments.

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  1. Xiao-Qing Qiu and George Y Wu: These authors contributed equally to this work.

Authors and Affiliations

  1. Laboratory of Transplant Immunology, West China Hospital, Sichuan University, No. 37 GuoXueXiang, Chengdu, 610041, Sichuan, China

    Xiao-Qing Qiu, Xiao-Fong Lu, Sheng-Fu Li, Gang Cheng, Lin Wan, Li Yang, Jun-Yong Zuo, Yu-Qi Zhou, Hai-Yun Wang, Xin Cheng, Zi-Cheng Zhong, Jing-Qiu Cheng & You-Ping Li

  2. Laboratory of Genetics, West China, 2nd Hospital, Sichuan University, Chengdu, 610041, China

    He Wang

  3. Laboratory of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China

    Jie Zhang

  4. Laboratory of Pharmacology, National Sichuan Institute of Antibiotic Industry, Chengdu, China

    Su-Hua Zhang & Zheng-Rong Ou

  5. Division of Gastroenterology-Hepatology, University of Connecticut Health Center, Farmington, 06030-1845, Connecticut, USA

    George Y Wu

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Correspondence to Xiao-Qing Qiu or George Y Wu.

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Qiu, XQ., Wang, H., Lu, XF. et al. An engineered multidomain bactericidal peptide as a model for targeted antibiotics against specific bacteria. Nat Biotechnol 21, 1480–1485 (2003). https://doi.org/10.1038/nbt913

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