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Infect Immun, June 1998, p. 2434-2440, Vol. 66, No. 6
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Structure-Function Relationship of Antibacterial Synthetic Peptides Homologous to a Helical Surface Region on Human Lactoferrin against Escherichia coli Serotype O111

Daniel S. Chapple,1,2,3 David J. Mason,3 Christopher L. Joannou,1 Edward W. Odell,2 Vanya Gant,3 and Robert W. Evans1,*

Metalloprotein Research Group, Division of Biochemistry and Molecular Biology,1 and Department of Oral Medicine and Pathology,2 UMDS, Guy's Hospital, London SE1 9RT, and Infection and Immunity Laboratory, Division of Infection, UMDS, St. Thomas's Hospital, London SE1 7EH,3 United Kingdom

Received 18 July 1997/Returned for modification 17 September 1997/Accepted 3 March 1998

Lactoferricin includes an 11-amino-acid amphipathic alpha-helical region which is exhibited on the outer surface of the amino-terminal lobe of lactoferrin. Synthetic peptides homologous to this region exhibited potent antibacterial activity against a selected range of both gram-negative and gram-positive bacteria. An analog synthesized with methionine substituted for proline at position 26, which is predicted to disrupt the helical region, abolished antibacterial activity against Escherichia coli and considerably reduced antibacterial activity against Staphylococcus aureus and an Acinetobacter strain. The mode of action of human lactoferrin peptide (HLP) 2 against E. coli serotype O111 (NCTC 8007) was established by using flow cytometry, surface plasmon resonance, and transmission electron microscopy. Flow cytometry was used to monitor membrane potential, membrane integrity, and metabolic processes by using the fluorescent probes bis-1,3-(dibutylbarbituric acid)-trimethine oxonol, propidium iodide, and carbonyl cyanide m-chlorophenylhydrazone, respectively. HLP 2 was found to act at the cell membrane, causing complete loss of membrane potential after 10 min and of membrane integrity within 30 min, with irreversible damage to the cell as shown by rapid loss of viability. The number of particles, measured by light scatter on the flow cytometer, dropped significantly, showing that bacterial lysis resulted. The peptide was shown to bind to E. coli O111 lipopolysaccharide by using surface plasmon resonance. Transmission electron microscopy revealed bacterial distortion, with the outer membrane becoming detached from the inner cytoplasmic membrane. We conclude that HLP 2 causes membrane disruption of the outer membrane, resulting in lysis, and that structural considerations are important for antibacterial activity.

* Corresponding author. Mailing address: Metalloprotein Research Group, Division of Biochemistry and Molecular Biology, UMDS, Guy's Hospital, London Bridge, London SE1 9RT, United Kingdom. Phone: (44) 171 955 4525. Fax: (44) 171 955 8881. E-mail: r.evans{at}umds.ac.uk.

Infect Immun, June 1998, p. 2434-2440, Vol. 66, No. 6
0019-9567/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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