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Infection and Immunity, March 2001, p. 1469-1476, Vol. 69, No. 3
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.3.1469-1476.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Human Lactoferrin and Peptides Derived from Its N Terminus Are Highly Effective against Infections with Antibiotic-Resistant Bacteria

P. H. Nibbering,1,* E. Ravensbergen,1 M. M. Welling,2 L. A. van Berkel,1 P. H. C. van Berkel,3 E. K. J. Pauwels,2 and J. H. Nuijens3

Department of Infectious Diseases1 and Department of Radiology, Division of Nuclear Medicine,2 Leiden University Medical Center, and Pharming Technologies B.V.,3 Leiden, The Netherlands

Received 20 September 2000/Returned for modification 13 October 2000/Accepted 27 November 2000

Since human lactoferrin (hLF) binds to bacterial products through its highly positively charged N terminus, we investigated which of the two cationic domains is involved in its bactericidal activity. The results revealed that hLF lacking the first three residues (hLF-3N) was less efficient than hLF in killing of antibiotic-resistant Staphylococcus aureus, Listeria monocytogenes, and Klebsiella pneumoniae. Both hLF preparations failed to kill Escherichia coli O54. In addition, hLF-3N was less effective than hLF in reducing the number of viable bacteria in mice infected with antibiotic-resistant S. aureus and K. pneumoniae. Studies with synthetic peptides corresponding to the first 11 N-terminal amino acids, designated hLF(1-11), and fragments thereof demonstrated that peptides lacking the first three N-terminal residues are less effective than hLF(1-11) in killing of bacteria. Furthermore, a peptide corresponding to residues 21 to 31, which comprises the second cationic domain, was less effective than hLF(1-11) in killing of bacteria in vitro and in mice having an infection with antibiotic-resistant S. aureus or K. pneumoniae. Using fluorescent probes, we found that bactericidal hLF peptides, but not nonbactericidal peptides, caused an increase of the membrane permeability. In addition, hLF killed the various bacteria, most probably by inducing intracellular changes in these bacteria without affecting the membrane permeability. Together, hLF and peptides derived from its N terminus are highly effective against infections with antibiotic-resistant S. aureus and K. pneumoniae, and the first two arginines play an essential role in this activity.

* Corresponding author. Mailing address: Department of Infectious Diseases, C5-P, Leiden University Medical Center, P.O. Box 9600, 2300 RC Leiden, The Netherlands. Phone: 31 71 5262620. Fax: 31 71 5266758. E-mail: p.h.nibbering{at}lumc.nl.

Infection and Immunity, March 2001, p. 1469-1476, Vol. 69, No. 3
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.3.1469-1476.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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