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Antimicrobial Agents and Chemotherapy, June 2002, p. 1634-1639, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1634-1639.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Internal Thiols and Reactive Oxygen Species in Candidacidal Activity Exerted by an N-Terminal Peptide of Human Lactoferrin

Antonella Lupetti,1,2 Akke Paulusma-Annema,1 Sonia Senesi,2 Mario Campa,2 Jaap T. van Dissel,1 and Peter H. Nibbering1*

Department of Infectious Diseases, Leiden University Medical Center, Leiden, The Netherlands,1 Dipartimento di Patologia Sperimentale, Biotecnologie Mediche, Infettivologia ed Epidemiologia, Università degli Studi di Pisa, Pisa, Italy2

Received 10 August 2001/ Returned for modification 12 November 2001/ Accepted 15 February 2002

We previously showed that the energized mitochondrion and extracellular ATP are essential for the candidacidal activity of the N-terminal peptide of human lactoferrin, subsequently referred to as hLF(1-11). The present study focuses on the involvement of internal thiols and reactive oxygen species (ROS) in the candidacidal activity exerted by hLF(1-11). Our results reveal that hLF(1-11) reduced the internal thiol level of Candida albicans by 20%. In agreement, N-acetyl-L-cysteine (NAC), which is a precursor of glutathione and an ROS scavenger, inhibited the candidacidal activity of hLF(1-11). In addition, azodicarboxylic acid bis(N,N-dimethylamide) (diamide), which oxidizes internal thiols, was candidacidal. Furthermore, hLF(1-11) increased the level of ROS production by C. albicans in a dose-dependent manner, and a correlation between ROS production and candidacidal activity was found. 6-Hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (trolox), which is an ROS scavenger, partially inhibited the hLF(1-11)-induced, but not the diamide-triggered, candidacidal activity. It is of interest that hLF(1-11) and diamide acted synergistically in killing C. albicans and in ROS production. In agreement, oxidized ATP, an irreversible inhibitor of extracellular ATP receptors, partially blocked the hLF(1-11)-induced, but not the diamide-triggered, candidacidal activity. Finally, the hLF(1-11)-induced activation of mitochondria was inhibited by NAC, indicating that internal thiols and ROS affect mitochondrial activity. Therefore, the candidacidal activity of hLF(1-11) involves both generation of ROS and reduction of internal thiols.

* 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.

Antimicrobial Agents and Chemotherapy, June 2002, p. 1634-1639, Vol. 46, No. 6
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.6.1634-1639.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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