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Antimicrobial Agents and Chemotherapy, September 1998, p. 2206-2214, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Activities of LL-37, a Cathelin-Associated Antimicrobial Peptide of Human Neutrophils

Jeffrey Turner, Yoon Cho, Nhu-Nguyen Dinh, Alan J. Waring, and Robert I. Lehrer*

Department of Medicine, Center for the Health Sciences, Los Angeles, California

Received 12 December 1997/Returned for modification 2 April 1998/Accepted 18 June 1998

Human neutrophils contain two structurally distinct types of antimicrobial peptides, beta -sheet defensins (HNP-1 to HNP-4) and the alpha -helical peptide LL-37. We used radial diffusion assays and an improved National Committee for Clinical Laboratory Standards-type broth microdilution assay to compare the antimicrobial properties of LL-37, HNP-1, and protegrin (PG-1). Although generally less potent than PG-1, LL-37 showed considerable activity (MIC, <10 µg/ml) against Pseudomonas aeruginosa, Salmonella typhimurium, Escherichia coli, Listeria monocytogenes, Staphylococcus epidermidis, Staphylococcus aureus, and vancomycin-resistant enterococci, even in media that contained 100 mM NaCl. Certain organisms (methicillin-resistant S. aureus, Proteus mirabilis, and Candida albicans) were resistant to LL-37 in media that contained 100 mM NaCl but were susceptible in low-salt media. Burkholderia cepacia was resistant to LL-37, PG-1, and HNP-1 in low- or high-salt media. LL-37 caused outer and inner membrane permeabilization of E. coli ML-35p. Chromogenic Limulus assays revealed that LL-37 bound to E. coli O111:B4 lipopolysaccharide (LPS) with a high affinity and that this binding showed positive cooperativity (Hill coefficient = 2.02). Circular dichroism spectrometry disclosed that LL-37 underwent conformational change in the presence of lipid A, transitioning from a random coil to an alpha -helical structure. The broad-spectrum antimicrobial properties of LL-37, its presence in neutrophils, and its inducibility in keratinocytes all suggest that this peptide and its precursor (hCAP-18) may protect skin and other tissues from bacterial intrusions and LPS-induced toxicity. The potent activity of LL-37 against P. aeruginosa, including mucoid and antibiotic-resistant strains, suggests that it or related molecules might have utility as topical bronchopulmonary microbicides in cystic fibrosis.

* Corresponding author. Mailing address: Department of Medicine, Center for the Health Sciences, Box 951690, Los Angeles, CA 90095-1690. Phone: (310) 825-5340. Fax: (310) 206-8766. E-mail: rlehrer{at}med1.medsch.ucla.edu.

Antimicrobial Agents and Chemotherapy, September 1998, p. 2206-2214, Vol. 42, No. 9
0066-4804/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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