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Antimicrobial Agents and Chemotherapy, March 2008, p. 944-953, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01090-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

Microbicidal Properties and Cytocidal Selectivity of Rhesus Macaque Theta Defensins{triangledown}

Dat Tran,1 Patti Tran,1 Kevin Roberts,1 George Ösapay,1 Justin Schaal,1 Andre Ouellette,1,2 and Michael E. Selsted1,2*

Departments of Pathology and Laboratory Medicine,1 Microbiology and Molecular Genetics, School of Medicine, University of California, Irvine, California 926972

Received 20 August 2007/ Returned for modification 22 September 2007/ Accepted 17 December 2007

Rhesus macaque {theta}-defensins (RTDs) are unique macrocyclic antimicrobial peptides. The three RTDs (RTD 1-3), isolated from macaque leukocytes, have broad-spectrum antimicrobial activities in vitro and share certain structural features with acyclic porcine protegrins, which are microbicidal peptides of the cathelicidin family. To understand the structural features that confer the respective cytocidal properties to {theta}-defensins and protegrins, we determined and compared the biological properties of RTD 1-3 and protegrin 1 (PG-1) in assays for antimicrobial activity, bacterial membrane permeabilization, and toxicity to human cells. RTD 1-3 and PG-1 had similar microbicidal potencies against Escherichia coli, Staphylococcus aureus, and Candida albicans in low-ionic-strength (10 mM) buffers at pH 7.4. The inclusion of physiologic sodium chloride partially inhibited the microbicidal activities of the RTDs, and the degree of inhibition depended on the buffer used in the assay. Similarly, the inclusion of 10% normal human serum partially antagonized the bactericidal activities of all four peptides. In contrast, the microbicidal activities of PG-1 and RTD 1-3 against E. coli were unaffected by physiologic concentrations of calcium chloride and magnesium chloride. Treatment of E. coli ML35 cells with RTD 1-3 or PG-1 rapidly rendered the bacteria permeable to o-nitrophenyl-β-D-galactopyranoside, and this was accompanied by the rapid entry of the RTDs. Finally, although PG-1 was toxic to human fibroblasts and caused a marked lysis of erythrocytes, the RTDs were not cytotoxic or hemolytic. Thus, compared to PG-1, RTD 1-3 possess substantially greater cytocidal selectivity against microbes. Surprisingly, the low cytotoxicity of the RTDs did not depend on the peptides’ cyclic conformation.

* Corresponding author. Mailing address: Department of Pathology and Laboratory Medicine, School of Medicine, University of California, Irvine, CA 92697-4800. Phone: (949) 824-2350. Fax: (949) 824-2346. E-mail: meselste{at}uci.edu

{triangledown} Published ahead of print on 26 December 2007.

Antimicrobial Agents and Chemotherapy, March 2008, p. 944-953, Vol. 52, No. 3
0066-4804/08/$08.00+0     doi:10.1128/AAC.01090-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



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