Retrocyclins kill bacilli and germinating spores of Bacillus anthracis and inactivate anthrax lethal toxin

Wei Wang, Chandrika Mulakala, Sabrina C. Ward, Grace Jung, Hai Luong, Duy Pham, Alan J. Waring, Yiannis Kaznessis, Wuyuan Lu, Kenneth A. Bradley, Robert I. Lehrer

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73 Scopus citations

Abstract

θ-defensins are cyclic octadecapeptides encoded by the modified α-defensin genes of certain nonhuman primates. The recent demonstration that human α-defensins could prevent deleterious effects of anthrax lethal toxin in vitro and in vivo led us to examine the effects of θ-defensins on Bacillus anthracis (Sterne). We tested rhesus θ-defensins 1-3, retrocyclins 1-3, and several analogues of RC-1. Low concentrations of θ-defensins not only killed vegetative cells of B. anthracis (Sterne) and rendered their germinating spores nonviable, they also inactivated the enzymatic activity of anthrax lethal factor and protected murine RAW-264.7 cells from lethal toxin, a mixture of lethal factor and protective antigen. Structure-function studies indicated that the cyclic backbone, intramolecular tri-disulfide ladder, and arginine residues of θ-defensins contributed substantially to these protective effects. Surface plasmon resonance studies showed that retrocyclins bound the lethal factor rapidly and with high affinity. Retrocyclin-mediated inhibition of the enzymatic activity of lethal factor increased substantially if the enzyme and peptide were preincubated before substrate was added. The temporal discrepancy between the rapidity of binding and the slowly progressive extent of lethal factor inhibition suggest that post-binding events, perhaps in situ oligomerization, contribute to the antitoxic properties of retrocyclins. Overall, these findings suggest that θ-defensins provide molecular templates that could be used to create novel agents effective against B. anthracis and its toxins.

Original languageEnglish (US)
Pages (from-to)32755-32764
Number of pages10
JournalJournal of Biological Chemistry
Volume281
Issue number43
DOIs
StatePublished - Oct 27 2006

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Copyright 2009 Elsevier B.V., All rights reserved.

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