Synthetic Antimicrobial Drug Shows Potent Antiviral Activity

A synthetic antimicrobial agent was found to effectively kill vaccinia virus under laboratory conditions and may prove to be useful for treating eczema vaccinatum, a serious and potentially fatal complication of the smallpox vaccine.

The drug candidate, CSA-13, is a member of the class of synthetic molecules known as ceragenins, or cationic steroid antibiotics (CSAs). They are small molecule chemical compounds comprising a sterol backbone with amino acids and other chemical groups attached to it. These compounds have a net positive charge that is electrostatically attracted to the negatively charged cell membranes of certain viruses, fungi, and bacteria. CSAs have a high binding affinity for such membranes, which they disrupt causing rapid cell death. While CSAs have a mechanism of action that is also seen in antimicrobial peptides, which form part of the body's innate immune system, they avoid many of the difficulties associated with the use of antimicrobial peptides as medicines.

Investigators from the U.S. National Jewish Health (Denver, CO, USA) studied the effect of one of the ceragenins, CSA-13, on the vaccinia virus as part of their search for a treatment for exzema vaccinatum. This is a potentially fatal, disseminated viral skin infection that develops in individuals with atopic dermatitis after exposure to the vaccinia virus.

The investigators reported in the June 11, 2009, online edition of the Journal of Investigative Dermatology that CSA-13 added to cultures of vaccinia virus killed more than 96% of the viruses. Treatment of cells infected with vaccinia with CSA-13 reduced vaccinia virus gene expression and promoted increased survival of the infected cells. When tested on immunocompromised mice infected with vaccinia virus, a topical application of CSA-13 penetrated the skin and reduced subsequent satellite lesion formation.

In addition to directly killing the virus, CSA-13 stimulated cells to produce their own antimicrobial proteins, LL-37 and HBD-3, which also exhibit antiviral activity against vaccinia virus.

"This compound is demonstrating broad effectiveness,” said first author Dr. Michael Howell, assistant professor of pediatrics at National Jewish Health. "While our experiments were designed to test its ability to attack the vaccinia virus, its immune-stimulating ability was a surprising observation. We knew from our plaque assays, that CSA-13 was directly killing the virus. But these experiments show that it also stimulates cells to produce their own antimicrobial proteins, which contribute to its disease-fighting capabilities. Our next step is to learn how CSA-13 stimulates cells' own innate immune defenses.”

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