New Drugs May Block Streptococcal Antitoxin Protein

X-ray crystallography studies have revealed how Streptococcus pyogenes bacteria protect themselves from the toxins they secrete, which may pave the way for development of a new class of drugs that will target this protective mechanism.

The virulence of Gram-positive bacteria is enhanced by toxins such as the S. pyogenes ("Strep A”) beta-NAD+ glycohydrolase known as SPN. SPN toxin is a highly efficient glycohydrolase with the potential to deplete the host cell's levels of beta-NAD+. SPN-producing strains of S. pyogenes additionally express the protein immunity factor for SPN (IFS), which forms an inhibitory complex with SPN.

Investigators at Washington University School of Medicine (St. Louis, MO, USA) determined crystal structures of the SPN-IFS complex and IFS alone. Their findings, which were published in the February 9, 2011, edition of the journal Structure, revealed that SPN was structurally related to ADP-ribosyl transferases but lacked the canonical binding site for protein substrates. SPN was instead a highly efficient glycohydrolase with the potential to deplete cellular levels of beta-NAD+.

The protective effect of IFS involved an extensive interaction with the SPN active site that blocked access to beta-NAD+. The conformation of IFS changed upon binding to SPN, with repacking of an extended C-terminal alpha-helix into a compact shape.

"The most important aspect of the structure is that it tells us a lot about how the antitoxin blocks the toxin activity and spares the bacterium,” said senior author Dr. Thomas E. Ellenberger, professor of biochemistry and molecular biophysics at Washington University School of Medicine. "That is the Achilles' heel that we would like to exploit.

IFS is an attractive target for the development of novel bacteriocidal compounds that would function by blocking the bacterium's self-immunity to the SPN toxin. "A drug that would stabilize the inactive form of the immunity factor would liberate the toxin in the bacteria,” said Dr. Ellenberger. "Obviously they could evolve resistance once you target the antitoxin, but this would be a new target. Understanding structures is a keystone of drug design.”

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Washington University School of Medicine