Research findings open door for Anthrax treatments

By Josh Qian, Daily Staff Reporter
Published May 9, 2012

University researchers have found a key enzyme in an anthrax bacterium that could lead to development of future drugs to treat anthrax infections.

Anthrax — commonly known for the biological terror it caused in 2001 when spores were mailed in letters to various media outlets and U.S. senators — is an acute, infectious disease caused by contact with infected livestock, wild animals or contaminated animal products.

A research team headed by David Sherman, professor of medicinal chemistry and a faculty member at the University’s Life Sciences Institute, discovered that the AsbB enzyme in Bacillus anthracis, an anthrax pathogen, is responsible for iron up-take of the bacteria — without adequate iron, the anthrax bacterium will die.

Sherman said Rackham student Tyler Nusca deserves credit for playing the primary role in driving the research forward. Microbiology and Immunology Professor Philip Hanna and a research group at Argonne National Laboratory also contributed to the study.

The team recently published the results in the Journal of Biological Chemistry after four years of investigation.

Sherman said his laboratory mainly investigated the biochemical characteristics of the AsbB target protein.

“This virulence factor is an iron-binding agent that captures the metal and brings it into the anthrax organism, and then releases the iron so it can be used in important biochemical processes,” Sherman said.

Sherman explained that iron is vital for bacteria, as any living cell needs this nutrient to carry out essential biological functions.

“If we can find a new antibiotic that binds and inhibits this key protein it will shut down the sources that make the virulence factor.” Sherman said. “The virulence factors are what enable infectious bacterial agents to cause diseases.”

Sherman said his lab is currently using a method known as high-throughput screening to identify possible compounds that can be used to develop a drug to treat anthrax. He added that the compounds must be very specific in targeting the AsbB enzyme, cannot be toxic to humans and must demonstrate high potency.

“High-throughput screening is done in the Center for Chemical Genomics at the Life Sciences Institute and we are using robots to screen thousands of different chemical compounds on a micro scale,” Sherman said. “Robots can test thousands of compounds in a short amount of time to determine which compound in the collection can disrupt the enzyme’s function.”

Sherman said he believes the finding will aid future medical research because it gives scientists a direction in finding a new drug that can bind to the AsbB enzyme in order to disrupt the bacterium’s iron up-take and ultimately eliminate its ability to spread.

He added that the findings they published in their paper could be used by scientists in translational research efforts.

“We described a basic discovery in the paper, which is understanding a key enzyme’s role in making the virulence factor,” Sherman said. “We take advantage of the information we’ve learned and apply it immediately to improve human health through discovery of new antibiotics.”

Professor Hanna said the University’s biomedical research covers a tremendous amount of territory, including labs that study a large number of infectious diseases.
“Michigan is one of the largest research universities in the world in terms of financial support for performing health-related research and we cover the gamut of challenges associated with this effort — from basic discoveries into how nature works to using those insights to develop new medicines,” Hanna said.
According to Hanna, his pathogenic microbiology research group at the medical school has worked very closely with Sherman’s lab at the Life Sciences Institute and an atomic structure team at Argonne for about a decade studying a unique aspect of the Anthrax bacterium.
“Dr. Sherman’s team provided the deep mechanistic enzymology that enables a full understanding of how the B. anthracis proteins function,” Hanna said. “Dr. Nusca’s strong effort as a graduate student with Sherman is the core of this exciting  paper and represents a long, dedicated effort by a very smart U-M graduate student.”

Nusca said the lab he worked in for the project is distinct because there are chemists, microbiologists, and biochemists readily available to offer assistance and expertise.

“Sherman’s lab is a representative of the way science is heading: with multiple disciplines and techniques overlapping to provide more useful and impactful stories to a wider range of people,” Nusca said. “During my time working with Dr. Sherman, I've come to explore subjects I didn't really initially expect to.”