Scientists use nature against nature to develop an antibiotic with reduced resistance

April 10, 2013

A new broad range antibiotic, developed jointly by scientists at The Rockefeller University and Astex Pharmaceuticals, has been found to kill a wide range of bacteria, including drug-resistant Staphylococcus (MRSA) bacteria that do not respond to traditional drugs, in mice. The antibiotic, Epimerox, targets weaknesses in bacteria that have long been exploited by viruses that attack them, known as phage, and has even been shown to protect animals from fatal infection by Bacillus anthracis, the bacteria that causes anthrax.

Target selection is critical for the development of new . To date, most approaches for target selection have focused on the importance of bacterial survival. However, in addition to survival, the Rockefeller scientists believe that should be identified by determining which have a low probability for developing resistance.

"For a billion years, phages repeatedly have infected populations of bacteria, and during this period of time they have identified weaknesses in the bacterial armor," says senior author Vincent A. Fischetti, professor and head of the Laboratory of and Immunology. "We're taking advantage of what phage have 'learned' during this period for us to identify new antibiotic targets that we believe will escape the problem of resistance found for other antibiotics."

The path to identification of this new target spanned more than seven years of effort. Fischetti and his colleagues used a phage-encoded molecule to identify a bacterial target enzyme called 2-epimerase, which is used by Bacillus anthracis to synthesize an essential cell wall structure. In 2008, Fischetti's lab, with Rockefeller's Erec Stebbins and his colleagues in the Laboratory of Structural Microbiology, solved the of this enzyme. Based on this work, the researchers identified a previously unknown in 2-epimerase that involves direct interaction between one substrate molecule in the enzyme's active site and another in the enzyme's allosteric site. Fischetti and his colleagues chose to target the allosteric site of 2-epimerase to develop inhibitory compounds, because it is found in other bacterial 2-epimerases but not in the human equivalent of the enzyme.

Through the collaboration with Astex, an inhibitor of 2-epimerase named Epimerox was developed. Raymond Schuch, a former postdoctoral researcher in Fischetti's lab, tested the inhibitor in mice infected with Bacillus anthracis. He found that not only did Epimerox protect the animals from anthrax, but the bacteria did not develop resistance to the inhibitor. The researchers also found that Epimerox was able to kill methicillin-resistant Staphylococcus aureus (or MRSA) with no evidence of resistance even after extensive testing. Their work was published this week in PLOS One.

"Since nearly all Gram-positive bacteria contain 2-epimerase, we believe that Epimerox should be an effective broad-range antibiotic agent," says Fischetti. "The long-term evolutionary interaction between phage and bacteria has allowed us to identify targets that bacteria cannot easily change or circumvent. That finding gives us confidence that the probability for developing resistance to Epimerox is rather low, thereby enabling treatment of infections caused by multi-drug-resistant bacteria such as MRSA. It is a very encouraging result at a time when antibiotic resistance is a major health concern."

Related Stories

Recommended for you

Study suggests ending opioid epidemic will take years

July 20, 2017
The question of how to stem the nation's opioid epidemic now has a major detailed response. A new study chaired by University of Virginia School of Law Professor Richard Bonnie provides extensive recommendations for curbing ...

Team-based model reduces prescription opioid use among patients with chronic pain by 40 percent

July 17, 2017
A new, team-based, primary care model is decreasing prescription opioid use among patients with chronic pain by 40 percent, according to a new study out of Boston Medical Center's Grayken Center for Addiction Medicine, which ...

Private clinics' peddling of unproven stem cell treatments is unsafe and unethical

July 7, 2017
Stem cell science is an area of medical research that continues to offer great promise. But as this week's paper in Science Translational Medicine highlights, a growing number of clinics around the globe, including in Australia, ...

Popular heartburn drugs linked to higher death risk

July 4, 2017
Popular heartburn drugs called proton pump inhibitors (PPIs) have been linked to a variety of health problems, including serious kidney damage, bone fractures and dementia. Now, a new study from Washington University School ...

Most reproductive-age women using opioids also use another substance

June 30, 2017
The majority of reproductive-age and pregnant women who use opioids for non-medical purposes also use at least one other substance, ranging from nicotine or alcohol to cocaine, according to a University of Pittsburgh Graduate ...

At-risk chronic pain patients taper opioids successfully with psychological tools

June 28, 2017
Psychological support and new coping skills are helping patients at high risk of developing chronic pain and long-term, high-dose opioid use taper their opioids and rebuild their lives with activities that are meaningful ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.