Ringing in New Antibiotic Drugs
Ann Arbor, Mich. and Minneapolis, Minn. -- When infections like Strep and tuberculosis become resistant to antibiotics, patients are in trouble. Infections become more difficult to treat as disease-causing bugs mutate in ways that render the most widely used drugs ineffective. Nearly all significant bacterial infections in the world are becoming resistant to the most commonly prescribed antibiotic treatments. In fact, the Centers for Disease Control has called antibiotic resistance one of the world’s most pressing public health problems.
The incidence of drug-resistant infections caused by these “superbugs” has increased at alarming rates in recent years. 
To combat this emerging public health threat, researchers have been studying how some important ring-shaped antibiotics like tetracycline and erythromycin become impotent against superbugs, and how to replenish the arsenal of drugs to fight infections.
Nearly all antibiotics in use today are natural molecules made by bacteria to kill their enemies. The bacteria use specialized proteins called enzymes to carry out the chemical steps in making antibiotic molecules. One way to increase the number of antibiotics for fighting infections is to start where Nature stopped and engineer the enzymes to produce new molecules. But to do this, scientists need to understand how a very large enzyme molecule works on a rather small antibiotic precursor molecule.
An interdisciplinary team of scientists from the University of Michigan’s Life Sciences Institute (UM LSI) and the University of Minnesota College of Pharmacy have discovered how enzymes generate the large rings in these antibiotics. Their work creates important opportunities for drug discovery to stay one step ahead of the superbugs, and will appear in two papers published in the scientific journal Nature Chemical Biology.
Research Professors David H. Sherman and Janet L. Smith of UM LSI and Professor Robert A. Fecik from the University of Minnesota are the first scientists to crystallize an enzyme in the process of closing the antibiotic ring, illustrating exactly how the ring is formed.
These so-called macrolide antibiotics comprise a class of cyclic drugs of particular interest because bacteria make them in a way that potentially allows for thousands of slightly different compounds to be synthesized and tested for antibiotic activity. The structure of macrolides is a large ring, itself constructed from a linear precursor molecule, which is built in an assembly-line fashion from smaller molecules. An enzyme at the end of the chain triggers ring formation.
“These findings are likely to enable the development of powerful new methods to build structural diversity into large ring systems that are a key component of many types of macrolide antibiotic molecules. This will provide yet another strategy to stay ahead of the emerging and persistent antibiotic resistance threat,” said Sherman.
To achieve this goal, a detailed understanding of the processes in each step of the molecular assembly line is critical. The research team of biochemists, synthetic chemists and crystallographers’ first paper focuses on the concept of using molecular tools called affinity labels to see details of how the precursor molecule binds in a special site to the large enzyme. The second paper applies these tools with a longer chemical compound that shows the exact shape and location of the antibiotic precursor in a surprising curl. This close-up view of how the catalyst brings two ends of the antibiotic precursor to form the critical ring provides key models for future studies. The research should enable scientists to design new catalysts capable of making new macrolide antibiotics.
“Having the tools to make the next generation of macrolide antibiotics is crucial because these drugs are so well tolerated and have so few side effects,” said Smith. “They are really a great class of antibiotics so we need more of them.”
The research team ultimately wants to use these results to make new antibiotics that overcome the defenses of emerging superbugs.
“We’re striving to create new drugs that can have a positive impact on the growing threat of infectious diseases.” said Fecik. “This type of research can help us make new antibiotic molecules.”
David Sherman is the John G. Searle Professor of Medicinal Chemistry, Department of Medicinal Chemistry at the UM College of Pharmacy and Janet Smith is Margaret J. Hunter Collegiate Professor of Life Sciences, Department of Biological Chemistry, UM Medical School. Robert Fecik is an Assistant Professor of Medicinal Chemistry at the University of Minnesota College of Pharmacy.
The papers will appear online together in the journal Nature Chemical Biology on September 10, 2006 and are titled “Structural and Mechanistic Insights of Polyketide Macrolactonization from Polyketide-based Affinity Labels,” and “Structural Basis for Macrolactonization by the Pikromycin Thioesterase.”
Links:
Janet Smith Lab
David Sherman Lab
Robert Fecik's Page at the University of Minnesota
