Grants Aim to Hasten Discovery of New TB Drugs

Forty-five years. That’s how long it’s been since the last drug – rifampin – hit the market to treat tuberculosis, an infection that affects nearly one third of the world’s population and causes 1.8 million deaths annually.

The University of Illinois at Chicago College of Pharmacy has received three new federally-funded grants to hasten the discovery of new therapeutic treatments.

Tuberculosis, once the leading cause of death in the U.S., is a still-common and in many cases lethal infectious disease caused by various strains of Mycobacterium tuberculosis. It usually attacks the lungs but can also affect other parts of the body. It is spread through the air when people who have an active infection cough or sneeze.

Medicinal chemistry researchers, led by Larry Klein, senior research scientist at UIC’s Institute for Tuberculosis Research, will chemically optimize a series of compounds, the prototype of which was originally discovered by feeding simple chemicals to a genetically altered strain of E. coli.

Optimization involves repeating a cycle of chemical synthesis followed by testing for potency against the tubercle bacillus, lack of toxicity in mammalian cells, and stability in the presence of enzymes in the blood and the liver.

“Managing tuberculosis is challenging in that there is an increasing abundance of multi-drug-resistant strains, which has led to a severe health problem,” Klein says. “The majority of cases are found in developing countries and regions with prevalent HIV/AIDS problems, and leads to an urgent need to find novel anti-tuberculosis compounds.”

Birgit Jaki, research assistant professor of medicinal chemistry and pharmacognosy and principal investigator of a second grant, will study actinomycetes — filamentous or rod-shaped microorganisms found in soil that have a great metabolic capability that generates unusual molecules of therapeutic value.

Jaki’s study will utilize a targeted isolation procedure using high-speed countercurrent chromatography to assign a structure or compound class to an active principle at an early stage of the drug discovery process. Once the structure is known, researchers at the Institute for Tuberculosis Research can rapidly isolate larger amounts of material.

This approach is a departure from the classic bioactivity-guided isolation procedure, said Jaki, who is an associate researcher at the institute. “Industry and funding agencies shy away from [the] traditional approach, because it is extremely time and labor intensive, and the outcome is often unpredictable.”

The new technology can handle large quantities of samples and will result in the discovery of “a plethora of new, unidentified anti-tuberculosis natural products, with one or more of these being a viable lead compound for tuberculosis drug development,” Jaki said.

The third project, under the direction of Scott Franzblau, director of the institute, will establish in vitro assays to rapidly detect the anti-tuberculosis activity of liver enzyme-derived metabolites — a weakness of many current methods, Franzblau said.

“Current algorithms for high-throughput, screening-based drug discovery for antimicrobial agents, including those for tuberculosis, fail to account for the possibility of active metabolites early in the drug discovery process,” he said. “Compounds that would only be active after metabolism in the liver are not detected in high-throughput screens.”

High-throughput screening uses robotics, data processing and control software, liquid handling devices and sensitive detectors to quickly conduct millions of chemical, genetic or pharmacological tests. The process can rapidly identify active compounds, antibodies or genes that modulate a particular biomolecular pathway. The results provide a starting point for drug design.

The tuberculosis-active metabolite assays should preclude the need for identifying the structure of active metabolites and then synthesizing them in order to confirm their presence or absence, Franzblau said.

The three two-year grants, totaling nearly $1.3 million, are funded through the National Institute of Allergy and Infectious Disease, one of the National Institutes of Health.

The Institute for Tuberculosis Research is a drug discovery research facility working to develop new drugs to combat an old, but still evolving, global public health threat. The institute is unique in bringing an industrial model of drug discovery into an academic environment and applying it to a neglected disease. In addition to in-house discovery projects, the institute also collaborates with public and private institutions worldwide in the effort to eradicate tuberculosis.

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