Understanding TB Drug Resistance: Super-Drug Inactivator Revealed

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Researchers at the University of Michigan’s Life Sciences Institute and College of Pharmacy have uncovered how tuberculosis builds drug resistance.

The discovery could provide scientists with a new direction to try to combat drug-resistant tuberculosis and to head off the continued spread of this deadly infectious disease.

Tuberculosis claims about 2 million lives worldwide each year. With the global spread of the pathogenic bacterium that currently infects one-third of the world’s population, there are also strains that are resistant to most types of antibiotics that are used to treat this infection.

These strains cause so-called multi-drug resistant tuberculosis and extensively drug resistant tuberculosis. The limited number of drugs that are used to treat these resilient infections are our last line of defense, and some bacteria have already evolved resistance even to these antibiotics. The family of aminoglycoside antibiotics is among these drugs.

Sylvie Garneau-Tsodikova, LSI research assistant professor and the John G. Searle Assistant Professor of Medicinal Chemistry, and collaborator Oleg Tsodikov, assistant professor of medicinal chemistry at the U-M College of Pharmacy, have uncovered a sophisticated and efficient mechanism that tuberculosis uses to inactivate aminoglycosides.

“Bacteria continuously come up with new tricks to inactivate the drugs that we develop and use to treat infections,” said Garneau-Tsodikova. “As a result, our antibiotic arsenal becomes more and more limited. To overcome bacterial resistance, a deeper understanding of the many resistance mechanisms evolved by bacteria is needed.”

The tuberculosis protein Eis destroys aminoglycoside antibiotics once they are inside of the microbe. In a collaborative effort, the Garneau-Tsodikova and Tsodikov labs discovered that Eis chemically changes (acetylates) the aminoglycoside drugs at many different places to ensure that they become completely inactive and lose their antibiotic activity. Amazingly, Eis inactivates most aminoglycosides that were tested, including all that are currently administered by doctors.

“It is always a humbling experience to realize the power of nature to combat the drugs that scientists develop,” said Garneau-Tsodikova.

This Eis multi-acetylation inactivation mechanism is completely novel and represents one more challenge to keep in mind for the future development of treatments for tuberculosis.

The researchers are now using this knowledge to change drug scaffolds to minimize this effect and to try to overcome the resistance with new drugs against Eis, which would make aminoglycoside antibiotics active again.

The details of their findings on this super-drug inactivator in tuberculosis were reported in the May 31 issue of the journal Proceedings of the National Academy of Sciences. Graduate student Wenjing Chen (Garneau-Tsodikova lab) and research investigator Tapan Biswas (Tsodikov lab) are the main co-authors of this work.

The research was supported by the Life Sciences Institute and the UM College of Pharmacy.

Read the paper at www.pnas.org/content/early/2011/05/23/1105379108.full.pdf+html

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