Clues to improving TB treatment

10/15/04



A team of French researchers may have discovered a way that may make some tuberculosis drugs more efficient at lower doses, according to a report in the 22 October issue of the journal Molecular Cell.

Details gleaned from an in-depth look at a protein found in tuberculosis bacteria suggest that the protein can be disabled when it binds to certain other molecules. With this protein sidelined, tuberculosis bacteria become more sensitive to treatment by a "second-line" drug called ethionamide, or ETH.

Second-line drugs such as ETH may prove useful in treating multidrug-resistant strains of tuberculosis that have already outwitted the usual battery of "first-line" tuberculosis drugs like isoniazide and rifampicin, say study authors Alain Baulard of the Institut Pasteur de Lille and colleagues. Drugs like ETH are successful against the disease, but only in large doses that produce high rates of side effects.

The combination of ETH and the disabled protein "may help reduce the dosage of potent antibacterial compounds that otherwise are too toxic to be used as first-line drugs," the researchers said.

Like several other tuberculosis drugs, ETH is activated by the presence of a tuberculosis enzyme called EthA. Normally, the production of EthA is suppressed by another protein called EthR. When EthR is missing or disabled in tuberculosis, the bacteria produce too much of the EthA enzyme, which increases their vulnerability to ETH's antimicrobial attack.

With this in mind, Baulard and colleagues decided to closely examine the molecular structure of EthR to see if it might hold the key to improving the effectiveness of drugs like ETH. Using an X-ray technique, the researchers gradually assembled a map of the crystal structure of EthR, pinpointing the exact details of its molecular structure down to the atomic level.

The crystal structure revealed that EthR was bound to an unexpected partner--a compound called HexOc. The presence of HexOc alters EthR's structure, opening up a wider gap between two key DNA recognition areas on the protein. The wider gap disrupts EthR's ability to bind to DNA and limit the production of the EthA enzyme, the researchers found.

The next step for Baulard and colleagues was to show that interfering with EthR function could increase drug sensitivity in Mycobacterium smegmatis, a close relative of tuberculosis bacterium. Using a compound called benzylacetone in place of HexOc to alter EthR's structure, the researchers found that a combination of benzylacetone and the drug ETH had a powerful antimicrobial effect on the bacteria.

"Obviously, benzylacetone will not be the only compound to give as a complement of the ETH treatment, but it is a good start to help combinatorial chemists to develop derivatives," Baulard said.

Although the researchers believe that their findings will prove most immediately useful for the treatment of resistant forms of tuberculosis, they note that EthR and EthA are both found in the bacteria that cause leprosy. In this case, a compound that alters EthR structure might also be a good partner for the drugs that treat leprosy.

Nearly one third of the world's population carries the tuberculosis bacterium and the disease kills about two million people worldwide each year. About 50 million people are infected with the multidrug resistant tuberculosis strain, which has proved especially deadly in developing countries.

F. Frénois, J. Engohang-Ndong, C. Locht, A. R. Baulard and V. Villeret: "Structure of EthR in a Ligand Bound Conformation Reveals Therapeutic Perspectives against Tuberculosis"

The other members of the research team include Vincent Villeret and Frédéric Frénois of CNRS and Jean Engohang-Ndong and Camille Locht of the Institut Pasteur de Lille. The study was supported in part by Région Nord-Pas de Calais, INSERM, CNRS and Institut Pasteur de Lille.

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