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 calle
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
21-Oct-2004