A new TB drug by 2010--or sooner?

Abstract

The last drug developed for TB was rifampicin, which first came into wide use in 1971-72. But the 30-year intermission may soon be over: on the starting blocks are fluororoquinolones, a class of drugs that are effective against several mycobacteria. TB is caused by Mycobacterium tuberculosis. "Fluoroquinolones might be quite strong for TB" says Mario Raviglione of Stop TB and WHO. Earlier this year, researchers led by P. R. Naranayan at the Tuberculosis Research Centre in Chennai, India, reported in the Indian Journal of Tuberculosis, 2002; 49:27-38 that they had successfully treated patients in just four months by replacing one of the four standard anti-TB drugs, ethambutol, with a fluoroquinolone called ofloxacin. The researchers treated patients with daily doses of isoniazid, rifampicin, pyrazinamide, and ofloxacin for three months, followed up with twice-weekly doses of isoniazid and rifampicin for an additional one or two months. Not only were the cure rates greater than 98%, but relapse rates were less than 5% in the two years following treatment. "If this study can be confirmed, perhaps with better, more powerful fluoroquinolones, it would already be a major advantage to TB control," says Raviglione. "This could come in three to rive years." "Ofloxacin is just a launching pad as replacement for ethambutol" in the standard DOTS therapy, says Bernard Fourie, Director of the Tuberculosis Research Lead Programme in South Africa. "Ofloxacin is essentially setting the scene for bigger work on more exciting fluoroquinolones such as moxifloxacin, gatifloxacin and levofloxacin." Rifamycins are another class of antibiotics that TB experts have their eyes on. One of the compounds, rifampicin, has been a cornerstone of TB treatment for decades. Now researchers are interested in some of its molecular relatives including rifabutin from Pharmacia Corporation, and rifapentine, which is manufactured by Aventis Pharmaceuticals and approved for TB in the United States. The newest class of broad-spectrum antibiotics, oxazolidinones, also show "very interesting activity against M. tuberculosis," says Giorgio Roscigno, Director of Strategic Development for the Global Alliance for TB Drug Development. Pharmacia Corporation recently received approval for linezolid, an oxazolidinone, for treating specific acute bacterial infections. Roscigno and other experts hope related compounds will be studied for TB as well. A compound dubbed PA-824 is also stirring up excitement. A member of a novel class of substances known as nitroimidazopyrans, PA-824 attacks M. tuberculosis on two fronts. It disrupts protein synthesis and cripples the ability of the pathogen to make a fatty acid needed for building the cell wall. In laboratory tests, the compound's one-two punch appears to be lethal to most versions of the microbe. "Its mechanism of action is sufficiently different from that of any other anti-TB drug that PA-824 kills drug-resistant cells, even strains resistant to six or seven anti-TB medications, at exactly the same level as it kills sensitive strains," says Bryan Walser, vice-president of corporate strategy at Chiron Corporation, a California-based pharmaceutical company. …