- Purpose
- Typical Antibacterial
Isoniazid
When news broke in 1952 about a wonder drug for tuberculosis (TB), newspapers ran the story on page one, photojournalists snapped pictures of patients dancing in the halls of Staten Island's Sea View Hospital in New York, and Time magazine proclaimed, "Never in the agelong history of tuberculosis had there been such excitement about a new treatment for the white scourge."
Despite cautioning that "it is far too soon to talk about tearing down the hospitals," Time was not far from the truth. In fact, shortly thereafter, sanatoriums--which had spread across Europe and the U.S. in the late 1800s and early 1900s to isolate TB patients--shut their doors.
More than a half-century later, isoniazid continues to be on the front line of the battle against TB.
TB kills as many as 2 million people each year and is caused by Mycobacterium tuberculosis. The chronic bacterial infection attacks the lungs and other organs; symptoms include fever, night sweats, weight loss, chest pain, and coughing.
Before the discovery of drugs such as isoniazid, weapons for fighting TB were blunt at best. For over 50 years, doctors treated TB patients at sanatoriums with a regimen of strict rest and fresh air. When that failed to produce long-term results, physicians added collapse therapy (surgical lung collapse) to the treatment.
In 1944, Selman A. Waksman discovered the first drug for TB: streptomycin. That same year, Jorgen Lehman in Sweden synthesized the para-amino salt of salicylic acid. The combination of these two drugs proved effective against drug resistance.
But the Holy Grail was found in 1952 when researchers added isoniazid, a remarkably simple and inexpensive drug, to the arsenal. Triple therapy, as it was called, led to a 90 to 95% cure rate among TB patients. Shortly thereafter, sanatoriums closed and collapse therapy ended.
 COURTESY OF THE AMERICAN LUNG ASSOCIATION |
PLENTY OF REST Before the discovery of antibiotics such as isoniazid, doctors believed that tuberculosis could be treated with rest. Shown here are tuberculosis patients sleeping at a sanatorium in upstate New York in 1921. |
PH.D. CANDIDATES Hans Meyer and Josef Mally of German Charles University in Prague first synthesized isoniazid in 1912 as part of their doctoral requirements, completely unaware of the enormous potential their compound held for treating TB.
Forgotten for nearly 40 years, isoniazid reemerged in 1951 after researchers at Hoffmann-La Roche and E. R. Squibb & Sons in the U.S. and at Bayer in West Germany simultaneously and ind ependently demonstrated that isoniazid had a high degree of anti-TB activity.
The chemical hunt had begun several years earlier when two U.S. doctors, H. Corwin Hinshaw of Stanford University and Walsh McDermott of Cornell Medical School, traveled to Germany to investigate reports that the Germans had treated 7,000 TB patients with a new synthetic chemical of the thiosemicarbazone series under study by Gerhard Domagk, who had discovered the first sulfonamide.
Hinshaw and McDermott returned to the U.S. with a supply of the drug, Conteben, for further testing. Thousands of derivatives later, researchers arrived at isoniazid. The key to the compound's effectiveness turned out to be a pyridine ring in place of the thiosemicarbazone molecule's benzene ring.
Over the years, isoniazid has proven highly effective, specific, and well-tolerated. And because it's inexpensive, the drug is accessible to people in some of the poorest countries.
Isoniazid and an equally effective drug, rifampin, are the first in a succession of drugs used to treat TB. But the rise in multi-drug-resistant TB (MDR-TB) is threatening to render these drugs useless. Globally, up to 4% of all TB cases are resistant to more than one anti-TB drug, according to the World Health Organization. And in parts of Eastern Europe, nearly half of all TB patients resist at least one first-line drug.
"We desperately need newer, shorter regimens for the treatment of TB," says Lee B. Reichman, executive director of the New Jersey Medical School National Tuberculosis Center, in Newark. He explains that because current drug regimens need to be taken for six to eight months, many patients don't complete the therapy--in effect sharpening the sword of drug resistance.
Clinical trials are under way on some existing drugs, such as the class of antibiotics called fluoroquinolones (C&EN, Dec. 13, 2004, page 7), the antibiotics capreomycin and cycloserine, and the antibiotic linezolid, which appear to have effectiveness against MDR-TB. Another area of research is in new targets to make current TB drugs, such as isoniazid and rifampin, useful again. And some researchers are studying new classes of drugs against the disease.
"Any way you can possibly imagine looking at this issue is being looked at," says Christine F. Sizemore, acting chief of the Tuberculosis & Other Mycobacterial Diseases Section of the Respiratory Diseases Branch at the National Institutes of Health's National Institute of Allergy & Infectious Diseases.
Yet Sizemore doesn't anticipate an end to isoniazid's role in TB therapy: "For people who have drug-sensitive TB, to get isoniazid is often a life-saving action."—
