The inside story

How popular tuberculosis drug works

By Indu Mathi S
Published: Saturday 15 December 2012

imageEMERGENCE of multi-drug resistant tuberculosis bacteria has rendered most TB drugs useless. Scientists are now scrambling to find new antibiotics to treat the disease. A study on how a popular TB drug works has come as the first step towards developing better strategies to fight the bacterium that kills millions every year.

For nearly 60 years, physicians have treated TB with an antibiotic para-amino salicylic acid (PAS). They believed that the drug kills TB bacteria by directly blocking dihydropteroate synthase or DHPS, an enzyme essential for the synthesis of folate, a nutrient produced by the bacteria that is crucial for its survival. The misconception arose because PAS does hinder the functioning of DHPS. But it was noted that other well-known DHPS inhibitors are useless in tuberculosis treatment. This prompted researchers at the Weill Cornell Medical College in New York, to reinvestigate how PAS kills TB bacteria.

The researchers used mass spectrometry to study the effect of drugs inside the bacterial cell. They found that PAS itself does not inhibit DHPS but induces poisonous downstream effects in the folate pathway. This means that it does not directly kill TB bacteria but rather gives rise to active derivatives that perform the task.

For the study, the researchers exposed TB bacteria to PAS and compared its effect with that of a sulpha drug, another potent antibiotic that inhibits DHPS. Sulpha drugs, though effective against various bacteria, have been found to be weak against TB. The scientists found that PAS underwent chemical disintegration inside the bacteria and gave rise to two components. Only one of them was active.

They found that this active derivative of PAS destroys the tuberculosis bacterium. The sulpha drugs on the other hand were degraded by the bacterium. “Both of these findings were unexpected,” says Kyu Y Rhee, corresponding author of the study. “The findings show that sometimes there is a profound disconnect between what we think a drug is doing and how it actually works inside cells.” The study was published online in the November 1 issue of Science Express.

For long, tuberculosis has remained a serious cause of concern and has resulted in millions of fatalities. In 2011, there were an estimated 8.7 million new cases of TB and 1.4 million people died from the disease. India and China together account for almost 40 per cent of the world’s TB cases, according to WHO’s 2012 global tuberculosis report. But unfortunately, mode of action of most antibiotics is not known, say the scientists. “Most TB drugs as well as other antibiotics have been developed through a combination of empirical approaches,” says Rhee. “Till now it had been impossible to know what the drug was doing inside the bacteria.”

Understanding how a drug acts on a pathogen is extremely important for designing newer, more effective and safer drugs, says Nagasuma Chandra, associate professor at the department of biochemistry of Indian Institute of Science in Bengaluru. “The study shows that PAS acts as a prodrug that converts into potent compounds that block enzymes in an important process. It can lead to new insights for designing prodrugs that are converted into active drugs by the cell itself.”

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