Hitting TB With Toxic Gas

Small amounts of sulfur dioxide can slow the growth of the bacteria that cause tuberculosis, researchers report (J. Med. Chem., DOI: 10.1021/jm201023g). The toxic gas could form a new avenue of drug research for the disease.

Researchers in India, led by Harinath Chakrapani at the Indian Institute of Science Education and Research Pune, were inspired by a drug in clinical trials for TB. It releases small amounts of nitric oxide, a toxic gas that can have beneficial physiological effects in small doses.

Chakrapani wanted to do the same with another toxic gas, SO₂, which finds use as an antibiotic in winemaking. He investigated a family of 2,4-dinitrophenylsulfonamides that can react with thiols to release SO₂. “Nobody has really thought of it before,” says Chakrapani.

To test the idea, the researchers added cysteine, a thiol-containing amino acid, to various 2,4-dinitrophenylsulfonamides to see which molecules produced the most SO₂. The researchers then added solutions of 11 SO₂-producing molecules to growing Mycobacterium tuberculosis colonies. After 28 days, they saw that the molecules that released the most SO₂ also were the best at inhibiting the growth of the bacteria. What’s more, the most potent molecule slowed growth at lower concentrations than the standard tuberculosis drug isoniazid did: At 0.37 µM, isoniazid reduced growth by 99%, while the researchers’ compound reached the same level of inhibition at 0.15 µM. To rule out sulfite as the active agent, the researchers tested sulfite ions against the bacteria. Sulfite did not inhibit bacterial growth.

The active molecules are as much as 50 times more toxic to tuberculosis than to human cells, Chakrapani found. Chakrapani now wants to investigate related molecules, because the dinotrophenylsulfonamide structure, he says, “gives us a handle to tune the rate of SO₂ generation using very simple structural changes.”