TUBERCULOSIS has plagued humanity for thousands of years. The discovery in the 19th century of its cause, a bacterium (pictured above) called Mycobacterium tuberculosis, and the consequent development of better hygiene, helped bring that plague under control. Then, in the mid-20th century, what many hoped would be the final nail in its coffin appeared: antibiotic drugs.
Unfortunately, TB is back. After a few decades in which antibiotics did indeed seem to be working miracles, some strains of M. tuberculosis have evolved resistance to them. In 2015 5% of the world’s 10m cases failed to respond to treatment with isoniazid and rifampicin, the drugs of first resort. Half of those non-responders were infected by strains of the bacterium immune to second-line treatments as well. Most microbiologists regard these numbers as portents of worse to come. That is driving a search for new antibiotics against which M. tuberculosis has evolved no resistance.
Eshwar Mahenthiralingam of Cardiff University and Greg Challis of the University of Warwick, both in Britain, think they have found one. As they and their colleagues describe in the Journal of the American Chemical Society, they have discovered a compound, produced by another bacterial pathogen, that kills resistant strains of M. tuberculosis.
This compound, which they call gladiolin, is created by Burkholderia gladioli—a bacterium, generally rare, that thrives in the lungs of those suffering from cystic fibrosis. It is able to gain a foothold there because the respiratory tracts of such patients are clogged with mucus that inhibits the actions of immune-system cells which would otherwise destroy the invaders. What interested Dr Mahenthiralingam and Dr Challis about B. gladioli was that, once established in a patient’s lungs, it seems able to keep rival bacteria such as M. tuberculosis at bay. This suggests it is engaging in chemical warfare.
To isolate the agent that inhibits B. gladioli’s competitors, the researchers cultivated samples from a patient with cystic fibrosis and analysed the chemicals secreted by bacteria therein. It was thus they discovered gladiolin, which shuts down bacterial versions of the gene for an enzyme called RNA polymerase that is crucial for life.
This was interesting. But it was also reminiscent of a false dawn involving another substance, etnangien, which was discovered in 2007 and which also inhibits RNA polymerase. Unfortunately, etnangien proved chemically unstable and thus impossible to use as a drug. The first task Dr Mahenthiralingam and Dr Challis undertook was therefore a detailed comparison of the two. They established that the parts of etnangien molecules which cause their instability are not shared by gladiolin. That suggested gladiolin might indeed be robust enough for use against tuberculosis, and encouraged them to test it further.
The new substance performed reasonably well against a strain of tuberculosis that had no resistance to antibiotics. A solution of 400 nanograms (billionths of a gram) per millilitre was enough to inhibit the growth of such bacteria. But isoniazid and rifampicin performed better. They needed only 40 nanograms and 1 nanogram per millilitre of solution respectively to keep the non-resistant bugs under control. Where gladiolin did shine, though, was against a strain of tuberculosis known for its resistance to isoniazid and rifampicin. Even 10,000 nanograms per millilitre of either of those two drugs was insufficient to harm it. However, a mere 1,700 nanograms per millilitre of gladiolin proved enough to knock it out.
Whether gladiolin can be taken out of the Petri dish and made into a useful drug will require many clinical trials to discover. But, in a world crying out for new antibiotics, it seems a useful lead.
Source: The Economist