A Patented Solution to Resistance

(March 7th, 2014) A few years ago, Jørn Bolstad Christensen, a chemist at the University of Copenhagen, found and patented a compound against multidrug resistant tuberculosis. Now he’s ready for the next stage: clinical trials. If only an investor could be found.

For a long time antibiotics have been our most powerful weapon against bacteria - but now the bacteria are fighting back. They developed resistance to antibiotics and rendered our weapons harmless. This could bring us back to times when infections were deadly. To keep on top, we need to find new antibiotics and search for ways to outsmart the bacteria. Jørn Bolstad Christensen made a potentially big step in that direction; he found a solution to the resistance problem.

"You could say that we cure bacteria of their resistance," Christensen explains. The bacteria he is particularly interested in are multidrug-resistant Mycobacterium tuberculosis. They cause tuberculosis, the second most common fatal infectious disease worldwide, after Aids. Although the tuberculosis death rate is falling continuously, the number of Multidrug Resistant Tuberculosis (MDR-TB) cases is rising. About 3.6% of newly infected tuberculosis patients and every fifth patient, who has previously been treated, carry MDR-TB strains. In general, tuberculosis is preventable and treatable, and even patients with MDR-TB can be cured. If you suffered from the "normal" drug-sensitive tuberculosis, you would spend six months on a standard mix of four antimicrobial drugs: Isoniazid, Rifampicin, Pyrazinamid and Ethambutol. If you still had bacteria after this treatment, your bacteria were probably multidrug resistant, meaning they didn't care about at least two of those anti-TB drugs at all.

Most likely, these bacteria simply pumped the antibiotics out with so-called efflux pumps - active transporters, pushing out toxic substances using energy. To the disadvantage of the bacteria, efflux pumps are also a great target for researchers in their fight against MDR-TB. The pumps can easily be blocked, the antibiotics stay inside and the bacteria die. But knowing the target is just the first step towards treating a disease, what is missing is the drug. Jørn Bolstad Christensen has found a substance able to block the efflux pump in MDR-TB. The curious thing about it: The substance, Thioridazine, is actually a psychoactive drug, previously prescribed for schizophrenia and psychosis. The original observation was already made centuries ago. Christensen explains, "Psychiatric patients were never seriously ill from infections, for some reason." One of his co-investigators, Jette Kristiansen, tested bacterial behaviour after treatment with pure Thioridazine. High doses killed many bacteria but lower doses also affect the central nervous system of humans. If you use Thioridazine in low concentrations, only the bacterial efflux pumps are inhibited. Bacteria and humans survive.

Furthermore, Thioridazine is a racemic mixture, which means it contains a left and a right handed enantiomer. As known from the horrible side effects of Contergan, the two enantiomers can have completely different effects on the body. So, Christensen separated the left and the right-handed form of Thioridazine. "We found out that bacteria do not care about what form they get but humans do! From the minus form you get three times less side effects in the central nervous system, in the end you just feel a bit dizzy," he says.

The results look promising, promising enough for a patent in Europe last year and one in the US this year for the minus form, JEK 47. The compound could be applied together with the common antibiotics to cure multidrug resistant tuberculosis. And it could even be applied to any resistant strain that uses efflux pumps for drug resistance.

But one last thing is still missing. JEK 47 has not been tested on humans - the researchers need funding and approval to test the compound in a clinical trial. The racemic mixture, though, has been successfully used in Argentina with 15 patients with Extensively Drug-Resistant Tuberculosis. But the side effects were too serious to ever get approval for the drug. In a mouse model, Christensen and his colleagues could show that the minus form causes much less side effects. Now, the scientists are searching for collaborators to carry out clinical trials and bring the drug onto the market. If Christensen cannot find a pharmaceutical company to produce it, “I would rather donate this discovery to an NGO able to use this substance in poor countries that suffer from drug resistance problems than watch it collect dust in the industrialised world. So, I hope that an investor comes along to develop this ground-breaking substance.”

Karin Lauschke

Photo: National Institute of Allergy and Infectious Diseases (Mycobacterium tuberculosis), University of Copenhagen (Christensen)

Further reading:

Reversal of resistance in microorganisms by help of non-antibiotics
Thioridazine protects the mouse from a virulent infection by Salmonella enterica serovar Typhimurium 74
A comparative Analysis of In Vitro and In Vivo Efficacies of the Enantiomers of Thioridazine and Its Racemate

Last Changes: 04.15.2014