Persistent tuberculosis resists treatment

 “If we succeed, these novel adjunct treatments will buy more time for current and also future antibiotics before the tuberculosis bacteria are able to develop resistance to them,” says Adjunct Professor Mataleena Parikka

“If we succeed, these novel adjunct treatments will buy more time for current and also future antibiotics before the tuberculosis bacteria are able to develop resistance to them,” says Adjunct Professor Mataleena Parikka.

A new study aims at halving treatment time.

A study conducted at the University of Tampere in Finland is seeking new ways to make the drug treatment of tuberculosis more effective. Under normal circumstances, tuberculosis is treated with a six-month course of four different antibiotics. In drug-resistant cases of the disease, the treatment may take as long as two years and require a combination of several more medicines.

Tuberculosis is a challenging research topic, and its pathomechanisms are still not fully understood. Mycobacterium tuberculosis strains that are susceptible to antibiotics in laboratory conditions firmly resist treatment within the human body.

“The reasons why the disease is so difficult to treat are not yet known. The infection biology of tuberculosis is not yet sufficiently well understood,” says Adjunct Professor Mataleena Parikka from the University of Tampere.

The research groups led by Parikka and Professor Seppo Parkkila recently received €1,055,000 of funding from the Jane and Aatos Erkko Foundation for their joint project. In addition, Parikka received €238,000 of Clinical Researcher funding from the Academy of Finland. The funding from both sources is for a four-year period.

In tuberculosis, granulomas – structures formed by immune cells bordering bacteria – develop in tissues. Inside these granulomas are free bacteria, which Parikka’s and Parkkila’s studies have found to form biofilms. Biofilms are organised bacterial communities embedded in the protective extracellular matrix they produce. These biofilms are known to cause various persistent chronic infections. The bacteria living within the biofilms are highly resistant to medication.

“In our project, we study the composition of biofilms formed during mycobacterial infections. We are looking for ways to weaken the biofilm so that traditional medicines can gain better access to the bacteria. Our hypothesis is that the natural phenotypic drug tolerance that develops in mycobacteria during an infection is caused by the formation of biofilms within the granulomas,” Parikka says.

The research groups are using different approaches to find a solution to their common conundrum. Parkkila’s group is developing drugs that inhibit mycobacteria’s carbonic anhydrase enzymes – thus preventing biofilm formation, while Parikka’s group is examining therapeutic enzymes to degrade the extracellular matrix of the biofilm.

These completely new types of adjunct treatments are being developed for use alongside traditional anti-tubercular medicines to make treatment more effective.

“Our goal is to halve the treatment time of tuberculosis,” Parikka says.

The studies use zebrafish, which have a very similar immune system to that of mammals. Parikka and her colleagues have developed a tuberculosis model for zebrafish that is well suited both for the study of the infection biology of mycobacterial infections and for large-scale drug discovery. Parikka directs the zebrafish core facility at the University of Tampere.

In Finland, there are around 200 new tuberculosis cases annually. The prevalence of drug-resistant strains of tuberculosis in the neighbouring areas of Russia and the Baltic countries is a cause for concern.
Worldwide, tuberculosis is particularly a problem in low income countries.

“The treatments are expensive and often remain unfinished, which promotes the development of drug-resistant strains. The treatment of drug-resistant tuberculosis is considerably more expensive, the medicines used have side effects, and the treatment fails more often than the treatment of ordinary tuberculosis,” Parikka explains.

The research groups are facing tough challenges. However, there are significant opportunities.
“Nothing like this has ever been done before. If we succeed, these novel adjunct treatments will buy more time for current and also future antibiotics before the tuberculosis bacteria are able to develop resistance to them,” Parikka says.

Text and photograph: Jaakko Kinnunen