Drug-resistant Tuberculosis – New Target For Treatment Found

A new target for combatting multi-resistant mycobacteria tuberculosis, the main cause of tuberculosis, has been found by scientists.

Working from a rejuvenated antibiotic series, scientists from the Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), the Helmholtz Centre for Infection Research (HZI) in and the German Center for Infection Research (DZIF) jcollaborated with scientists from the global health care company Sanofi, identified a new agent which might potentially help fight tuberculosis.

The current treatment for drug-susceptible tuberculosis calls for the daily ingestion of multiple drugs, for a minimum of six months. Non-adherence to this demanding regimen can lead to the treatment’s failure and the development of drug resistance.

The World Health Organization estimates that around 8.7 million people contracted tuberculosis in 2012. The disease is fatal for some 1.3 million people globally each year. One of the main difficulties is that tuberculosis pathogens have become resistant to antibiotics used to fight them.

Prof Rolf Müller, who is the Executive Director and head of the Microbial Natural Substances department of the HIPS, said:

“Complexity and duration of the treatment are true issues and the main reasons for the development of resistant pathogens.”

So there is an urgent need for new therapeutic medications and approaches to fight the resistant pathogens, as well as shorten the duration for the treatment of drug-susceptible organisms.

A natural substance called griselimycin, discovered in the 1960s The potential of this substance, which earlier reports had focused on, was not developed any further at the time because of the success of other tuberculosis medications.

“We resumed the work on this agent and optimised it such that it shows excellent activity in the infection model — even against multi-resistant tuberculosis pathogens,” says Müller.

In their research, the scientists found that cyclohexylgriselimycin, a variant of griselimycin, is distinctly active against Mycobacterium tuberculosis, both in cells and in the animal model.

Moreover, cyclohexylgriselimycin was effective when administered orally, an important consideration in tuberculosis treatment. Non-orally available drugs are very challenging to administer daily during the many months of treatment. Combining cyclohexylgriselimycin with current TB antibiotics increases the efficacy compared to the antibiotic blend that is usually administered.

“In the tuberculosis pathogen, the substance binds to the so-called DNA clamp and thus suppresses the activity of the DNA polymerase enzyme, which multiplies the genetic information inside the cell,” says Müller.

Becasue this works via a different mechanism from the antibiotics previously used against tuberculosis and other bacterial pathogens, risk of resistance developing is low for now.

R. Muller et al
Targeting DnaN for tuberculosis therapy using novel griselimycins
Science, 2015; 348 (6239): 1106 DOI: 10.1126/science.aaa4690

Illustration: Protein forms a ring (shown as blue cartoon & surface representation). Each polypetide chain binds one molecule of griselimycin (red). The optimized compound cyclohexylgriselimycin contains an additional cyclohexane moiety (yellow, shown only for the ligand in the foreground). Credit: HZI/Lukat