New Hope In The Fight Against Tuberculosis

According to figures of the World Health Organization, some 8.7 million people contracted tuberculosis in 2012 and this disease is fatal for approximately 1.3 million people throughout the world each year. One of the main problems is that the tuberculosis pathogens have become resistant to the antibiotics used to fight them. Researchers have now identified a new agent, which might potentially remedy these problems. The research was described in the journal Science.
 
Mycobacterium tuberculosis is the main cause of tuberculosis. The treatment for drug-susceptible tuberculosis consists of the daily administration of multiple drugs for a minimum of six months. Lack of adherence to this regimen can result in treatment failure and the emergence of drug resistance.
 
Consequently, there is an urgent need for new medications and therapeutic approaches to both fight the resistant pathogens, as well as to shorten the duration for the treatment of drug-susceptible organisms. Based on earlier reports, the researchers initially focused on the natural substance called griselimycin. The potential of this natural substance, was discovered in the 1960s. However, due to the success of other tuberculosis medications and its low efficacy in an infection model, the substance was not developed any further at the time.
 
New Hope In The Fight Against Tuberculosis
The protein forms a homodimeric ring (shown as blue cartoon &
surface representation). Each polypetide chain binds one molecule
of griselimycin (red). The optimized compound cyclohexyl-
griselimycin contains an additional cyclohexane moiety
(yellow, shown only for the ligand in the foreground).
(Credit: HZI/Lukat)
In the course of their work, the scientists discovered that cyclohexylgriselimycin, a variant of griselimycin, is particularly effective against Mycobacterium tuberculosis, both in cells and in the animal model. Importantly, cyclohexylgriselimycin was effective when administered orally, which is key in tuberculosis treatment, non-orally available drugs are extremely burdensome to administer daily during the many months of treatment. Moreover, combining this substance with current TB antibiotics increases the efficacy compared to the antibiotic cocktail that is usually administered.
 
The scientists were not only able to demonstrate the efficacy of cyclohexylgriselimycin against tuberculosis, but they also elucidated the underlying mechanism of action. 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. Neither DNA replication nor efficient DNA repair can proceed in the absence of the DNA clamp, which means that the bacterial pathogens are prevented from proliferating in the body.
 
Since this mechanism is different from the mechanism of action of the antibiotics used previously against tuberculosis and all other bacterial pathogens, the risk of resistance developing is low for now. In addition, the scientists were able to show that the development of resistance in mycobacteria, which include the tuberculosis pathogen, albeit possible, is associated with a drastic decrease in the growth of the pathogens such that the potential of the development of resistance is estimated to be low.
 
Based on material originally posted by Helmholtz Centre for Infection Research.