New anti-tuberculosis drug could shorten patient treatment time: study

Washington: A new experimental antibiotic for tuberculosis (TB) might be more effective than isoniazid, a decades-old drug that is currently one of the standard treatments for the disease, says a study. In mouse models, the drug has shown a much lower tendency to develop resistance, according to the study published in the journal Antimicrobial Agents and Chemotherapy.

The drug stays in tissues where Mycobacterium tuberculosis bacteria live longer and kills them more effectively. "The goal of TB drug development programs is to develop universal treatment regimens that will shorten and simplify the treatment of TB in patients months and sometimes over a year," said Gregory T Robertson, Assistant Professor at Colorado State University in the United States.

The new drug, called AN12855, has several advantages over isoniazid, which requires the conversion of its active form to a mycobacterial enzyme, KatG, in order to kill the pathogen. This creates some problems. First, in some cases of tuberculosis, KatG is not functional. This does not make TB less pathogenic, but prevents the drug from acting. This creates an easy avenue for the development of drug resistance, say researchers

Under the selection pressure of isoniazid, non-functional KatG tuberculosis bacteria – those that do not activate the drug – are the ones that recur. In these circumstances, drug resistance may develop. Human tuberculosis is characterized by the presence of a "heterogeneous lung disease".

This includes a host defense involving the containment of invading bacteria in small bodies resembling cysts called granulomas, devoid of vascular system and often preventing the drug from reaching the pathogen. Most models of murine tuberculosis used for the clinical evaluation of new drugs do not produce this advanced lung pathology. Thus, they give little information on how the drugs might behave in the presence of an advanced lung disease typical of human tuberculosis.

In this study, researchers used a new model of tuberculous mice developing these granulomas containing M tuberculosis to compare isoniazid and AN12855. "We found that the drugs differed significantly in their ability to kill the pathogen in very sick tissues, making AN12855 more effective, without choosing an appreciable drug resistance," Robertson said.

The superior efficacy is not surprising: AN12855 was superior in terms of entry and retention in granulomas, where M tuberculosis is found in very large numbers, he said. "That this translates into improved treatment of the human disease will be the subject of future studies," Robertson said.

"Our studies also confirm the use of a new model of efficacy of the TB mouse (called C3HeB / FeJ) as a research tool to study the impact of disease states similar to those of the man on the activity and distribution of TB antibiotics at various stages of development, "Robertson said. This could accelerate the development of better TB treatments, researchers said.