Washington: A new experimental antibiotic for tuberculosis (TB) may be more effective than isoniazid, a decades-old drug which is currently one of the standard treatments for the disease, a study claims. In mouse models, the drug showed a much lower tendency to develop resistance, according to the study published in the journal Antimicrobial Agents and Chemotherapy.
The drug remains in the tissues where the Mycobacterium tuberculosis bacteria reside for longer, killing them more effectively. “The goal of TB drug development programmes is to develop universal treatment regimens that will shorten and simplify TB treatment in patients, which typically takes at least six months, and sometimes more than a year,” said Gregory T Robertson, an assistant professor at Colorado State University in the US.
The new drug, called AN12855, has several advantages over isoniazid, which requires conversion to its active form by a Mycobacterial enzyme, KatG, in order to kill the pathogen. This creates a couple of problems. First, in some M tuberculosis, KatG is nonfunctional. That does not make M tuberculosis any less pathogenic, but it prevents the drug from working.
That creates an easy avenue for the development of drug resistance, researchers said. Under selection pressure from isoniazid, the tuberculosis bacteria with nonfunctional KatG — those that do not activate the drug — are the ones that reproduce. Under these circumstances, drug resistance may develop.
A hallmark of human tuberculosis is the presence of “heterogeneous pulmonary disease.” This includes a host defence involving confinement of invading bacteria within small cyst-like bodies called granulomas, that lack vasculature and often prevent the drug from reaching the pathogen.
Most mouse TB models used for clinical evaluation of new drugs fail to produce this advanced lung pathology. Thus, they give little insight into how drugs might behave in the presence of advanced lung disease that is typical of human tuberculosis.
In the study, the researchers used a new TB mouse model that develops these M tuberculosis-containing granulomas to compare isoniazid and AN12855. “We discovered that the drugs differed dramatically with respect to their abilities to kill the pathogen in highly diseased tissues. AN12855 proved more effective, without selecting for appreciable drug resistance,” said Robertson.
The superior efficacy is not surprising: AN12855 was superior in gaining entry and being retained in the granulomas, where M tuberculosis is found in highest numbers, he said. “Whether this translates into improvements in treatment of human disease will be the subject of future studies,” Robertson said.
“Our studies also further validate the use of a new TB mouse efficacy model (dubbed C3HeB/FeJ) as a research tool to study the impact of heightened human-like disease states on the activity and distribution of TB antibiotics that are in various stages of development,” said Robertson. That could accelerate development of better TB treatments, researchers said.