The goal of drug development for tuberculosis is to find treatment regimens that will shorten and simplify treatments in patients. This is because with the current methods, it typically takes at least 6 months and sometimes more than a year to treat patients.
Research published in Antimicrobial Agents and Chemotherapy, illustrates a new experimental antibiotic for TB, AN12855, which has several advantages over isoniazid, a decades-old drug which is currently one of the standard treatments.
In the mouse studies a major find was that the new drug showed a much lower tendency to develop resistance. As well as this, it remains in the tissues where the Mycobacterium tuberculosis bacteria reside for longer, killing them more effectively.
For Isoniazid to work and kill the pathogen, it needs to be converted into its active form by a Mycobacterial enzyme, KatG – this creates a couple of problems. First, in some M. tuberculosis, KatG is nonfunctional. Although this does not make M. tuberculosis any less pathogenic, it does prevent the drug from working.
Hence, this creates the opportunity for the emergence of drug resistance. Under selection pressure from isoniazid, the tuberculosis bacteria with nonfunctional KatG are the ones that reproduce. Under these circumstances, drug resistance may develop.
A more effective mouse model
A hallmark of human tuberculosis is the presence of ‘heterogeneous pulmonary disease.’ This is where, in an attempt to defend, the host will confine the invading bacteria within small cyst-like bodies called granulomas that lack vasculature and often prevent the drug from reaching the pathogen.
Many mouse models use today 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 in human tuberculosis.
In this 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," explained Gregory T. Robertson, Assistant Professor, Department of Microbiology, Immunology and Pathology, Colorado State (CO, USA).
AN125855 has not only proved to be more effective, it does so “without selecting for appreciable drug resistance,” added Robertson.
This efficacy is not surprising; AN12855 was superior in gaining entry and being retained in the granulomas, “where M. tuberculosis is found in highest numbers,” stated Robertson. "Whether this translates into improvements in treatment of human disease will be the subject of future studies."
"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," commented Robertson. That could accelerate development of better TB treatments.
According to WHO, 10 million people fell ill with TB in 2017 and 1.6 million died from the disease. Robertson concluded, “Multidrug resistance is a further challenge to the mission to control TB globally. Collectively, our group has pioneered the use of new TB mouse efficacy models to help advance innovative new therapies designed to shorten the length of TB treatment."
Sources: Robertson GT, Ektniphong VA, Scherman MS et al. Efficacy and improved potential of a cofactor-independent InhA inhibitor of Mycobacterium tuberculosis in a C3HeB/FeH mouse model. Antimicrob. Agents Chemother. (2019): https://doi.org/10.1128/AAC.02071-18; https://www.asm.org/Press-Releases/New-Tuberculosis-Drug-May-Shorten-Treatment-Time-f