The Potentials and Difficulties of Two New Drugs, TMC 207 and PA-824, against Drug-Susceptible and Drug-Resistant Strains of Mycobacterium tuberculosis

Abstract:

Tuberculosis has for decades been the leading cause of death, worldwide, originating from merely one infectious matter i.e. the bacilli Mycobacterium tuberculosis (MTB). It is killing approximately 1.5 million people every year. The World Health Organization (WHO) estimates that 2 billion people might be infected by this specific bacterium, and that there emerges about 9 million new, active cases of TB each year. The aim with this thesis is to elucidate the possibilities and the difficulties with two new drugs against susceptible and resistant, latent and replicating strains of M. tuberculosis.

A search for relevant articles on Pub Med, through the university library, was undertaken and approximately 35 articles were found. These articles were read; facts were sorted out and used for this paper. Figures were found through Creative Commons.

The two new drugs discussed in this paper are TMC 207 and PA-824. They have two different mechanisms of action, and additionally and most importantly, that differ from the drugs used as first-line and second-line options. TMC 207 targets the mycobacterial ATP synthase. PA-824, a pro-drug, targets the cell wall synthesis and in addition causes respiratory poisoning, through the release of nitric oxide. The different mechanisms are vital in order to combat emerging resistance, due to various missense mutations in specific genes in the bacilli. The bactericidal activity of the drugs against mycobacteria is high, promising a successful cure for MDR (multi drug resistant)/XDR (extensively drug resistant) patients. The median survival is 4.1 years for MDR patients and 2.9 years for XDR patients, with currently available treatments. This is noticeably worse than some cancer prognoses. Perhaps with these drugs there is even a possibility of shortening the treatment time. The adverse events are mild to moderate, for both drugs. This is another additive advantage, since the toxicity of the drugs will be minimal and hopefully tolerable, and most importantly will bring about treatment commitment and the sought elimination of the disease.

However, as with all new drugs the outcomes are still to be proven in real settings, the complex fields (in low- and middle income countries, with difficult TB cases), and with complicated cases (e.g. HIV co-morbidity) during a longer period of time. Reporting and evaluating the outcomes is crucial, since whatever is displayed from the drug consumption and the effects of it can lead to alterations in regimens, doses and treatment commitment.