Thioridazine: an old neuroleptic effective against totally drug resistant tuberculosis

Globally, tuberculosis infections continue to increase their resistance to antibiotics. Multidrug resistant tuberculosis infections (MDR TB) have progressed to extensively drug resistance status (XDR TB) and the latter have evolved in some parts of the world to totally drug resistant (TDR TB) infections. MDR TB is difficult to treat successfully, and when therapy is ineffective, a single case can cost almost $500,000. When the infection is XDR TB therapy is mostly unsuccessful and is accompanied with high mortality. TDR TB-a yet to be defined infection, is resistant to all forms of therapy and mortality is almost certain. We have, over a period of 14 years, studied thioridazine (TZ) an old neuroleptic that we have shown to: i) have in vitro activity against all antibiotic resistant forms of Mycobacterium tuberculosis; ii) have activity against intracellular Mycobacterium tuberculosis regardless of its antibiotic resistance status; iii) cure the infected mouse of an antibiotic susceptible and MDR TB infections; and, iv) when used in combination with antibiotics used for therapy of tuberculosis, would render the organism significantly more susceptible. These studies have guided our Argentinian colleagues to treat successfully XDR TB infections with thioridazine in combination with three antibiotics to which the infection was initially resistant. This mini review will describe our further work and the mechanisms by which TZ alone and in combination with antibiotics cures an XDR TB infection and why it is expected to cure TDR TB infections as well. The concepts presented are totally new and because they focus on the activation of killing by non-killing macrophages where Mycobacterium tuberculosis normally resides during infection, and coupled to the inhibition of efflux pumps which contribute to the antibiotic resistant status, effective therapy of any antibiotic resistant TB infection is possible. Because TZ is cheap and therefore affordable to any economically disadvantaged country, and will produce no harm when appropriate measures are taken, it is the ideal drug for immediate use in countries that have high frequencies of MDR, XDR and TDR TB infections.