Why and how thioridazine in combination with antibiotics to which the infective strain is resistant will cure totally drug-resistant tuberculosis

Abstract

Over a period of 14 years, the authors have studied thioridazine, an old neuroleptic, that has been shown to have in vitro activity against intracellular Mycobacterium tuberculosis, regardless of its antibiotic resistance status, thioridazine cures infected mice of antibiotic-susceptible and multidrug-resistant tuberculosis (TB) infections and, when used in combination with antibiotics used for therapy of TB, renders the organism significantly more susceptible. This article will describe the authors’ further work and the mechanisms by which thioridazine alone and in combination with antibiotics cures an extensively drug-resistant infection and why it is expected to cure totally drug-resistant TB infections as well. The concepts presented are entirely new and because they focus on the activation of killing by nonkilling macrophages where M. 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.

Keywords::

• efflux pumps
• inhibition
• killing
• MDR TB
• TDR TB
• TDR TB cures
• thioridazine
• XDR TB

Financial and competing interests disclosure

This work was supported by EU-FSE/FEDER-PTDC/BIAMIC/ 105509/2008 and EU-FSE/FEDERPTDC/SAU-CF/102807/2008 from the Fundacão para a Ciência e a Tecnologia de Portugal (FCT). LAmaral was supported by BCC grant SFRH/BCC/51099/2010 provided by the FCT. J Molnar was supported by the Cancer Foundation of Szeged. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.