New Patentable Use of an Old Neuroleptic Compound Thioridazine to Combat Tuberculosis: A Gene Regulation Perspective

Noton      K. Dutta; Kaushiki      Mazumdar; Sujata      G. Dastidar; Petros      C. Karakousis; Leonard      Amaral

doi:10.2174/157489111796064597

Abstract

Use of the old antipsychotic phenothiazine thioridazine (THZ) for therapy of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) infection is now being seriously considered. It is reported that THZ primarily acts on enzymes involved in fatty acid metabolism and membrane proteins, particularly efflux pumps, as well as oxidoreductases and proteins involved in aerobic respiration that overlap with a number of conventional antituberculous drugs. It targets the products of the Rv3160c-Rv3161c operon, which are perhaps required for the detoxification of THZ, members of the sigma factor SigB regulon that play a crucial role in protecting the pathogen against cell envelope damage, and Rv2745c, a transcription factor that regulates ATP-dependent proteolysis. Some of these genes have been shown to be essential for the survival or persistence of Mycobacterium tuberculosis in the infected host. Since THZ targets multiple pathways, including those involved in cell wall processes and respiratory chain components, it may serve as a model for multi-target drug development, as well as constitute a highly potent addition to a combination of antituberculous drug regimens. The discussion of some of the patents relevant to thioridazine to combat tuberculosis is also included in the present manuscript.

Keywords: Cell envelope stress, drug targets, gene essentiality, Mycobacterium tuberculosis, Thioridazine, respiratory chain components, sigma factor B, KEY GENES OF M. TUBERCULOSIS, thioredoxin regulons, Expression of hsp/acr2