Thioridazine Alters the Cell-Envelope Permeability of Mycobacterium tuberculosis

Abstract

The increasing occurrence of multidrug resistant tuberculosis exerts a major burden on treatment of this infectious disease. Thioridazine, previously used as a neuroleptic, is active against extensively drug resistant tuberculosis when added to other second- and third-line antibiotics. By quantitatively studying the proteome of thioridazine-treated Mycobacterium tuberculosis, we discovered the differential abundance of several proteins that are involved in the maintenance of the cell-envelope permeability barrier. By assessing the accumulation of fluorescent dyes in mycobacterial cells over time, we demonstrate that long-term drug exposure of M. tuberculosis indeed increased the cell-envelope permeability. The results of the current study demonstrate that thioridazine induced an increase in cell-envelope permeability and thereby the enhanced uptake of compounds. These results serve as a novel explanation to the previously reported synergistic effects between thioridazine and other antituberculosis drugs. This new insight in the working mechanism of this antituberculosis compound could open novel perspectives of future drug-administration regimens in combinational therapy.

Synthesis and SAR evaluation of novel thioridazine derivatives active against drug-resistant tuberculosis

“…The compounds 12b and 12e which showed the most promising antimycobacterial activity proved to be poor efflux pump inhibitors (Figure 2). These compounds could interfere with the cell-envelope permeability, as already hypothesized for 1, [23] by means other than inhibiting efflux pumps. On the other hand, the piperazine derivatives 7a and 7c which did not show antimycobacterial activity, were found to inhibit efflux pumps better than the reference chlorpromazine.…”

“…[20] Despite the mechanism of action of TZ having not been fully elucidated, recent studies showed that it inhibits efflux pumps in mycobacteria and alters the cell-envelope permeability of MTB. [21][22][23] Furthermore, TZ 1 is able to affects the physiology of alveolar macrophages, enhancing the retention of potassium ions and promoting the acidification of phagolysosomal vacuole, [24] finally leading to the degradation of intramacrophagic MTB.…”

Thioridazine: A Non-Antibiotic Drug Highly Effective, in Combination with First Line Anti-Tuberculosis Drugs, against Any Form of Antibiotic Resistance of Mycobacterium tuberculosis Due to Its Multi-Mechanisms of Action

“…Among the genes affected were those that encode efflux pumps that extrude antibiotics, oxido-reductases, enzymes involved in fatty acid metabolism and aerobic respiration, and genes that are co-expressed with the global SigmaB regulon, which are involved in the response to stress [38]. Other studies have confirmed these observations and have extended the understanding that TZ affects a large number of essential genes that code for proteins of the plasma membrane, many of which are involved in controlling essential energy production, active transport and permeability processes in response to antibiotic and oxidative stress stimuli [39]. In particular, several studies confirmed that TZ acts in mycobacterial respiratory chain components involved in ATP oxidative phosphorylation, namely, the type-II NADH-menaquinone oxidoreductase (NDH-2)—a key component of respiratory chain of Mtb—thus raising the hypothesis that this is the main molecular target of TZ and making it also effective against latent TB [40,41,42].…”

Systems proteomics approaches to study bacterial pathogens: application to Mycobacterium tuberculosis

“…A study showed that the abundance of several proteins responsible for the maintenance of cell-envelope permeability barrier changed significantly in Mtb exposed to thioridazine. Thioridazine increases cell-envelope permeability and thereby facilitates components uptake [59]. …”