Thioridazine Alters the Cell-Envelope Permeability of Mycobacterium tuberculosis

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.