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Exposure of Mycobacterium tuberculosis to thioridazine alters the cell envelope permeability; an alternative mechanism for the synergistic effects with other antibiotics

ABSTRACT: The emergence of multidrug resistant tuberculosis and the increasing level of resistance urges the search for alternative drugs in treatment. Several neuroleptics, like thioridazine, reveal activity against Mycobacterium tuberculosis. Thioridazine was even successfully applied in compassionate therapy of extensively drug resistant tuberculosis in patients when added to other second and third line antibiotics. The synergistic effects between thioridazine and other anti-tuberculosis drugs is usually assigned to the inhibition of efflux pumps by thioridazine. Using an unbiased proteomic approach, we set out to unravel the molecular mechanism of this potential new anti-tuberculosis component by examining the impact of continuous thioridazine exposure on the proteome of M. tuberculosis. We discovered that under the influence of thioridazine several proteins involved in the maintenance of the cell wall permeability barrier are differentially regulated, while none of the known mycobacterial efflux pumps was differentially regulated on the protein level. By assessing accumulation of fluorescent dyes in M. tuberculosis over time, we demonstrated that long-term drug exposure of M. tuberculosis indeed affected the mycobacterial cell envelope and increased the permeability towards both hydrophilic and hydrophobic compounds. Furthermore, we demonstrated that treatment of M. tuberculosis with thioridazine altered the composition of the plasma membrane. Thioridazine induced an increase in cell envelope permeability, and thereby the enhanced uptake of compounds, this could explain the previously reported synergistic effects between thioridazine and other anti-tuberculosis drugs. Although the hypothesis of higher intercellular drug concentrations by THZ has not changed in this study, the more exact knowledge on its mode of action is a major step forward. This new insight in the molecular mechanism of this anti-tuberculosis compound could facilitate further development of this class of drugs for application in drug therapy of multidrug resistant tuberculosis. In fact, the efficacy of many existing drugs could be improved significantly.

INSTRUMENT(S): LTQ FT

ORGANISM(S): Mycobacterium Tuberculosis H37rv

DISEASE(S): Tuberculosis

SUBMITTER: Jeroen de Keijzer

LAB HEAD: Peter van Veelen

PROVIDER: PXD001208 | Pride | 2016-07-06

REPOSITORIES: pride

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Thioridazine Alters the Cell-Envelope Permeability of Mycobacterium tuberculosis.

de Keijzer Jeroen J Mulder Arnout A de Haas Petra E W PE de Ru Arnoud H AH Heerkens Evy M EM Amaral Leonard L van Soolingen Dick D van Veelen Peter A PA

Journal of proteome research 20160509 6

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 pe ...[more]

PMID: 27068340

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Project description:The identification of multidrug resistant (MDR), extensively and totally drug resistant Mycobacterium tuberculosis (Mtb), in vulnerable sites such as Mumbai, is a grave threat to the control of tuberculosis. The current study aimed at explaining the rapid expression of MDR in Directly Observed Treatment Short Course (DOTS) compliant patients, represents the first study comparing global transcriptional profiles of 3 pairs of clinical Mtb isolates, collected longitudinally at initiation and completion of DOTS. While the isolates were drug susceptible (DS) at onset and MDR at completion of DOTS, they exhibited identical DNA fingerprints at both points of collection. The whole genome transcriptional analysis was performed using total RNA from H37Rv and 3 locally predominant spoligotypes viz. MANU1, CAS and Beijing, hybridized on MTBv3 (BuG@S) microarray, and yielded 36, 98 and 45 differentially expressed genes respectively. Genes encoding transcription factors (sig, rpoB), cell wall biosynthesis (emb genes), protein synthesis (rpl) and additional central metabolic pathways (ppdK, pknH, pfkB) were found to be down regulated in the MDR isolates as compared to the DS isolate of the same genotype. Up regulation of drug efflux pumps, ABC transporters, trans-membrane proteins and stress response transcriptional factors (whiB) in the MDR isolates was observed. The data indicated that Mtb, without specific mutations in drug target genes may persist in the host due to additional mechanisms like drug efflux pumps and lowered rate of metabolism. Furthermore this population of Mtb, which also showed reduced DNA repair activity, would result in selection and stabilization of spontaneous mutations in drug target genes, causing selection of a MDR strain in the presence of drug pressures. Efflux pump such as drrA may play a significant role in increasing fitness of low level drug resistant cells and assist in survival of Mtb till acquisition of drug resistant mutations with least fitness cost. [Data is also available from http://bugs.sgul.ac.uk/E-BUGS-134]

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