Thioridazine affects transcription of genes involved in cell wall biosynthesis in methicillin-resistant Staphylococcus aureus

Abstract

The antipsychotic drug thioridazine is a candidate drug for an alternative treatment of infections caused by methicillin-resistant Staphylococcus aureus (MRSA) in combination with the β-lactam antibiotic oxacillin. The drug has been shown to have the capability to resensitize MRSA to oxacillin. We have previously shown that the expression of some resistance genes is abolished after treatment with thioridazine and oxacillin. To further understand the mechanism underlying the reversal of resistance, we tested the expression of genes involved in antibiotic resistance and cell wall biosynthesis in response to thioridazine in combination with oxacillin. We observed that the oxacillin-induced expression of genes belonging to the VraSR regulon is reduced by the addition of thioridazine. The exclusion of such key factors involved in cell wall biosynthesis will most likely lead to a weakened cell wall and affect the ability of the bacteria to sustain oxacillin treatment. Furthermore, we found that thioridazine itself reduces the expression level of selected virulence genes and that selected toxin genes are not induced by thioridazine. In the present study, we find indications that the mechanism underlying reversal of resistance by thioridazine relies on decreased expression of specific genes involved in cell wall biosynthesis.

Genetic response of Salmonella enterica serotype Enteritidis to thioridazine rendering the organism resistant to the agent

“…We do not believe that the phenothiazine actually has a direct effect on the genes, but rather limits or obviates access to calcium by calcium signalling-dependent systems. That this may indeed be true is supported by the wide-ranging effects that the phenothiazine has on hundreds of genes of mycobacteria [18,27] as well as the many genes of S. aureus [26] where calcium signalling plays a major role. Nevertheless, it remains for future studies to assess accurately the role played by the phenothiazines in mechanisms that lead to resistance.…”

“…In recent years, phenothiazines have been shown to affect the expression of genes that code for components of the cell wall of Staphylococcus aureus [26] as well as essential genes, including efflux pump genes, of Mycobacterium tuberculosis [18,27]. These studies were conducted with concentrations of TZ that exceeded the MIC against the respective organism.…”

Combination approaches to combat multidrug-resistant bacteria

“…45 The antipsychotic phenothiazine thioridazine (Figure 3e) has been demonstrated to increase the susceptibility of MRSA to oxacillin 46 and dicloxacillin 47 in a number of clinical isolates. 47 It was shown that the oxacillin-induced transcription of mecA and expression of PBP2a 46a is reduced in the presence of thioridazine, as is transcription of several genes belonging to the VraSR regulon. 46b Thioridazine has also long been known to exhibit antibiotic effects against M. tuberculosis , 48 including multi-drug resistant strains, though not at clinically relevant concentrations.…”

Efficacy of two novel 2,2’-bifurans to inhibit methicillin-resistant Staphylococcus aureus infection in male mice in comparison to vancomycin

“…The short period of exposure to bifurans and MRSA in this animal model was selected to reduce interference from the host defense mechanisms. The used bifurans were able to resensitize MRSA to methicillin, ampicillin, and ciprofloxacin (Table 1), which may indicate the potential of such antistaphylocoocal compounds to abolish the expression of some resistance genes involved in cell-wall biosynthesis, reflecting the ability of these small molecules to overcome the cell-membrane barrier 21. In a previous study, a dicationic bifuran similar to 1B was reported to bind specific human telomeric quadruplex in more than one groove 22…”