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 PI3K inhibitor 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. Methicillin-resistant Staphylococcus aureus (MRSA) is a major human pathogen that causes an increasing number of infections in hospitals as well as in the community. Many strains are multiresistant with only a few active antibiotics available and the development of new antibiotics Selleckchem Tanespimycin is lagging behind (Fischbach & Walsh, Oxalosuccinic acid 2009). Consequently, attempts have been made to resolve antibiotic resistance by antibiotic restriction and enforcement of hygiene in hospital settings, but has only been partly
successful. Alternative solutions to the resistance problem are therefore urgently needed. We have previously shown that thioridazine can reverse resistance to oxacillin (a methicillin analogue), if the two drugs are used in combination against MRSA in vitro (Klitgaard et al., 2008). This synergy, which restores susceptibility to oxacillin, has been confirmed in 10 clinical isolates by others (Hadji-nejad et al., 2010). Thioridazine is a phenothiazine derivate, which has been shown to have therapeutic applications in problematic infections caused by antibiotic-resistant bacteria (Amaral et al., 2004). Within the pharmacological class of phenothiazines, thioridazine is the most efficacious and least toxic, when used as an antipsychotic drug (Kristiansen, 1979). The notable potential of thioridazine in treatment of bacterial infections is well known in many bacteria including S. aureus (Hendricks et al., 2003). The mechanism behind the reversal effect by thioridazine remains unexplained. MRSA strains are characterized by the presence of the acquired mecA gene, which encodes a penicillin-binding protein (PBP) with a low-affinity transpeptidase, PBP2a or PBP2′ and the β-lactamase gene, blaZ.