Evaluation of forty new phenothiazine derivatives for activity against intrinsic efflux pump systems of reference Escherichia coli, Salmonella Enteritidis, Enterococcus faecalis and Staphylococcus aureus strains.

Abstract

BACKGROUND: Because phenothiazines inhibit efflux pumps of bacteria, forty new phenothiazine derivatives were tested for their inhibition of the efflux pump systems of Gram-positive and Gram-negative pathogenic bacteria. MATERIALS AND METHODS: Detection of efflux pump activity was conducted by a previously described automated fluorimetric method. RESULTS: Although many of the compounds significantly inhibited efflux by distinct bacteria, four compounds had exceptional activity against the efflux pump systems of the pathogenic wild type bacteria Escherichia coli, Salmonella Enteritidis, Enterococcus faecalis and Staphylococcus aureus. These four compounds were then evaluated for ability to reduce or reverse resistance of multi-drug resistant members of Escherichia coli, Salmonella and Staphylococcus aureus whose MDR phenotypes are mediated by specific over-expressed efflux pumps. One of the compounds, 2173, significantly reduced resistance of MDR Staphylococcus aureus. CONCLUSION: These results suggest possible use of compound 2173 for therapy of infections caused by this organism.