Fluoxetine and thioridazine inhibit efflux and attenuate crystalline biofilm formation by Proteus mirabilis

Abstract

Proteus mirabilis forms extensive crystalline biofilms on indwelling urethral catheters that block urine flow and lead to serious clinical complications. The Bcr/CflA efflux system has previously been identified as important for development of P. mirabilis crystalline biofilms, highlighting the potential for efflux pump inhibitors (EPIs) to control catheter blockage. Here we evaluate the potential for drugs already used in human medicine (fluoxetine and thioridazine) to act as EPIs in P. mirabilis, and control crystalline biofilm formation. Both fluoxetine and thioridazine inhibited efflux in P. mirabilis, and molecular modelling predicted both drugs interact strongly with the biofilm-associated Bcr/CflA efflux system. Both EPIs were also found to significantly reduce the rate of P. mirabilis crystalline biofilm formation on catheters, and increase the time taken for catheters to block. Swimming and swarming motilies in P. mirabilis were also significantly reduced by both EPIs. The impact of these drugs on catheter biofilm formation by other uropathogens (Escherichia coli, Pseudomonas aeruginosa) was also explored, and thioridazine was shown to also inhibit biofilm formation in these species. Therefore, repurposing of existing drugs with EPI activity could be a promising approach to control catheter blockage, or biofilm formation on other medical devices.

Bacterial biofilm formation on indwelling urethral catheters

“…Drugs from classes including the selective serotonin reuptake inhibitors and phenothiazines were found to exhibit putative EPI activity, with fluoxetine and thioridazine subsequently shown to significantly reduce crystalline biofilm formation and delay catheter blockage in in vitro models (; Nzakizwanayo et al . ) (Fig. ).…”

“…; Nzakizwanayo et al . ). Importantly, such studies also serve to highlight potential new targets for biofilm control, with subsequent investigations demonstrating that inhibitors of efflux in P. mirabilis can also reduce crystalline biofilm formation (Nzakizwanayo et al .…”

“…; Nzakizwanayo et al . ). Of particular significance are findings that drugs already used in human medicine can function as EPIs and attenuate the formation P. mirabilis crystalline biofilm formation (Nzakizwanayo et al .…”

“…Of particular significance are findings that drugs already used in human medicine can function as EPIs and attenuate the formation P. mirabilis crystalline biofilm formation (Nzakizwanayo et al . ). Drugs from classes including the selective serotonin reuptake inhibitors and phenothiazines were found to exhibit putative EPI activity, with fluoxetine and thioridazine subsequently shown to significantly reduce crystalline biofilm formation and delay catheter blockage in in vitro models (; Nzakizwanayo et al .…”

“…Impact of repurposed drugs on crystalline biofilm formation (from Nzakizwanayo et al . ). Images show impact of the repurposed efflux inhibitors thioridazine and fluoxetine on P. mirabilis crystalline biofilm formation in an in vitro bladder model.…”