School of Pharmacy and Biomolecular Sciences, University of Brighton, Lewes Road, Brighton, BN2 4GJ, United Kingdom.
Department of Microbiology, Instituto de Investigaciones Biológicas Clemente Estable, Montevideo, CP, 11600, Uruguay.
Sci Rep. 2017 Sep 22;7(1):12222. doi: 10.1038/s41598-017-12445-w.
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.
奇异变形杆菌在留置的尿道导管上形成广泛的结晶生物膜,从而阻塞尿液流动,并导致严重的临床并发症。先前已经确定 Bcr/CflA 外排系统对于奇异变形杆菌结晶生物膜的形成很重要,这凸显了外排泵抑制剂 (EPI) 控制导管阻塞的潜力。在这里,我们评估了已经在人类医学中使用的药物(氟西汀和硫利达嗪)在奇异变形杆菌中作为 EPI 并控制结晶生物膜形成的潜力。氟西汀和硫利达嗪均抑制奇异变形杆菌的外排作用,分子建模预测这两种药物均与生物膜相关的 Bcr/CflA 外排系统强烈相互作用。这两种 EPI 还被发现可显著降低奇异变形杆菌在导管上形成结晶生物膜的速度,并延长导管堵塞的时间。EPI 还显著降低了奇异变形杆菌的游泳和群集运动。还探索了这些药物对其他尿路病原体(大肠杆菌、铜绿假单胞菌)在导管生物膜形成的影响,结果表明硫利达嗪也能抑制这些物种的生物膜形成。因此,具有 EPI 活性的现有药物的再利用可能是控制导管阻塞或其他医疗器械上生物膜形成的有前途的方法。
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