Department of Science, University Roma Tre, Rome, Italy.
Inter University Centre for Bioscience, Kannur University, Palayad, Kerala, India.
Sci Rep. 2017 Sep 12;7(1):11392. doi: 10.1038/s41598-017-11892-9.
Efflux pumps of the resistance-nodulation-cell-division (RND) family increase antibiotic resistance in many bacterial pathogens, representing candidate targets for the development of antibiotic adjuvants. RND pumps have also been proposed to contribute to bacterial infection, implying that efflux pump inhibitors (EPIs) could also act as anti-virulence drugs. Nevertheless, EPIs are usually investigated only for their properties as antibiotic adjuvants, while their potential anti-virulence activity is seldom taken into account. In this study it is shown that RND efflux pumps contribute to Pseudomonas aeruginosa PAO1 pathogenicity in an insect model of infection, and that the well-characterized EPI Phe-Arg-β-naphthylamide (PAβN) is able to reduce in vivo virulence of the P. aeruginosa PAO1 laboratory strain, as well as of clinical isolates. The production of quorum sensing (QS) molecules and of QS-dependent virulence phenotypes is differentially affected by PAβN, depending on the strain. Transcriptomic and phenotypic analyses showed that the protection exerted by PAβN from P. aeruginosa PAO1 infection in vivo correlates with the down-regulation of key virulence genes (e.g. genes involved in iron and phosphate starvation). Since PAβN impacts P. aeruginosa virulence, anti-virulence properties of EPIs are worthy to be explored, taking into account possible strain-specificity of their activity.
耐药-天然-细胞分裂（RND）家族的外排泵增加了许多细菌病原体的抗生素耐药性，代表了抗生素佐剂开发的候选靶点。RND 泵也被认为有助于细菌感染，这意味着外排泵抑制剂（EPIs）也可以作为抗毒药物。然而，EPIs 通常仅因其作为抗生素佐剂的特性而被研究，而很少考虑其潜在的抗毒活性。在这项研究中，表明 RND 外排泵在感染昆虫模型中对铜绿假单胞菌 PAO1 的致病性有贡献，并且特征良好的 EPI Phe-Arg-β-萘基酰胺（PAβN）能够降低铜绿假单胞菌 PAO1 实验室株以及临床分离株的体内毒力。PAβN 对群体感应（QS）分子和 QS 依赖性毒力表型的产生有不同的影响，这取决于菌株。转录组学和表型分析表明，PAβN 对铜绿假单胞菌 PAO1 感染的保护作用与关键毒力基因（例如参与铁和磷酸盐饥饿的基因）的下调相关。由于 PAβN 影响铜绿假单胞菌的毒力，因此值得探索 EPIs 的抗毒性质，同时考虑到其活性的可能菌株特异性。
