Centro Nacional de Biotecnología, CSIC, Darwin 3, 28049, Madrid, Spain.
The Novo Nordisk Foundation Center for Biosustainability, Technical University of Denmark, 2800, Kgs. Lyngby, Denmark.
Microb Biotechnol. 2023 Jul;16(7):1492-1504. doi: 10.1111/1751-7915.14252. Epub 2023 Mar 28.
Multidrug efflux pumps are among the main Pseudomonas aeruginosa antibiotic-resistance determinants. Besides, efflux pumps are also involved in other relevant activities of bacterial physiology, including the quorum sensing-mediated regulation of bacterial virulence. Nevertheless, despite the relevance of efflux pumps in bacterial physiology, their interconnection with bacterial metabolism remains obscure. The effect of several metabolites on the expression of P. aeruginosa efflux pumps, and on the virulence and antibiotic resistance of this bacterium, was studied. Phenylethylamine was found to be both inducer and substrate of MexCD-OprJ, an efflux pump involved in P. aeruginosa antibiotic resistance and in extrusion of precursors of quorum-sensing signals. Phenylethylamine did not increase antibiotic resistance; however, the production of the toxin pyocyanin, the tissue-damaging protease LasB and swarming motility were reduced in the presence of this metabolite. This decrease in virulence potential was mediated by a reduction of lasI and pqsABCDE expression, which encode the proteins that synthesise the signalling molecules of two quorum-sensing regulatory pathways. This work sheds light on the interconnection between virulence and antibiotic-resistance determinants, mediated by bacterial metabolism, and points to phenylethylamine as an anti-virulence metabolite to be considered in the study of therapies against P. aeruginosa infections.
多药外排泵是铜绿假单胞菌抗生素耐药性的主要决定因素之一。此外，外排泵还参与细菌生理学的其他相关活动，包括群体感应介导的细菌毒力调节。然而，尽管外排泵在细菌生理学中具有重要意义，但它们与细菌代谢之间的联系仍然不清楚。本研究探讨了几种代谢物对铜绿假单胞菌外排泵表达、毒力和抗生素耐药性的影响。研究发现，苯乙胺既是MexCD-OprJ 外排泵的诱导物，也是其底物，该外排泵参与铜绿假单胞菌的抗生素耐药性和群体感应信号前体的外排。苯乙胺不会增加抗生素耐药性；然而，在这种代谢物存在的情况下，会减少毒力因子如绿脓菌素、组织破坏性蛋白酶 LasB 和群集运动的产生。这种毒力降低是通过降低编码两种群体感应调控途径信号分子的 lasI 和 pqsABCDE 表达来介导的。这项工作阐明了细菌代谢介导的毒力和抗生素耐药性决定因素之间的联系，并指出苯乙胺作为一种抗毒力代谢物，可在研究针对铜绿假单胞菌感染的治疗方法时加以考虑。
