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Abstract：
Pseudomonas aeruginosa is a notorious multidrug-resistant pathogen that poses a serious and growing threat to the worldwide public health. The expression of resistance determinants is exquisitely modulated by the abundant regulatory proteins and the intricate signal sensing and transduction systems in this pathogen. Downregulation of antibiotic influx porin proteins and upregulation of antibiotic efflux pump systems owing to mutational changes in their regulators or the presence of distinct inducing molecular signals represent two of the most efficient mechanisms that restrict intracellular antibiotic accumulation and enable P. aeruginosa to resist multiple antibiotics. Treatment of P. aeruginosa infections is extremely challenging due to the highly inducible mechanism of antibiotic resistance. This review comprehensively summarizes the regulatory networks of the major porin proteins (OprD and OprH) and efflux pumps (MexAB-OprM, MexCD-OprJ, MexEF-OprN, and MexXY) that play critical roles in antibiotic influx and efflux in P. aeruginosa. It also discusses promising therapeutic approaches using safe and efficient adjuvants to enhance the efficacy of conventional antibiotics to combat multidrug-resistant P. aeruginosa by controlling the expression levels of porins and efflux pumps. This review not only highlights the complexity of the regulatory network that induces antibiotic resistance in P. aeruginosa but also provides important therapeutic implications in targeting the inducible mechanism of resistance.
摘要：
铜绿假单胞菌是一种臭名昭著的多重耐药病原体，对全球公共卫生构成严重且日益严重的威胁。抗性决定簇的表达受到该病原体中丰富的调节蛋白和复杂的信号传感和转导系统的精细调节。由于其调节剂的突变变化或不同诱导分子信号的存在，抗生素内流孔蛋白的下调和抗生素外排泵系统的上调代表了两种最有效的机制，这些机制限制了细胞内抗生素的积累并使铜绿假单胞菌能够抵抗多种抗生素。由于抗生素抗性的高度诱导机制,铜绿假单胞菌感染的治疗是极具挑战性的。这篇综述全面总结了主要孔蛋白（OprD和OprH）和外排泵（MexAB-OprM，MexCD-OprJ,MexEF-Oprn,和MexXY）在铜绿假单胞菌的抗生素流入和流出中起关键作用。它还讨论了使用安全有效的佐剂通过控制孔蛋白和外排泵的表达水平来增强常规抗生素对抗多药耐药铜绿假单胞菌的功效的有前途的治疗方法。这篇综述不仅强调了在铜绿假单胞菌中诱导抗生素抗性的调节网络的复杂性，而且在靶向抗性的诱导机制方面提供了重要的治疗意义。
