Guangdong Province Key Laboratory of Microbial Signals and Disease Control, Integrative Microbiology Research Centre, South China Agricultural University, Guangzhou, China.
Microb Biotechnol. 2024 May;17(5):e14487. doi: 10.1111/1751-7915.14487.
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.
铜绿假单胞菌是一种臭名昭著的多药耐药病原体，对全球公共卫生构成严重且日益严重的威胁。该病原体中丰富的调节蛋白和复杂的信号感应和转导系统精细地调节耐药决定因素的表达。抗生素流入孔蛋白的下调和抗生素外排泵系统的上调，归因于其调节剂的突变改变或存在不同的诱导分子信号，是限制细胞内抗生素积累并使铜绿假单胞菌能够抵抗多种抗生素的两种最有效的机制。由于抗生素耐药性的高度诱导机制，铜绿假单胞菌感染的治疗极具挑战性。本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）的调控网络，这些蛋白在铜绿假单胞菌中抗生素流入和流出中发挥关键作用。它还讨论了使用安全有效的佐剂来增强传统抗生素疗效的有前途的治疗方法，通过控制孔蛋白和外排泵的表达水平来对抗多药耐药铜绿假单胞菌。本综述不仅强调了诱导铜绿假单胞菌抗生素耐药性的调控网络的复杂性，还为靶向耐药性的诱导机制提供了重要的治疗意义。
