Kavanaugh Logan G, Hinrichsen Megan E, Dunham Christine M, Conn Graeme L
Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA.
Graduate Program in Microbiology and Molecular Genetics, Emory University, Atlanta, Georgia, USA.
Antimicrob Agents Chemother. 2025 Apr 7;69(5):e0182524. doi: 10.1128/aac.01825-24.
The current crisis in bacterial antibiotic resistance can be attributed to the overuse (or misuse) of these essential medicines in healthcare and agriculture, coupled with the slowed progression of new drug development. In the versatile, opportunistic pathogen , the Resistance-Nodulation-Division (RND) efflux pump MexXY plays critical roles in both cell physiology and the acquisition of multidrug resistance. The operon is not constitutively expressed, but this process is instead controlled by a complex network of multiple interconnected regulatory mechanisms. These include induction by several of the pump's ribosome-targeting antibiotic substrates and transcriptional repression and anti-repression processes that are themselves influenced by various cellular factors, processes, or stresses. Although extensive studies of the MexXY complex are currently lacking as compared to other RND efflux pumps such as AcrAB-TolC, recent studies have provided valuable insights into the MexXY architecture and substrate profiles, including its contribution to clinical resistance. Furthermore, while MexXY primarily associates with the outer membrane protein OprM, emerging evidence suggests that this transporter-periplasmic adaptor pair may also partner with other outer membrane proteins, potentially to alter the efflux substrate profile and activity under specific environmental conditions. In this minireview, we summarize current understanding of MexXY regulation, structure, and substrate selectivity within the context of clinical resistance and as a framework for future efflux pump inhibitor development.
当前细菌对抗生素的耐药危机可归因于这些基本药物在医疗保健和农业中的过度使用（或滥用），以及新药开发进展的放缓。在这种具有多种特性的机会致病菌中，耐药-结瘤-分裂（RND）外排泵MexXY在细胞生理学和多重耐药性的获得中都起着关键作用。MexXY操纵子并非组成型表达，而是由多个相互关联的复杂调控机制网络控制。这些机制包括由该泵的几种靶向核糖体的抗生素底物诱导，以及转录抑制和抗抑制过程，而这些过程本身又受各种细胞因子、过程或应激的影响。尽管与其他RND外排泵（如AcrAB-TolC）相比，目前对MexXY复合物的研究还不够广泛，但最近的研究为MexXY的结构和底物谱提供了有价值的见解，包括其对临床耐药性的影响。此外，虽然MexXY主要与外膜蛋白OprM结合，但新出现的证据表明，这种转运蛋白-周质适配体对也可能与其他外膜蛋白结合，可能会在特定环境条件下改变外排底物谱和活性。在这篇小型综述中，我们总结了目前在临床耐药背景下对MexXY调控、结构和底物选择性的理解，并将其作为未来外排泵抑制剂开发的框架。
