Bisht Renu, Charlesworth Pierre D, Sperandeo Paola, Polissi Alessandra
Department of Pharmacological and Biomolecular Sciences, University of Milano, 20133 Milano, Italy.
Pathogens. 2024 Oct 11;13(10):889. doi: 10.3390/pathogens13100889.
Antimicrobial resistance (AMR) has emerged as a global health threat, necessitating immediate actions to develop novel antimicrobial strategies and enforce strong stewardship of existing antibiotics to manage the emergence of drug-resistant strains. This issue is particularly concerning when it comes to Gram-negative bacteria, which possess an almost impenetrable outer membrane (OM) that acts as a formidable barrier to existing antimicrobial compounds. This OM is an asymmetric structure, composed of various components that confer stability, fluidity, and integrity to the bacterial cell. The maintenance and restoration of membrane integrity are regulated by envelope stress response systems (ESRs), which monitor its assembly and detect damages caused by external insults. Bacterial communities encounter a wide range of environmental niches to which they must respond and adapt for survival, sustenance, and virulence. ESRs play crucial roles in coordinating the expression of virulence factors, adaptive physiological behaviors, and antibiotic resistance determinants. Given their role in regulating bacterial cell physiology and maintaining membrane homeostasis, ESRs present promising targets for drug development. Considering numerous studies highlighting the involvement of ESRs in virulence, antibiotic resistance, and alternative resistance mechanisms in pathogens, this review aims to present these systems as potential drug targets, thereby encouraging further research in this direction.
抗菌药物耐药性（AMR）已成为全球健康威胁，因此需要立即采取行动，制定新的抗菌策略，并加强对现有抗生素的严格管理，以应对耐药菌株的出现。当涉及到革兰氏阴性菌时，这个问题尤为令人担忧，因为革兰氏阴性菌拥有几乎不可穿透的外膜（OM），这层外膜对现有的抗菌化合物来说是一个巨大的屏障。这种外膜是一种不对称结构，由各种赋予细菌细胞稳定性、流动性和完整性的成分组成。膜完整性的维持和恢复由包膜应激反应系统（ESR）调节，该系统监测其组装并检测外部损伤造成的损害。细菌群落会遇到各种各样的环境生态位，它们必须对这些环境做出反应并适应，以实现生存、维持生计和致病。ESR在协调毒力因子的表达、适应性生理行为和抗生素耐药性决定因素方面发挥着关键作用。鉴于它们在调节细菌细胞生理学和维持膜稳态方面的作用，ESR为药物开发提供了有前景的靶点。考虑到众多研究强调了ESR在病原体的毒力、抗生素耐药性和替代耐药机制中的作用，本综述旨在将这些系统作为潜在的药物靶点进行介绍，从而鼓励在这一方向上开展进一步的研究。
