The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Medical Research Institute, Wuhan University, Wuhan, China.
Frontier Science Center for Immunology and Metabolism, Wuhan University, Wuhan, China.
Elife. 2024 Oct 4;13:RP99194. doi: 10.7554/eLife.99194.
Biofilms are complex bacterial communities characterized by a high persister prevalence, which contributes to chronic and relapsing infections. Historically, persister formation in biofilms has been linked to constraints imposed by their dense structures. However, we observed an elevated persister frequency accompanying the stage of cell adhesion, marking the onset of biofilm development. Subsequent mechanistic studies uncovered a comparable type of toxin-antitoxin (TA) module (TA-like system) triggered by cell adhesion, which is responsible for this elevation. In this module, the toxin HipH acts as a genotoxic deoxyribonuclease, inducing DNA double strand breaks and genome instability. While the second messenger c-di-GMP functions as the antitoxin, exerting control over HipH expression and activity. The dynamic interplay between c-di-GMP and HipH levels emerges as a crucial determinant governing genome stability and persister generation within biofilms. These findings unveil a unique TA system, where small molecules act as the antitoxin, outlining a biofilm-specific molecular mechanism influencing genome stability and antibiotic persistence, with potential implications for treating biofilm infections.
生物膜是由高持留菌流行率特征的复杂细菌群落，这导致了慢性和复发性感染。从历史上看，生物膜中的持留菌形成与它们密集结构所施加的限制有关。然而，我们观察到在细胞黏附阶段伴随着升高的持留菌频率，标志着生物膜发育的开始。随后的机制研究揭示了一种类似的毒素-抗毒素（TA）模块（TA 样系统）被细胞黏附触发，这是导致这种升高的原因。在这个模块中，毒素 HipH 作为一种遗传毒性脱氧核糖核酸酶，诱导 DNA 双链断裂和基因组不稳定性。而第二信使 c-di-GMP 作为抗毒素，对 HipH 的表达和活性进行控制。c-di-GMP 和 HipH 水平之间的动态相互作用是决定生物膜内基因组稳定性和持留菌产生的关键决定因素。这些发现揭示了一种独特的 TA 系统，其中小分子作为抗毒素，概述了影响基因组稳定性和抗生素持留的生物膜特异性分子机制，这对治疗生物膜感染具有潜在意义。
