Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success
复制标题
DOI：
10.1073/pnas.2014920118
复制
发表时间：
2021-02-16
影响因子：
11.1
通讯作者：
Zinkernagel, Annelies S.
中科院分区：
文献类型：
--
作者：
Huemer, Markus;Shambat, Srikanth Mairpady;Zinkernagel, Annelies S.
金黄色葡萄球菌引起侵袭性感染，容易产生抗生素耐药性。即使是对抗生素敏感的金黄色葡萄球菌也能在抗生素治疗中存活并持续存在，需要长期治疗和手术干预。这些所谓的顽固分子表现出生长停滞的表型，耐受高浓度抗生素，并与慢性和复发性感染有关。为了描述这些持续性感染，我们评估了从持续性感染患者直接恢复的金黄色葡萄球菌。我们发现宿主介导的应激，包括酸性pH值、脓肿环境和抗生素暴露，促进了体外和体内持久性的形成。多组学分析确定了金黄色葡萄球菌在酸胁迫下的分子变化，导致整体毒力群体。然而，对持久性基因丰富的群体的进一步分析揭示了持久性基因的主要分子重编程，包括毒力和细胞分裂的下调以及核糖体蛋白、核苷酸和氨基酸代谢途径的上调，这表明它们需要为持久性基因提供能量并维持其表型，并强调持久性基因并非完全代谢不活跃。此外，乌头酶活性和ATP水平的降低以及参与转录、翻译和能量产生的不溶性蛋白的积累与金黄色葡萄球菌的持久性相关，这支持了驱动持久性表型的分子机制。在再生过程中，这些持久体恢复了其毒力潜力和代谢活性表型，包括不溶性蛋白的减少，表现出可逆状态，这对复发性感染至关重要。我们进一步表明，在小鼠感染模型中，使用类维生素a衍生物和抗生素的靶向抗持久性联合治疗显着降低了滞后期异质性和持久性。我们的研究结果提供了持久性的分子见解，并有助于解释为什么持久性金黄色葡萄球菌感染如此难以治疗。
Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistance. Even antibiotic-susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations, and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic pH, abscess environment, and antibiotic exposure promoted persister formation in vitro and in vivo. Multiomics analysis identified molecular changes in S. aureus in response to acid stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters, including down-regulation of virulence and cell division and up-regulation of ribosomal proteins, nucleotide-, and amino acid-metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP levels and accumulation of insoluble proteins involved in transcription, translation, and energy production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype, including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted antipersister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult to treat.