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Genetic Screen Reveals the Role of Purine Metabolism in Staphylococcus aureus Persistence to Rifampicin

机译：遗传筛查揭示嘌呤代谢在金黄色葡萄球菌对利福平持续存在中的作用

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Chronic infections with Staphylococcus aureus such as septicemia, osteomyelitis, endocarditis, and biofilm infections are difficult to treat because of persisters. Despite many efforts in understanding bacterial persistence, the mechanisms of persister formation in S. aureus remain elusive. Here, we performed a genome-wide screen of a transposon mutant library to study the molecular mechanisms involved in persistence of community-acquired S. aureus. Screening of the library for mutants defective in persistence or tolerance to rifampicin revealed many genes involved in metabolic pathways that are important for antibiotic persistence. In particular, the identified mutants belonged to metabolic pathways involved in carbohydrate, amino acid, lipid, vitamin and purine biosynthesis. Five mutants played a role in purine biosynthesis and two mutants, purB, an adenylosuccinate lyase, and purM, a phosphoribosylaminoimidazole synthetase, were selected for further confirmation. Mutants purB and purM showed defective persistence compared to the parental strain USA300 in multiple stress conditions including various antibiotics, low pH, and heat stress. The defect in persistence was restored by complementation with the wildtype purB and purM gene in the respective mutants. These findings provide new insights into the mechanisms of persistence in S. aureus and provide novel therapeutic targets for developing more effective treatment for persistent infections due to S. aureus.
机译：金黄色葡萄球菌的慢性感染，例如败血病，骨髓炎，心内膜炎和生物膜感染，由于持续存在而难以治疗。尽管在理解细菌持久性方面进行了许多努力，但是金黄色葡萄球菌中持久性形成的机制仍然难以捉摸。在这里，我们进行了转座子突变体文库的全基因组筛选，以研究参与社区获得性金黄色葡萄球菌持久性的分子机制。筛选持久性或对利福平的耐受性有缺陷的突变体的文库揭示了许多与代谢途径有关的基因，这些基因对于抗生素的持久性很重要。特别地，所鉴定的突变体属于涉及碳水化合物，氨基酸，脂质，维生素和嘌呤生物合成的代谢途径。有五个突变体在嘌呤生物合成中起作用，并选择了两个突变体purB（腺苷琥珀酸裂合酶）和purM（磷酸核糖氨基咪唑合成酶）进行进一步确认。与亲本菌株USA300相比，突变体purB和purM在多种胁迫条件下（包括各种抗生素，低pH和热胁迫）显示出持久的缺陷。通过与相应突变体中的野生型purB和purM基因互补，恢复了持久性缺陷。这些发现为金黄色葡萄球菌持续性机制提供了新见解，并为开发针对金黄色葡萄球菌持续感染的更有效治疗方法提供了新的治疗靶标。

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