金黄色葡萄球菌在三甲双胍-磺胺甲噁唑诱导的无甲状腺死亡中存活的机制。

IF 5.1 1区 生物学 Q1 MICROBIOLOGY
mBio Pub Date : 2024-11-13 Epub Date: 2024-10-24 DOI:10.1128/mbio.01634-24
Lauren J Gonsalves, Allyson Tran, Tessa Gardiner, Tiia Freeman, Angshita Dutta, Carson J Miller, Sharon McNamara, Adam Waalkes, Dustin R Long, Stephen J Salipante, Lucas R Hoffman, Daniel J Wolter
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引用次数: 0

摘要

三甲双胍-磺胺甲噁唑(SXT)常用于治疗各种金黄色葡萄球菌感染,包括与囊性纤维化(CF)肺病相关的感染。对大肠杆菌的研究发现,SXT 会影响四氢叶酸的产生,导致 DNA 损伤、应激反应诱导和活性氧(ROS)积累,这一过程被称为无甲状腺死亡(TLD)。TLD可通过吸收外源性胸腺嘧啶而存活,从而抵消SXT的影响;然而,越来越多的研究表明,中枢代谢是细菌在SXT和其他抗生素作用下存活的另一个潜在重要决定因素。在此,我们进行了研究,以更好地了解金黄色葡萄球菌 TLD 的存活机制。我们发现,CF 痰中胸腺嘧啶的丰度不足以阻止金黄色葡萄球菌的 TLD,这凸显了替代生存机制在体内的重要性。在使用 SXT 和低胸苷体外培养的金黄色葡萄球菌中,我们经常发现编码碳水化合物、核苷酸和氨基酸代谢的基因发生了适应性突变,这证明代谢降低是一种常见的生存机制。虽然细胞内的 ROS 水平随着体外 SXT 处理而升高,但与大肠杆菌不同的是,在有 ROS 清除剂存在的情况下,存活率并没有提高。SXT 挑战会诱发 SOS 反应,而添加胸苷后这种反应会得到缓解。最后,磷酸转移酶基因 ptsI 的失活突变既限制了细胞 ATP,又提高了对 TLD 的存活率。重要意义金黄色葡萄球菌是一种无处不在的生物,也是导致人类感染的主要原因之一,其中许多感染由于持久性、抗生素耐药性或抗生素耐受性而难以治疗。随着我们有效抗生素的减少,改进治疗方法的需求变得越来越迫切,这就要求我们更好地了解病原体逃避我们最关键的抗菌药物的确切机制。在此,我们报告了金黄色葡萄球菌在一线抗葡萄球菌抗生素三甲氧苄嘧啶-磺胺甲噁唑的治疗下存活的机制的系统特征,确定了提高现有抗菌药物疗效的途径和候选靶点。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Mechanisms of Staphylococcus aureus survival of trimethoprim-sulfamethoxazole-induced thymineless death.

Trimethoprim-sulfamethoxazole (SXT) is commonly used to treat diverse Staphylococcus aureus infections, including those associated with cystic fibrosis (CF) pulmonary disease. Studies with Escherichia coli found that SXT impairs tetrahydrofolate production, leading to DNA damage, stress response induction, and accumulation of reactive oxygen species (ROS) in a process known as thymineless death (TLD). TLD survival can occur through the uptake of exogenous thymidine, countering the effects of SXT; however, a growing body of research has implicated central metabolism as another potentially important determinant of bacterial survival of SXT and other antibiotics. Here, we conducted studies to better understand the mechanisms of TLD survival in S. aureus. We found that thymidine abundances in CF sputum were insufficient to prevent TLD of S. aureus, highlighting the importance of alternative survival mechanisms in vivo. In S. aureus cultured in vitro with SXT and low thymidine, we frequently identified adaptive mutations in genes encoding carbohydrate, nucleotide, and amino acid metabolism, supporting reduced metabolism as a common survival mechanism. Although intracellular ROS levels rose with SXT treatment in vitro, survival was not improved in the presence of ROS scavengers, unlike in E. coli. SXT challenge induced the SOS response, which was alleviated by added thymidine. Finally, an inactivating mutation in the phosphotransferase gene ptsI conferred both limitation in cellular ATP and improved survival against TLD. Collectively, these results suggest that alterations in core metabolic functions, particularly those that reduce ATP levels, predominantly confer S. aureus survival and persistence during SXT treatment, potentially identifying novel targets for co-treatment.IMPORTANCEStaphylococcus aureus is a ubiquitous organism and one of the leading causes of human infections, many of which are difficult to treat due to persistence, antibiotic resistance, or antibiotic tolerance. As our arsenal of effective antibiotics dwindles, the need for improved treatments becomes increasingly urgent, necessitating a better understanding of the precise mechanisms by which pathogens evade our most critical antimicrobial agents. Here, we report a systematic characterization of the mechanisms of S. aureus survival to treatment with the first-line antistaphylococcal antibiotic trimethoprim-sulfamethoxazole, identifying pathways and candidate targets for enhancing the efficacy of available antimicrobial agents.

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来源期刊
mBio
mBio MICROBIOLOGY-
CiteScore
10.50
自引率
3.10%
发文量
762
审稿时长
1 months
期刊介绍: mBio® is ASM''s first broad-scope, online-only, open access journal. mBio offers streamlined review and publication of the best research in microbiology and allied fields.
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