Two heme-dependent terminal oxidases power Staphylococcus aureus organ-specific colonization of the vertebrate host.
Two heme-dependent terminal oxidases power Staphylococcus aureus organ-specific colonization of the vertebrate host.
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DOI：
10.1128/mbio.00241-13
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发表时间：
2013-07-30
期刊：
影响因子：
6.4
通讯作者：
Skaar EP
中科院分区：
文献类型：
--
作者：
Hammer ND;Reniere ML;Cassat JE;Zhang Y;Hirsch AO;Indriati Hood M;Skaar EP
金黄色葡萄球菌是世界范围内感染的一个重要原因，它能够利用有氧呼吸、厌氧呼吸或发酵作为产生增殖所需能量的手段。有氧呼吸是由依赖于血红素的末端氧化酶支持的，该酶催化有氧呼吸的最后一步，即将O2还原为H2O。无法呼吸迫使细菌通过发酵产生能量，导致生长减慢。阐明这些能量产生途径在宿主定植过程中的作用可以发现有吸引力的治疗靶点。与这一想法一致，我们报告了通过灭活血红素生物合成来抑制有氧呼吸显著削弱金黄色葡萄球菌定植宿主的能力。两种依赖于血红素的末端氧化酶支持金黄色葡萄球菌的有氧呼吸，这意味着葡萄球菌的呼吸链是分支的。全身感染金黄色葡萄球菌突变体，限制在单一末端氧化酶，导致器官特异性定植缺陷，导致肝脏或心脏的细菌负担减少。最后，通过将金黄色葡萄球菌暴露于非铁的血红素类似物，可以抑制有氧呼吸。这些数据提供了证据，证明有氧呼吸在金黄色葡萄球菌在宿主的定植中起着主要作用，这种能量产生过程是一个可行的治疗靶点。金黄色葡萄球菌对公众健康构成重大威胁，因为这种病原体的抗药性菌株不断出现。我们对金黄色葡萄球菌在宿主内繁殖的能量产生过程的理解是不完整的。宿主来源的血红素是感染期间营养铁的首选来源；然而，金黄色葡萄球菌可以从头合成血红素，并用它来促进有氧呼吸。我们证明了金黄色葡萄球菌血红素的生物合成为由两个末端氧化酶组成的分支好氧呼吸链提供动力。在系统感染期间，两种末端氧化酶在不同器官的定植中起着至关重要的作用，这一发现证明了具有两种末端氧化酶的重要性。此外，这一过程可以被称为非铁原卟啉的小分子血红素类似物靶向。这项研究证明，血红素的生物合成支持两种末端氧化酶，这两种酶是有氧呼吸所必需的，也是金黄色葡萄球菌致病所必需的。
Staphylococcus aureus is a significant cause of infections worldwide and is able to utilize aerobic respiration, anaerobic respiration, or fermentation as the means by which it generates the energy needed for proliferation. Aerobic respiration is supported by heme-dependent terminal oxidases that catalyze the final step of aerobic respiration, the reduction of O2 to H2O. An inability to respire forces bacteria to generate energy via fermentation, resulting in reduced growth. Elucidating the roles of these energy-generating pathways during colonization of the host could uncover attractive therapeutic targets. Consistent with this idea, we report that inhibiting aerobic respiration by inactivating heme biosynthesis significantly impairs the ability of S. aureus to colonize the host. Two heme-dependent terminal oxidases support aerobic respiration of S. aureus, implying that the staphylococcal respiratory chain is branched. Systemic infection with S. aureus mutants limited to a single terminal oxidase results in an organ-specific colonization defect, resulting in reduced bacterial burdens in either the liver or the heart. Finally, inhibition of aerobic respiration can be achieved by exposing S. aureus to noniron heme analogues. These data provide evidence that aerobic respiration plays a major role in S. aureus colonization of the host and that this energy-generating process is a viable therapeutic target. Staphylococcus aureus poses a significant threat to public health as antibiotic-resistant isolates of this pathogen continue to emerge. Our understanding of the energy-generating processes that allow S. aureus to proliferate within the host is incomplete. Host-derived heme is the preferred source of nutrient iron during infection; however, S. aureus can synthesize heme de novo and use it to facilitate aerobic respiration. We demonstrate that S. aureus heme biosynthesis powers a branched aerobic respiratory chain composed of two terminal oxidases. The importance of having two terminal oxidases is demonstrated by the finding that each plays an essential role in colonizing distinct organs during systemic infection. Additionally, this process can be targeted by small-molecule heme analogues called noniron protoporphyrins. This study serves to demonstrate that heme biosynthesis supports two terminal oxidases that are required for aerobic respiration and are also essential for S. aureus pathogenesis.