在称为“营养免疫”的过程中,宿主蛋白钙卫蛋白通过金属螯合抑制多种细菌病原体的生长。“钙卫蛋白在体外抑制金黄色葡萄球菌的生长,钙卫蛋白在感染期间在体内定位于葡萄球菌脓肿。然而,提供营养免疫防御的葡萄球菌适应性和金属反应性调节剂的作用没有得到充分表征.在这项工作中,我们定义了金黄色葡萄球菌的转录反应和金属反应调节因子的作用,祖尔,毛皮,和MntR,响应钙卫蛋白暴露对金属的限制。此外,我们通过转座子测序(Tn-seq)方法鉴定了在金属限制期间影响金黄色葡萄球菌适合度的基因.clpP功能缺失突变,它编码ATP依赖性Clp蛋白酶的蛋白水解亚基,证明金黄色葡萄球菌对钙卫蛋白存在的适应性降低。ClpP以钙卫蛋白依赖性方式参与体内发病机理。这些研究确立了ClpP对抗钙卫蛋白对金属的限制的关键作用,并揭示了金黄色葡萄球菌竞争金属所需的基因。
目的:金黄色葡萄球菌是皮肤和软组织感染的主要原因,血流感染,和心内膜炎.金黄色葡萄球菌感染期间的抗生素治疗失败越来越普遍,突出了对新型抗菌剂的需求。由于对细菌病原体表现出的营养金属的严格要求,基于金属螯合剂的治疗剂具有作为抗微生物剂的巨大潜力。钙卫蛋白的高亲和力过渡金属结合特性代表了通过金属螯合起作用的潜在治疗策略。我们的研究为定义金黄色葡萄球菌对抗营养免疫的机制提供了基础,并且可能有助于开发新的疗法来对抗金黄色葡萄球菌在金属受限环境中存活的能力。
The host protein calprotectin inhibits the growth of a variety of bacterial pathogens through metal sequestration in a process known as \"nutritional immunity.\" Staphylococcus aureus growth is inhibited by calprotectin in vitro, and calprotectin is localized in vivo to staphylococcal abscesses during infection. However, the staphylococcal adaptations that provide defense against nutritional immunity and the role of metal-responsive regulators are not fully characterized. In this work, we define the transcriptional response of S. aureus and the role of the metal-responsive regulators, Zur, Fur, and MntR, in response to metal limitation by calprotectin exposure. Additionally, we identified genes affecting the fitness of S. aureus during metal limitation through a Transposon sequencing (Tn-seq) approach. Loss of function mutations in clpP, which encodes a proteolytic subunit of the ATP-dependent Clp protease, demonstrate reduced fitness of S. aureus to the presence of calprotectin. ClpP contributes to pathogenesis in vivo in a calprotectin-dependent manner. These studies establish a critical role for ClpP to combat metal limitation by calprotectin and reveal the genes required for S. aureus to outcompete the host for metals.
OBJECTIVE: Staphylococcus aureus is a leading cause of skin and soft tissue infections, bloodstream infections, and endocarditis. Antibiotic treatment failures during S. aureus infections are increasingly prevalent, highlighting the need for novel antimicrobial agents. Metal chelator-based therapeutics have tremendous potential as antimicrobials due to the strict requirement for nutrient metals exhibited by bacterial pathogens. The high-affinity transition metal-binding properties of calprotectin represents a potential therapeutic strategy that functions through metal chelation. Our studies provide a foundation to define mechanisms by which S. aureus combats nutritional immunity and may be useful for the development of novel therapeutics to counter the ability of S. aureus to survive in a metal-limited environment.