Mapping the Protein Interaction Network in Methicillin-Resistant Staphylococcus aureus

Mortality attributable to infection with methicillin-resistant Staphylococcus aureus (MRSA) has now overtaken the death rate for AIDS in the United States, and advances in research are urgently needed to address this challenge. We report the results of the systematic identification of protein−protein interactions for the hospital-acquired strain MRSA-252. Using a high-throughput pull-down strategy combined with quantitative proteomics to distinguish specific from nonspecific interactors, we identified 13 219 interactions involving 608 MRSA proteins. Consecutive analyses revealed that this protein interaction network (PIN) exhibits scale-free organization with the characteristic presence of highly connected hub proteins. When clinical and experimental antimicrobial targets were queried in the network, they were generally found to occupy peripheral positions in the PIN with relatively few interacting partners. In contrast, the hub proteins identified in this MRSA PIN that are essential for network integrity and stability have largely been overlooked as drug targets. Thus, this empirical MRSA-252 PIN provides a rich source for identifying critical proteins essential for network stability, many of which can be considered as prospective antimicrobial drug targets.耐甲氧西林金黄色葡萄球菌（methicillin-resistant Staphylococcus aureus, MRSA）感染所致的死亡率目前已超越美国的艾滋病死亡率，亟需通过研究进展应对这一公共卫生挑战。本研究针对医院获得性菌株MRSA-252开展了系统的蛋白质-蛋白质相互作用鉴定工作，并报告其研究成果。研究采用高通量下拉策略结合定量蛋白质组学技术，以区分特异性与非特异性相互作用蛋白，最终鉴定得到608个MRSA蛋白参与的13219条蛋白质相互作用。后续连续分析显示，该蛋白质相互作用网络（protein interaction network, PIN）呈现无尺度组织特征，即存在大量高度连接的枢纽蛋白。当在该网络中检索临床与实验性抗菌药物靶点时，发现此类靶点大多处于蛋白质相互作用网络的外围位置，其相互作用伴侣的数量相对较少。与之形成鲜明对比的是，本研究在MRSA蛋白质相互作用网络中鉴定出的、对网络完整性与稳定性至关重要的枢纽蛋白，在很大程度上未被纳入药物靶点的考量范畴。综上，本研究构建的MRSA-252经验性蛋白质相互作用网络，为筛选对网络稳定性至关重要的关键蛋白提供了丰富的资源，其中诸多蛋白可被视为潜在的抗菌药物靶点。