Correlative proteomics identify the key roles of stress tolerance strategies in Acinetobacter baumannii in response to polymyxin and human macrophages.
Correlative proteomics identify the key roles of stress tolerance strategies in Acinetobacter baumannii in response to polymyxin and human macrophages.
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DOI：
10.1371/journal.ppat.1010308
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发表时间：
2022-03
期刊：
影响因子：
6.7
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Kho ZY;Azad MAK;Han ML;Zhu Y;Huang C;Schittenhelm RB;Naderer T;Velkov T;Selkrig J;Zhou QT;Li J
条件致病菌鲍曼不动杆菌具有抵抗宿主天然免疫和抗生素杀伤的应激耐受策略。然而，宿主-病原体-抗生素相互作用如何影响细菌发病机制和宿主反应的整体分子调控仍然未被探索。在这里，我们同时调查蛋白质组的变化，在A。鲍曼不动杆菌和巨噬细胞在感染后在不存在或存在多粘菌素的情况下。我们发现巨噬细胞和多粘菌素在解除A.鲍曼不动杆菌，包括氧化应激抗性，铜耐受性，细菌铁的收购和严格的反应调节系统。使用spoT突变菌株，我们证明了与野生型菌株相比，具有严格响应缺陷的细菌细胞表现出对多粘菌素杀伤的敏感性增强，并降低了感染小鼠的存活率。总之，我们的研究结果强调，更好地了解宿主-病原体-抗生素的相互作用对于优化患者的抗生素使用和发现新的抗微生物策略以应对多重耐药细菌感染至关重要。细菌对抗生素的反应对周围环境敏感;然而，宿主免疫微环境如何影响条件致病菌鲍氏不动杆菌对多粘菌素的反应仍然在很大程度上未被探索。在这项研究中，我们建立了一个宿主-病原体-抗生素三方体外模型，从细菌和巨噬细胞的角度研究复杂的三方分子相互作用，模拟生理感染治疗条件。这是A.鲍曼不动杆菌与宿主细胞相互作用，具有非常大的覆盖范围（即，50%）。即使在感染条件下也存在鲍曼不动杆菌蛋白质组。我们首次报道了巨噬细胞和多粘菌素利用互补机制解除几种A.鲍曼不动杆菌的应激耐受策略在巨噬细胞中持续存在。我们的宿主-病原体-抗生素机制研究和潜在的可药用靶点的发现（例如，细菌严格应激反应调节剂SpoT）代表了一个重大进展，为抗生素优化和药物发现铺平了道路，以解决多重耐药细菌感染。
The opportunistic pathogen Acinetobacter baumannii possesses stress tolerance strategies against host innate immunity and antibiotic killing. However, how the host-pathogen-antibiotic interaction affects the overall molecular regulation of bacterial pathogenesis and host response remains unexplored. Here, we simultaneously investigate proteomic changes in A. baumannii and macrophages following infection in the absence or presence of the polymyxins. We discover that macrophages and polymyxins exhibit complementary effects to disarm several stress tolerance and survival strategies in A. baumannii, including oxidative stress resistance, copper tolerance, bacterial iron acquisition and stringent response regulation systems. Using the spoT mutant strains, we demonstrate that bacterial cells with defects in stringent response exhibit enhanced susceptibility to polymyxin killing and reduced survival in infected mice, compared to the wild-type strain. Together, our findings highlight that better understanding of host-pathogen-antibiotic interplay is critical for optimization of antibiotic use in patients and the discovery of new antimicrobial strategy to tackle multidrug-resistant bacterial infections. Bacterial response towards antibiotics is sensitive to the surrounding environment; however, how the host immune microenvironment affects the response of opportunistic pathogen Acinetobacter baumannii towards polymyxins remains largely unexplored. In this study, we established a host-pathogen-antibiotic tripartite in vitro model to examine the complex tripartite molecular interplay from both bacteria and macrophages perspectives, mimicking the physiological infection-treatment condition. This is the first comprehensive proteomics dataset for A. baumannii interacting with host cells, with an extraordinary coverage (i.e., 50%) of A. baumannii proteome even in infection conditions. For the first time, we report that macrophages and polymyxins utilize complementary mechanisms to disarm several A. baumannii stress tolerance strategies to persist in the macrophages. Our host-pathogen-antibiotic mechanistic study and the discovery of potential druggable targets (e.g., bacterial stringent stress response regulator SpoT) represent a significant advance, paving way to antibiotic optimization and drug discovery to tackle multidrug-resistant bacterial infections.
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4.4
作者：
Méndez JA;Mateos J;Beceiro A;Lopez M;Tomás M;Poza M;Bou G
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