A New Class of Cell Wall-Recycling l,d-Carboxypeptidase Determines β-Lactam Susceptibility and Morphogenesis in Acinetobacter baumannii.
A New Class of Cell Wall-Recycling l,d-Carboxypeptidase Determines β-Lactam Susceptibility and Morphogenesis in Acinetobacter baumannii.
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DOI：
10.1128/mbio.02786-21
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发表时间：
2021-12-21
期刊：
影响因子：
6.4
通讯作者：
Geisinger E
中科院分区：
文献类型：
--
作者：
Dai Y;Pinedo V;Tang AY;Cava F;Geisinger E
医院获得性病原体鲍曼不动杆菌具有复杂的细胞包膜，这是其多药耐药和毒力的关键。然而，这种细菌缺乏许多在模式生物中构建包膜的典型酶。相反，鲍曼不动杆菌含有许多注释不良的蛋白质，这些蛋白质可能允许包膜生物发生的其他机制。我们之前已经证明了其中一种不寻常的蛋白质，ElsL，是维持一个特征的短杆形状和抵抗攻击间隔细胞壁的抗生素所必需的。奇怪的是，ElsL是由通常在分泌的细胞壁修饰l，d-转肽酶（LDTs）中发现的无前导ykd家族结构域组成的。在这里，我们表明，ElsL实际上不是LDT，而是一类新的细胞质l，d-羧基肽酶（LDC），它提供了细胞壁循环的关键步骤，以前认为这是鲍曼不动杆菌所缺少的。缺乏ElsL会损害细胞壁的完整性、形态和内在抗性，这是由于小鼠四肽前体的积累，其毒性可以通过阻止多肽再循环来绕过。当ElsL失活时，细胞内多种通路成为易损位点，包括l、d交联形成、细胞分裂、外膜脂质稳态等，反映了其对包膜生理的多效性影响。因此，我们揭示了一类新的细胞壁循环LDC，对鲍曼不动杆菌和许多其他细菌的生长和稳态至关重要。
The hospital-acquired pathogen Acinetobacter baumannii possesses a complex cell envelope that is key to its multidrug resistance and virulence. The bacterium, however, lacks many canonical enzymes that build the envelope in model organisms. Instead, A. baumannii contains a number of poorly annotated proteins that may allow alternative mechanisms of envelope biogenesis. We demonstrated previously that one of these unusual proteins, ElsL, is required for maintaining a characteristic short rod shape and for withstanding antibiotics that attack the septal cell wall. Curiously, ElsL is composed of a leaderless YkuD-family domain usually found in secreted, cell wall-modifying l,d-transpeptidases (LDTs). Here, we show that, rather than being an LDT, ElsL is actually a new class of cytoplasmic l,d-carboxypeptidase (LDC) that provides a critical step in cell wall recycling previously thought to be missing from A. baumannii. Absence of ElsL impairs cell wall integrity, morphology, and intrinsic resistance due to buildup of murein tetrapeptide precursors, toxicity of which is bypassed by preventing muropeptide recycling. Multiple pathways in the cell become sites of vulnerability when ElsL is inactivated, including l,d-cross-link formation, cell division, and outer membrane lipid homoeostasis, reflecting its pleiotropic influence on envelope physiology. We thus reveal a novel class of cell wall-recycling LDC critical to growth and homeostasis of A. baumannii and likely many other bacteria.