A penicillin-binding protein inhibits selection of colistin-resistant, lipooligosaccharide-deficient Acinetobacter baumannii
A penicillin-binding protein inhibits selection of colistin-resistant, lipooligosaccharide-deficient Acinetobacter baumannii
复制标题
DOI：
10.1073/pnas.1611594113
复制
发表时间：
2016-10-11
影响因子：
11.1
通讯作者：
Trent, M. Stephen
中科院分区：
文献类型：
--
作者：
Boll, Joseph M.;Crofts, Alexander A.;Trent, M. Stephen
革兰氏阴性细菌的外膜强化细胞抵抗环境毒素，包括抗生素。被称为脂多糖/脂寡糖（LPS/LOS）的独特糖脂在外膜的细胞表面单层中富集并促进抗菌剂耐药性。多粘菌素靶向LPS/LOS的脂质A结构域以裂解细胞，是多重耐药革兰氏阴性菌感染的最后一线治疗。脂质A对于大多数革兰氏阴性菌的存活是必不可少的，但在粘菌素暴露后分离出缺乏脂质A的粘菌素耐药鲍氏不动杆菌。以前，菌株ATCC 19606是唯一的A.鲍曼不动杆菌菌株证明在没有脂质A的情况下存活。在这里，我们展示了另一个A。鲍曼不动杆菌菌株也可以在没有脂质A的情况下存活，但有些不能，这为研究内毒素的必要性提供了一个独特的模型。我们评估了15个临床A.包括9个最近临床分离株在内的鲍曼不动杆菌分离株通过脂质A生物合成途径的失活而产生粘菌素抗性，脂质A生物合成途径的产物组装LOS前体。我们的研究确定，表达的保守的青霉素结合蛋白（PBP）1A，防止LOS缺陷集落分离。PBP 1A的糖基转移酶活性有助于肽聚糖细胞壁的聚合，对LOS缺陷型A是致命的。鲍曼不动杆菌。PBP 1A缺陷型突变体和4个LOS缺陷型A.鲍曼不动杆菌菌株表现出脂蛋白及其转运蛋白转录的伴随增加。对LOS缺陷型A.在鲍曼不动杆菌细胞表面上发现，特异性脂蛋白被过表达并修饰细胞表面，潜在地补偿LOS的去除。这项工作扩展了我们对脂质A重要性的认识，并阐明了耐药机制。
The Gram-negative bacterial outer membrane fortifies the cell against environmental toxins including antibiotics. Unique glycolipids called lipopolysaccharide/lipooligosaccharide (LPS/LOS) are enriched in the cell-surface monolayer of the outer membrane and promote antimicrobial resistance. Colistin, which targets the lipid A domain of LPS/LOS to lyse the cell, is the last-line treatment for multidrug-resistant Gram-negative infections. Lipid A is essential for the survival of most Gram-negative bacteria, but colistin-resistant Acinetobacter baumannii lacking lipid A were isolated after colistin exposure. Previously, strain ATCC 19606 was the only A. baumannii strain demonstrated to subsist without lipid A. Here, we show that other A. baumannii strains can also survive without lipid A, but some cannot, affording a unique model to study endotoxin essentiality. We assessed the capacity of 15 clinical A. baumannii isolates including 9 recent clinical isolates to develop colistin resistance through inactivation of the lipid A biosynthetic pathway, the products of which assemble the LOS precursor. Our investigation determined that expression of the well-conserved penicillin-binding protein (PBP) 1A, prevented LOS-deficient colony isolation. The glycosyltransferase activity of PBP1A, which aids in the polymerization of the peptidoglycan cell wall, was lethal to LOS-deficient A. baumannii. Global transcriptomic analysis of a PBP1A-deficient mutant and four LOS-deficient A. baumannii strains showed a concomitant increase in transcription of lipoproteins and their transporters. Examination of the LOS-deficient A. baumannii cell surface demonstrated that specific lipoproteins were overexpressed and decorated the cell surface, potentially compensating for LOS removal. This work expands our knowledge of lipid A essentiality and elucidates a drug resistance mechanism.