Peptidoglycan Recycling Promotes Outer Membrane Integrity and Carbapenem Tolerance in Acinetobacter baumannii.
Peptidoglycan Recycling Promotes Outer Membrane Integrity and Carbapenem Tolerance in Acinetobacter baumannii.
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作者：
β-内酰胺类抗生素通过扰乱肽聚糖层来利用细菌细胞膜的重要性，通常会导致快速溶解和死亡。许多革兰氏阴性细菌不能溶解，而是表现出“耐受性”，即在杀菌抗生素存在的情况下长期维持生存的能力。抗生素耐药与治疗失败有关，是获得真正耐药的垫脚石，而促进内在耐药的分子因素尚不清楚。鲍曼不动杆菌是一种严重威胁医院的病原菌，因其快速产生多药耐药性而臭名昭著。碳青霉烯β-内酰胺类抗生素(即美罗培南)是治疗鲍曼不动杆菌感染的一线处方，但治疗失败的情况越来越普遍。革兰氏阴性病原菌对美罗培南的耐受性以球体群体的形态特征为特征，但球体形成的影响尚不完全清楚。在这里，我们显示敏感的鲍曼不动杆菌临床分离株表现出对高水平美罗培南治疗的耐受性，暴露于抗生素后形成球体，并在去除抗生素后恢复正常生长。利用转录学和基因筛选，我们证明了几个与外膜完整性维持和外排相关的基因可能通过限制进入周质来促进耐受性。与周质和细胞质中的肽聚糖稳态相关的基因也响应了我们的筛选，它们的破坏损害了细胞膜屏障的功能。最后，我们确定了耐受决定基因青霉素结合蛋白7(PBP7)和ElsL(一种细胞质LD-羧基肽酶)的酶活性。这些数据表明，外膜完整性和肽聚糖循环在鲍曼不动杆菌美罗培南耐受性中的作用密切相关。
β-Lactam antibiotics exploit the essentiality of the bacterial cell envelope by perturbing the peptidoglycan layer, typically resulting in rapid lysis and death. Many Gram-negative bacteria do not lyse but instead exhibit “tolerance,” the ability to sustain viability in the presence of bactericidal antibiotics for extended periods. Antibiotic tolerance has been implicated in treatment failure and is a stepping-stone in the acquisition of true resistance, and the molecular factors that promote intrinsic tolerance are not well understood. Acinetobacter baumannii is a critical-threat nosocomial pathogen notorious for its ability to rapidly develop multidrug resistance. Carbapenem β-lactam antibiotics (i.e., meropenem) are first-line prescriptions to treat A. baumannii infections, but treatment failure is increasingly prevalent. Meropenem tolerance in Gram-negative pathogens is characterized by morphologically distinct populations of spheroplasts, but the impact of spheroplast formation is not fully understood. Here, we show that susceptible A. baumannii clinical isolates demonstrate tolerance to high-level meropenem treatment, form spheroplasts upon exposure to the antibiotic, and revert to normal growth after antibiotic removal. Using transcriptomics and genetic screens, we show that several genes associated with outer membrane integrity maintenance and efflux promote tolerance, likely by limiting entry into the periplasm. Genes associated with peptidoglycan homeostasis in the periplasm and cytoplasm also answered our screen, and their disruption compromised cell envelope barrier function. Finally, we defined the enzymatic activity of the tolerance determinants penicillin-binding protein 7 (PBP7) and ElsL (a cytoplasmic ld-carboxypeptidase). These data show that outer membrane integrity and peptidoglycan recycling are tightly linked in their contribution to A. baumannii meropenem tolerance.
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影响因子：
6.4
作者：
Dai Y;Pinedo V;Tang AY;Cava F;Geisinger E
通讯作者：
Geisinger E
DOI：
10.1073/pnas.1611594113
发表时间：
2016-10-11
影响因子：
11.1
作者：
Boll, Joseph M.;Crofts, Alexander A.;Trent, M. Stephen
通讯作者：
Trent, M. Stephen
影响因子：
3.5
作者：
Catel-Ferreira, Manuella;Marti, Sara;De, Emmanuelle
通讯作者：
De, Emmanuelle
影响因子：
2.6
作者：
Gribun, A;Nitzan, Y;Katcoff, DJ
通讯作者：
Katcoff, DJ
影响因子：
2.1
作者：
HOLTJE, JV;KOPP, U;WIEDEMANN, B
通讯作者：
WIEDEMANN, B