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Modulating Isoprenoid Biosynthesis Increases Lipooligosaccharides and Restores Acinetobacter baumannii Resistance to Host and Antibiotic Stress.
Cell Reports ( IF 8.8 ) Pub Date : 2020-09-08 , DOI: 10.1016/j.celrep.2020.108129
Lauren D Palmer 1 , Keaton E Minor 2 , Joshua A Mettlach 2 , Emilio S Rivera 3 , Kelli L Boyd 1 , Richard M Caprioli 4 , Jeffrey M Spraggins 5 , Zachary D Dalebroux 2 , Eric P Skaar 6
Affiliation  

Acinetobacter baumannii is a leading cause of ventilator-associated pneumonia and a critical threat due to multidrug resistance. The A. baumannii outer membrane is an asymmetric lipid bilayer composed of inner leaflet glycerophospholipids and outer leaflet lipooligosaccharides. Deleting mlaF of the maintenance of lipid asymmetry (Mla) system causes A. baumannii to become more susceptible to pulmonary surfactants and antibiotics and decreases bacterial survival in the lungs of mice. Spontaneous suppressor mutants isolated from infected mice contain an ISAba11 insertion upstream of the ispB initiation codon, an essential isoprenoid biosynthesis gene. The insertion restores antimicrobial resistance and virulence to ΔmlaF. The suppressor strain increases lipooligosaccharides, suggesting that the mechanism involves balancing the glycerophospholipids/lipooligosaccharides ratio on the bacterial surface. An identical insertion exists in an extensively drug-resistant A. baumannii isolate, demonstrating its clinical relevance. These data show that the stresses bacteria encounter during infection select for genomic rearrangements that increase resistance to antimicrobials.



中文翻译:

调节类异戊二烯生物合成可增加脂寡糖并恢复鲍曼不动杆菌对宿主和抗生素应激的抵抗力。

鲍曼不动杆菌是呼吸机相关性肺炎的主要原因,也是多重耐药性带来的严重威胁。鲍曼不动杆菌外膜是由内叶甘油磷脂和外叶脂寡糖组成的不对称脂质双层。删除脂质不对称(Mla)系统维持的mlaF会导致鲍曼不动杆菌对肺部表面活性剂和抗生素更敏感,并降低小鼠肺部细菌的存活率。从受感染小鼠中分离出的自发抑制突变体在ispB起始密码子(一种重要的类异戊二烯生物合成基因)上游含有 IS Aba11插入。插入恢复了 Δ mlaF的抗菌素耐药性和毒力。抑制菌株增加了脂寡糖,表明其机制涉及平衡细菌表面的甘油磷脂/脂寡糖比率。广泛耐药的鲍曼不动杆菌分离株中存在相同的插入,证明了其临床相关性。这些数据表明,细菌在感染过程中遇到的压力会选择基因组重排,从而增加对抗菌药物的耐药性。

更新日期:2020-09-09
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