Department of Biology, Northeastern University, Boston, MA, 02115, USA.
Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, MA, 02111, USA.
Nat Commun. 2020 Sep 9;11(1):4522. doi: 10.1038/s41467-020-18301-2.
A unique, protective cell envelope contributes to the broad drug resistance of the nosocomial pathogen Acinetobacter baumannii. Here we use transposon insertion sequencing to identify A. baumannii mutants displaying altered susceptibility to a panel of diverse antibiotics. By examining mutants with antibiotic susceptibility profiles that parallel mutations in characterized genes, we infer the function of multiple uncharacterized envelope proteins, some of which have roles in cell division or cell elongation. Remarkably, mutations affecting a predicted cell wall hydrolase lead to alterations in lipooligosaccharide synthesis. In addition, the analysis of altered susceptibility signatures and antibiotic-induced morphology patterns allows us to predict drug synergies; for example, certain beta-lactams appear to work cooperatively due to their preferential targeting of specific cell wall assembly machineries. Our results indicate that the pathogen may be effectively inhibited by the combined targeting of multiple pathways critical for envelope growth.
一种独特的保护性细胞包膜有助于医院获得性病原体鲍曼不动杆菌的广泛耐药性。在这里,我们使用转座子插入测序来鉴定对多种不同抗生素敏感性改变的鲍曼不动杆菌突变体。通过检查抗生素敏感性谱与已鉴定基因中的突变相似的突变体,我们推断出多个未鉴定的包膜蛋白的功能,其中一些在细胞分裂或细胞伸长中起作用。值得注意的是,影响预测细胞壁水解酶的突变导致脂寡糖合成的改变。此外,对改变的敏感性特征和抗生素诱导的形态模式的分析允许我们预测药物协同作用;例如,某些β-内酰胺类抗生素由于其优先靶向特定的细胞壁组装机制,因此似乎具有协同作用。我们的结果表明,通过针对对包膜生长至关重要的多个途径的联合靶向,该病原体可能被有效抑制。