摘要

      鲍曼不动杆菌（MDRAB）多药耐药谱是重要的医院感染病原菌。由于tigecycline对大多数MDRAB仍然有效，我们试图调查tigecycline抗性是否影响生物适应性。从个体患者中恢复的两对治疗前（AB210；W6976）和治疗后（AB211；W7282）临床配对研究了治疗引起的tigecycline耐药的效应，其中tigecycline耐药与外排活性上调相关。所有的分离株都属于同一个流行的英国血统。使用梅隆内拉型凯丹菌感染模型，AB210和AB211的终点存活率存在显著差异，而W6976和W7282的终点存活率不存在显著差异。AB211分离物在体内的竞争能力超过了AB210，而W7282分离物在治疗前的竞争能力超过了W6972。分离株W6976和W7282的全基因组测序显示，adeABC调控基因adeS在W7282中突变，导致Ser-8→Arg替换。先前对AB210和AB211的全基因组比较还发现了adeS中的一个非同义突变，以及与生物膜形成和DNA错配修复相关的基因中的一些其他损伤；与这里描述的表型差异一致。综上所述，从抗生物谱或克隆谱系来看，尽管存在一个共同的抗替加环素机制，但对更广泛表型的不同影响是不可预测的。

      Multidrug-resistant lineages of Acinetobacter baumannii (MDRAB) are important nosocomial pathogens. As tigecycline remains active against most MDRAB we sought to investigate whether tigecycline resistance impacts biological fitness. The effects of treatment-emergent tigecycline resistance were investigated in vitro and in vivo using two pre- (AB210; W6976) and post-therapy (AB211; W7282) clinical pairs, recovered from individual patients, where tigecycline resistance was associated with up-regulated efflux activity. All isolates belonged to the same epidemic UK lineage. Significant differences were observed in end-point survival proportions between AB210 and AB211, but not between W6976 and W7282, using the Galleria mellonella infection model. Isolate AB211 outcompeted AB210 in vivo, in contrast to isolate W7282, which was outcompeted by its pre-therapy counterpart, W6972. Whole-genome sequencing of isolates W6976 and W7282 revealed a mutation in the adeABC regulatory gene, adeS in W7282; resulting in a Ser-8 → Arg substitution. Previous whole-genome comparison of AB210 and AB211 also identified a non-synonymous mutation in adeS, among several other lesions in genes involved in biofilm formation and DNA mismatch repair; consistent with the phenotypic differences described here. In conclusion, the differing effects on the wider phenotype were not predictable from the antibiograms or clonal lineage, despite a common mechanism of tigecycline resistance.

       https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844891/