摘要

鲍曼不动杆菌是医院获得性感染的常见病原体，也是烧伤患者感染的主要原因。碳青霉烯耐药鲍曼不动杆菌被认为是一种重大的公共卫生威胁，并被世界卫生组织确定为需要新型抗菌药物的最优先的生物体。鲍曼不动杆菌对碳青霉烯抗性的最常见机制是通过水平获取碳青霉烯酶基因。在这项研究中，我们从患有广泛烧伤的患者中采集了20个鲍曼不动杆菌分离株，并且通过Illumina和牛津纳米孔测序在45天时间内表征了碳青霉烯抗性的进展。所有分离株都是多药耐药的，携带两个基因组岛，其中包含几个抗生素抗性基因。大多数菌株基因相同，代表了单一的创始人基因型。我们发现与美洛培南耐药相关的三个新的非同义替换：AdeBC（AdeABC外排泵的一部分）中的F136L和G288S与美洛培南MIC增加≥8μgml-1有关;和FtsI中的A515V（PBP3，一种青霉素结合蛋白）与MIC进一步增加至32μg/ ml相关。 AdeB和FtsI的结构模型表明这些突变影响了它们的药物结合位点并揭示了美罗培南抗性的机制。值得注意的是，其中一种adeB突变在美洛培南治疗前出现，但在环丙沙星治疗后出现，表明暴露于一种由外排泵介导的耐药性的药物可诱导对尚未暴露细菌的其他药物的附带抵抗。

Acinetobacter baumannii is a common causative agent of hospital-acquired infections and a leading cause of infection in burns patients. Carbapenem-resistant A. baumannii is considered a major public-health threat and has been identified by the World Health Organization as the top priority organism requiring new antimicrobials. The most common mechanism for carbapenemresistance in A. baumannii is via horizontal acquisition of carbapenemase genes. In this study, we sampled 20 A. baumannii isolates from a patient with extensive burns, and characterized the evolution of carbapenem resistance over a 45 day period via Illumina and Oxford Nanopore sequencing. All isolates were multidrug resistant, carrying two genomic islands that harboured several antibiotic-resistance genes. Most isolates were genetically identical and represented a single founder genotype. We identified three novel non-synonymous substitutions associated with meropenem resistance: F136L and G288S in AdeB (part of the AdeABC efflux pump) associated with an increase in meropenem MIC to ≥8 µg ml-1; and A515V in FtsI (PBP3, a penicillin-binding protein) associated with a further increase in MIC to 32 µg ml-1. Structural modelling of AdeB and FtsI showed that these mutations affected their drug-binding sites and revealed mechanisms for meropenem resistance. Notably, one of the adeB mutations arose prior to meropenem therapy but following ciprofloxacin therapy, suggesting exposure to one drug whoseresistance is mediated by the efflux pump can induce collateral resistance to other drugs to which the bacterium has not yet been exposed.

https://www.ncbi.nlm.nih.gov/pubmed/29547094