1Faculty of Science, Health, Education and Engineering, University of the Sunshine Coast, Sippy Downs, QLD, Australia.
2Global and Tropical Health Division, Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia.
Microb Genom. 2018 Aug;4(8). doi: 10.1099/mgen.0.000194. Epub 2018 Jul 10.
The melioidosis bacterium, Burkholderia pseudomallei, is increasingly being recognised as a pathogen in patients with cystic fibrosis (CF). We have recently catalogued genome-wide variation of paired, isogenic B. pseudomallei isolates from seven Australasian CF cases, which were collected between 4 and 55 months apart. Here, we extend this investigation by documenting the transcriptomic changes in B. pseudomallei in five cases. Following growth in an artificial CF sputum medium, four of the five paired isolates exhibited significant differential gene expression (DE) that affected between 32 and 792 genes. The greatest number of DE events was observed between the strains from patient CF9, consistent with the hypermutator status of the latter strain, which is deficient in the DNA mismatch repair protein MutS. Two patient isolates harboured duplications that concomitantly increased expression of the β-lactamase-encoding gene penA, and a 35 kb deletion in another abolished expression of 29 genes. Convergent expression profiles in the chronically-adapted isolates identified two significantly downregulated and 17 significantly upregulated loci, including the resistance-nodulation-division (RND) efflux pump BpeEF-OprC, the quorum-sensing hhqABCDE operon, and a cyanide- and pyocyanin-insensitive cytochrome bd quinol oxidase. These convergent pathoadaptations lead to increased expression of pathways that may suppress competing bacterial and fungal pathogens, and that enhance survival in oxygen-restricted environments, the latter of which may render conventional antibiotics less effective in vivo. Treating chronically adapted B. pseudomallei infections with antibiotics designed to target anaerobic infections, such as the nitroimidazole class of antibiotics, may significantly improve pathogen eradication attempts by exploiting this Achilles heel.
类鼻疽伯克霍尔德菌（Burkholderia pseudomallei）作为一种病原体，在囊性纤维化（CF）患者中越来越受到重视。我们最近对来自 7 例澳大利亚 CF 病例的 7 对同源、同源 B. pseudomallei 分离株进行了全基因组变异编目，这些分离株的采集时间相隔 4 至 55 个月。在此，我们通过记录 5 例 B. pseudomallei 的转录组变化扩展了这一研究。在人工 CF 痰培养基中生长后，5 对配对分离株中有 4 对表现出显著的差异基因表达（DE），影响了 32 至 792 个基因。DE 事件最多的是来自 CF9 患者的菌株，这与后者菌株的高突变状态一致，后者菌株缺乏 DNA 错配修复蛋白 MutS。两个患者分离株携带同时增加β-内酰胺酶编码基因 penA 表达的重复序列，另一个 35kb 缺失使 29 个基因的表达缺失。在慢性适应的分离株中，趋同的表达谱鉴定出两个显著下调和 17 个显著上调的基因座，包括 RND 外排泵 BpeEF-OprC、群体感应 hhqABCDE 操纵子和一种对氰化物和绿脓菌素不敏感的细胞色素 bd 醌氧化酶。这些趋同的病理适应导致可能抑制竞争细菌和真菌病原体的途径的表达增加，以及增强在缺氧环境中的存活能力，后者可能使传统抗生素在体内的效果降低。用旨在针对厌氧感染的抗生素（如硝基咪唑类抗生素）治疗慢性适应的 B. pseudomallei 感染，可能会通过利用这一致命弱点显著提高病原体清除尝试。
