Centre for Infectious Diseases and Microbiology, The Westmead Institute for Medical Research (WIMR), Westmead, NSW, Australia.
School of Medicine, Sydney Medical School, University of Sydney, NSW, Australia.
FASEB J. 2020 Aug;34(8):10801-10817. doi: 10.1096/fj.201902735R. Epub 2020 Jun 29.
Multidrug resistant (MDR) carbapenemase-producing (CP) Klebsiella pneumoniae, belonging to clonal group CG258, is capable of causing severe disease in humans and is classified as an urgent threat by health agencies worldwide. Bacteriophages are being actively explored as therapeutic alternatives to antibiotics. In an effort to define a robust experimental approach for effective selection of lytic viruses for therapy, we have fully characterized the genomes of 18 Kumoniae target strains and tested them against novel lytic bacteriophages (n = 65). The genomes of K pneumoniae carrying bla and bla were sequenced and CG258 isolates selected for bacteriophage susceptibility testing. The local K pneumoniae CG258 population was dominated by sequence type ST258 clade 1 (86%) with variations in capsular locus (cps) and prophage content. CG258-specific bacteriophages primarily targeted the capsule, but successful infection is also likely blocked in some by immunity conferred by existing prophages. Five tailed bacteriophages against K pneumoniae ST258 clade 1 were selected for further characterization. Our findings show that effective control of K pneumoniae CG258 with bacteriophage will require mixes of diverse lytic viruses targeting relevant cps variants and allowing for variable prophage content. These insights will facilitate identification and selection of therapeutic bacteriophage candidates against this serious pathogen.
产多药耐药（MDR）碳青霉烯酶（CP）肺炎克雷伯菌，属于克隆群 CG258，能够在人类中引起严重疾病，被全球卫生机构列为紧急威胁。噬菌体作为抗生素的治疗替代品正在被积极探索。为了定义一种有效的实验方法，以有效地选择用于治疗的溶菌病毒，我们对 18 株 Kumoniae 靶株的基因组进行了全面表征，并对其进行了新型溶菌噬菌体（n = 65）的测试。对携带 bla 和 bla 的肺炎克雷伯菌基因组进行了测序，并选择 CG258 分离物进行噬菌体药敏试验。当地肺炎克雷伯菌 CG258 群体主要由序列型 ST258 分支 1（86%）组成，其荚膜基因座（cps）和前噬菌体含量存在差异。CG258 特异性噬菌体主要靶向荚膜，但由于现有前噬菌体赋予的免疫作用，一些成功的感染也可能受阻。针对肺炎克雷伯菌 ST258 分支 1 选择了 5 种长尾噬菌体进行进一步表征。我们的研究结果表明，要有效控制肺炎克雷伯菌 CG258，需要使用针对相关 cps 变体的多种溶菌病毒混合物，并允许可变的前噬菌体含量。这些见解将有助于鉴定和选择针对这种严重病原体的治疗性噬菌体候选物。
