Department of Ophthalmology and Department of Microbiology, Harvard Medical School, Boston, MA 02114, USA.
Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
Sci Transl Med. 2019 Apr 10;11(487). doi: 10.1126/scitranslmed.aat8418.
Multidrug-resistant enterococcal strains emerged in the early 1980s and are now among the leading causes of drug-resistant bacterial infection worldwide. We used functional genomics to study an early bacterial outbreak in patients in a Wisconsin hospital between 1984 and 1988 that was caused by multidrug-resistant The goal was to determine how a clonal lineage of became adapted to growth and survival in the human bloodstream. Genome sequence analysis revealed a progression of increasingly fixed mutations and repeated independent occurrences of mutations in a relatively small set of genes. Repeated independent mutations suggested selection within the host during the course of infection in response to pressures such as host immunity and antibiotic treatment. We observed repeated independent mutations in a small number of loci, including a little studied polysaccharide utilization pathway and the locus. Functional studies showed that mutating these loci rendered better able to withstand antibiotic pressure and innate immune defenses in the human bloodstream. We also observed a shift in mutation pattern that corresponded to the introduction of carbapenem antibiotics in 1987. This work identifies pathways that allow enterococci to survive the transition from the human gut into the bloodstream, enabling them to cause severe bacteremia associated with high mortality.
耐多药肠球菌菌株于 20 世纪 80 年代初出现，现已成为全球导致耐药性细菌感染的主要原因之一。我们使用功能基因组学研究了 1984 年至 1988 年期间威斯康星州一家医院的患者中发生的一种早期细菌爆发，该爆发是由耐多药引起的。目标是确定一个克隆系是如何适应人类血液中的生长和存活的。基因组序列分析显示，在相对较小的一组基因中，固定突变的逐渐增加和重复独立发生的突变反复出现。重复的独立突变表明，在感染过程中，宿主会针对宿主免疫和抗生素治疗等压力进行选择。我们观察到少数几个基因座中重复的独立突变，包括一个研究较少的多糖利用途径和基因座。功能研究表明，这些基因座的突变使肠球菌更能耐受抗生素压力和人类血液中的固有免疫防御。我们还观察到突变模式的转变，这与 1987 年碳青霉烯类抗生素的引入相对应。这项工作确定了使肠球菌能够从人类肠道过渡到血液中生存的途径，使它们能够引起与高死亡率相关的严重菌血症。
